Systematic review update and economic evaluation for the New Zealand setting

Transcription

1 Systematic review update and economic evaluation for the New Zealand setting February 2008 Subcutaneous insulin pump therapy Suzanne Campbell Arsupol Suebwongpat Lachlan Standfield Adele Weston

2 This report should be referenced as follows: Campbell S, Suebwongpat A, Standfield L, Weston A. Systematic review update and economic evaluation for the New Zealand setting: Subcutaneous insulin pump therapy. HSAC Report 2008; 1(3). Health Services Assessment Collaboration (HSAC), University of Canterbury ISBN (Online) ISSN (Online)

3 i Review Team This review was undertaken by the Health Services Assessment Collaboration (HSAC). HSAC is a collaboration of the Health Sciences Centre of the University of Canterbury, New Zealand and Health Technology Analysts, Sydney, Australia. This report was authored by Dr Suzanne Campbell, Health Outcomes Manager, who developed and undertook the literature search, extracted the data, conducted the critical appraisals, and prepared the clinical component of the report. A preliminary economic evaluation was undertaken by Arsupol Suebwongpat, Health Economist and Lachlan Standfield, Senior Health Economist. Adele Weston assisted with the interpretation of the clinical and economic components of the report. Acknowledgements Dr Ray Kirk and Dr Adele Weston (as HSAC Directors) reviewed the final draft. Cecilia Tolan (Administrator) provided administrative support. The current review was conducted under the auspices of a contract funded by the New Zealand Ministry of Health. This report was requested by the Long Term Conditions Policy and Strategy team of the Clinical Services Directorate of New Zealand s Ministry of Health. We thank Sandy Dawson and Christine Andrews for their assistance in developing the scope of the review and providing clinical practice and cost information for the review. The systematic review of the evidence will ultimately be used by the Long Term Conditions Policy and Strategy team to inform policy decision making in conjunction with other information. The content of the review alone does not constitute clinical advice or policy recommendations. Copyright Statement & Disclaimer This report is copyright. Apart from any use as permitted under the Copyright Act 1994, no part may be reproduced by any process without written permission from HSAC. Requests and inquiries concerning reproduction and rights should be directed to the Director, Health Services Assessment Collaboration, Health Sciences Centre, University of Canterbury, Private Bag 4800, Christchurch, New Zealand HSAC take great care to ensure the accuracy of the information in this report, but neither HSAC, the University of Canterbury, Health Technology Analysts Pty Ltd nor the Ministry of Health make any representations or warranties in respect of the accuracy or quality of the information, or accept responsibility for the accuracy, correctness, completeness or use of this report. The reader should always consult the original database from which each abstract is derived along with the original articles before making decisions based on a document or abstract. All responsibility for action based on any information in this report rests with the reader.

4 ii This report is not intended to be used as personal health advice. People seeking individual medical advice should contact their physician or health professional. The views expressed in this report are those of HSAC and do not necessarily represent those of the University of Canterbury New Zealand, Health Technology Analysts Pty Ltd, Australia or the Ministry of Health. Contact Details Health Services Assessment Collaboration (HSAC) Health Sciences Centre University of Canterbury Private Bag 4800 Christchurch 8140 New Zealand Tel: Fax: [email protected] Website: healthsac.net (under development)

5 iii Executive summary Introduction The systematic review update was requested by the Long Term Conditions Policy and Strategy team of the Clinical Services Directorate of New Zealand s Ministry of Health. The update was to be based on one of two systematic reviews provided by the requestor: a Canadian review from Agence d'evaluation des technologies et des modes d'intervention en santé (AETMIS) (Côté & St-Hilaire, 2005), or the NHS technology assessment report (Colquitt et al, 2004) which informed the National Institute for Health and Clinical Excellence (NICE) recommendations for the use of continuous subcutaneous insulin infusion (CSII) in diabetes. Although the NHS report is not as current as the AETMIS report, it was chosen as the basis of the systematic review update because it considers the use of CSII in people with type 1 and type 2 diabetes. Methods The aim of this review was to evaluate the relative effectiveness, safety, and costeffectiveness of CSII in patients with insulin-treated diabetes, when compared with optimised multiple daily injections (MDI). The primary research question to be addressed by this review was: Is subcutaneous insulin pump therapy effective, safe, and cost-effective compared with multiple daily injections? A systematic method of literature searching, study selection, data extraction and appraisal was employed in the preparation of this report. The literature was searched using the following bibliographic databases: Medline and Embase. In addition, the bibliographies of included papers were examined for relevant studies. The Cochrane Library was also searched to help identify existing systematic reviews and original studies. Searches were limited to English-language material published from January 2002 to August 2007 inclusive. Studies were included if they were randomised trials of crossover or parallel-group design, which compared CSII therapy with optimised MDI therapy (at least three injections per day) for at least 10 weeks in insulin-treated type 1 or type 2 diabetic patients (including adults, children, adolescents, and pregnant women with preexisting diabetes). The key outcomes examined were: HbA 1c levels, lipid levels, quality of life, severe hypoglycaemic episodes, and ketoacidotic episodes. NHMRC dimensions of evidence, levels of evidence and quality assessment criteria were used to evaluate each of the included studies. Data was extracted onto standardised data extraction forms by one reviewer. A systematic search of the published literature was also conducted to identify any relevant economic evaluations of CSII versus MDI. The literature was searched using the following bibliographic databases: Medline and Embase. Searches were limited to English-language material published through January Relevant publications were briefly reviewed to inform a qualitative discussion of the incremental costs and outcomes likely to be associated with CSII relative to MDI.

6 iv An economic analysis was also undertaken to examine the cost-effectiveness of CSII compared with MDI for a patient with Type 1 diabetes. The economic model was based mainly on the method and approach presented in the NHS assessment report (Colquitt et al, 2004), with modification to inputs in order to populate the model with NZ data wherever available. Cost-effectiveness is presented as the incremental cost per severe hypoglycaemic attack avoided over six years (ie, the pump life-time). The total additional costs of using CSII can also be considered relative to the improvements seen in glycaemic control, and any reduction in diabetic complications that this may confer. Key results The search strategy for clinical evidence identified a total of 726 potentially relevant publications. After consideration of titles and abstracts using the pre-defined study selection criteria, 32 full papers were retrieved and scrutinised in detail for possible inclusion in the review. For excluded studies, the reasons for exclusion were documented. As a result 12 publications, referring to 11 randomised trials, were ultimately included in the review. Three publications (two original reports of clinical trials and one systematic review) compared CSII with MDI in adults with type 1 diabetes, four publications (all original reports referring to three clinical trials) compared CSII with MDI in children and/or adolescents with type 1 diabetes, four publications (all original reports of clinical trials) compared CSII with MDI in adults with type 2 diabetes, and one publication (a systematic review) compared CSII with MDI in pregnant women with diabetes. Efficacy In trials of adults with type 1 diabetes, therapy with CSII was associated with a greater reduction in HbA 1c levels compared with MDI, at all timepoints examined (4, 6, and 8 months); however, although the magnitude of the difference was small. Although the publications reported a statistically significant difference between CSII and MDI in terms of endpoint HbA 1c levels, meta-analysis of baseline adjusted data from the two trials at a common timepoint (four months) favoured CSII but failed to reach statistical significance. Quality of life endpoints were poorly reported but indicate that treatment with CSII may be associated with significantly improved quality of life compared with MDI. The effect of treatment on lipid levels was not reported in either trial. In children and/or adolescents with type 1 diabetes, HbA 1c levels were lower at endpoint after CSII than MDI, although the magnitude of the difference was small. Meta-analysis of baseline adjusted data at a common timepoint (3-4 months) confirmed the trend in favour of CSII but did not reveal a significant difference between treatment modalities in terms of HbA 1c levels at endpoint. Quality of life was assessed in all three trials using a youth-specific questionnaire. Whilst two studies found no statistically significant difference between CSII and MDI, the third reported a significant difference in favour of CSII in the satisfaction subscale (P< 0.05), but not other subscales. The effect of treatment on lipid levels was not reported. In adults with type 2 diabetes, the change from baseline in HbA 1c levels was greater with CSII than MDI. Meta-analysis of data from the four trials (using the longest

7 v timepoint in each trial) confirmed the trend in favour of CSII but the difference was not statistically significant. One of the four trials reported quality of life outcomes and showed no difference between treatment modalities. Of the two studies that reported the effect of treatment on lipid levels, there was no significant difference between CSII and MDI. In pregnant women with diabetes, HbA 1c levels were lower in women treated with MDI compared with CSII, in both second and third trimester, but the difference was not significant. No other outcomes of relevance were reported in the review and therefore no firm conclusions can be drawn with respect to best practice in pregnant women with diabetes. Safety In adults with type 1 diabetes, episodes of severe hypoglycaemia were infrequent in both trials but were consistently lower during treatment with CSII compared with MDI. Ketoacidotic events were also uncommon but occurred more frequently during treatment with CSII than MDI. In children and/or adolescents with type 1 diabetes, all three trials reported that episodes of severe hypoglycaemia were less frequent during treatment with CSII compared with MDI. Ketoacidotic events were uncommon with both treatment modalities and therefore no firm conclusions can be drawn. Overall, in adults with type 2 diabetes, the total number of severe hypoglycaemic episodes across the four trials was higher in patients treated with MDI; however, this was driven by only one trial. Two of the trials reported no cases of severe hypoglycaemia and one trial reported more episodes in during treatment with CSII. There was insufficient evidence to draw any conclusions regarding the effect of treatment on the incidence of ketoacidosis. Economic implications The search strategy for economic evaluations identified a total of four relevant publications published in English. All four studies reported results favouring insulin pump therapy over MDI and concluded that CSII could be a worthwhile investment, however these conclusion were heavily dependent upon the magnitude of clinical benefit assumed. The cost-effectiveness analysis undertaken for this report was conducted as a whatif scenario. It is postulated, however unproven, that CSII may reduce the number of severe hypoglycaemic attacks a patient experiences compared with MDI. If CSII were to reduce the number of hypoglycaemic attacks by 0.5 per patient per year, the incremental cost per severe hypoglycaemic event avoided would be ~NZ$6,000 per hypoglycaemic attack avoided over a 6-year time horizon. In addition, based of the clinical evidence the CSII pump appears to improve a patient s HbA 1c by around 0.37% compared to MDI after approximately four months of therapy. It is unknown, but not inconceivable that this benefit will be sustained in the long-term, bringing potential benefits of reduced disease sequelae in the long-term. These benefits come at an additional cost of approximately NZ$16,000 per patient over six years. Although not quantified in the current analyses, when a realistic magnitude of benefit (eg, a

8 vi 0.37 improvement in HbA 1c ) is applied within the models of others, the cost/qaly is likely to well exceed NZ$100,000. Conclusions The review conclusions are based on the current evidence available from this report s critical appraisal of literature published since the NHS assessment report on the efficacy, safety, and cost-effectiveness of CSII compared with MDI. In general, the findings of the current review support the findings of the original NHS assessment report, that is, an improvement in glycaemic control that is of small magnitude and borderline statistical significance. When compared with optimised MDI, CSII results in a modest but potentially worthwhile improvement in glycosylated haemoglobin levels in all patient groups assessed (ie, adults with type 1 diabetes, children and adolescents with type 1 diabetes, and adults with type 2 diabetes). Due to the short duration of the clinical trials is not possible to evaluate the longer term benefits of such a difference in HbA 1c levels; however, there is an expectation that it would be reflected in a reduction in long-term complications. Although more immediate primary benefits from CSII may be associated with an impact on the incidence of severe hypoglycaemic events and improved quality of life (through greater flexibility of lifestyle), there is limited evidence to support this from the studies identified in this update. However, despite the limited evidence it is postulated that CSII may reduce the number of severe hypoglycaemic attacks a patient experiences compared with MDI. According to the results of the cost-effectiveness analysis conducted herein, it is estimated that if every patient who changed from MDI to CSII therapy was able to avoid one severe hypoglycaemic attack every two years (ie, an improvement of 0.5 events per annum), the incremental cost per severe hypoglycaemic event avoided would be approximately $6,000. The total incremental cost associated with the introduction of CSII compared to MDI for a patient with type 1 diabetes is approximately $16,000 over six years (the approximated life of the pump).

9 vii Table of Contents Review Team...i Acknowledgements...i Copyright Statement & Disclaimer...i Contact Details...ii Executive summary... iii Introduction... iii Methods... iii Key results...iv Efficacy...iv Safety...v Economic implications...v Conclusions...vi Table of Contents...vii List of Tables...ix List of Figures...xi List of Figures...xi List of Abbreviations and Acronyms...xii Introduction...1 Objective...1 Insulin-dependent diabetes...1 Continuous subcutaneous insulin infusion...2 Structure of report...2 Methods...3 Research questions...4 Literature search...6 Bibliographic databases...6 Review databases...6 HTA Groups...6 Clinical Practice Guidelines...6 Assessment of study eligibility...7 Appraisal of included studies...8 Dimensions of evidence...8 Data extraction...11 Data synthesis...11 Limitations of the review methodology...12 Evaluation of economic implications...14

10 viii Results...17 Overview...17 Clinical evidence: study characteristics and outcomes...17 Adults with type 1 diabetes...17 Children and/or adolescents with type 1 diabetes...20 Adults with type 2 diabetes...22 Pregnant women with diabetes...25 Clinical evidence: results and meta-analyses...27 Glycosylated haemoglobin...27 Lipid levels...36 Quality of life...36 Severe hypoglycaemia...37 Ketoacidosis...37 Economic considerations...39 Results of the literature search...39 Background to the economic evaluation...40 Costs incorporated in the model...40 Health benefits incorporated in the economic model...43 Cost-effectiveness...44 Sensitivity analyses...44 Limitations of economic evaluation...46 Summary and conclusions...47 Summary of evidence for evidence review...47 Adults with type 1 diabetes...47 Children and/or adolescents with type 1 diabetes...47 Adults with type 2 diabetes...47 Pregnant women with diabetes...48 Summary of results from economic evaluation...48 Limitations of evidence base...48 Conclusions...49 References...50 Glossary...53 Appendix A: Included Studies...55 Appendix B: Excluded Studies Annotated by Reason for Exclusion...57 Appendix C: Data extraction tables...97 Studies of adults with type 1 diabetes...97 Studies of children and/or adolescents with type 1 diabetes Studies of adults with type 2 diabetes Studies of pregnant women with pre-existing diabetes Appendix D: Forest plots...127

11 ix List of Tables Table 1: Recent systematic reviews, candidates for updating...3 Table 2: Criteria for determining study eligibility...5 Table 3: Nature of the evidence...5 Table 4: Search strategy for relevant clinical trials...7 Table 5: Application of selection criteria to citations...8 Table 6: NHMRC Dimensions of evidence...9 Table 7: Table 8: NHMRC Interim Levels of Evidence (NHMRC 2005) for Evaluating Intervention Studies...10 Quality criteria for different levels of evidence...11 Table 9: Reporting biases in systematic reviews a...13 Table 10: Search strategy for economic evaluations...15 Table 11: Summary of evidence for adults with type 1 diabetes...19 Table 12: Summary of evidence for children and/or adolescents with type 1 diabetes...21 Table 13: Summary of evidence for adults with type 2 diabetes...23 Table 14: Table 15: Table 16: Table 17: Table 18: Table 19: Table 20: Table 21: Table 22: Table 23: Table 24: Summary of evidence for pregnant women with diabetes...26 Detailed data extraction from Level II evidence glycosylated haemoglobin at endpoint...29 Detailed data extraction from Level II evidence change from baseline to endpoint in glycosylated haemoglobin...31 Glycosylated haemoglobin at endpoint: Studies comparing the same insulin type with CSII and MDI a...33 Glycosylated haemoglobin at endpoint: All included studies, regardless of type of insulin a...34 Change in glycosylated haemoglobin: Studies comparing the same insulin type with CSII and MDI a...35 Change in glycosylated haemoglobin: All included studies, regardless of type of insulin a...36 Data extraction from Level II evidence episodes of severe hypoglycaemia and ketoacidosis...38 Existing economic evaluations: methods...39 Existing economic evaluations: results...40 Costs of insulin pump and consumables...41 Table 25: Cost of a patient education programme for CSII...41 Table 26: Cost of additional outpatient management...42

12 x Table 27: Reduction of insulin use with continuous subcutaneous insulin infusion...42 Table 28: Cost of managing a severe hypoglycaemic event...42 Table 29: Table 30: Table 31: Incremental costs associated with the introduction of CSII over year Incremental costs associated with the introduction of CSII over 6-years...43 Incremental cost per severe hypoglycaemic event avoided per patient per annum...44

13 xi List of Figures Figure 1: Figure 2: Figure 3: Figure 4: Figure 5: Figure 6: Figure 7: Figure 8: Figure 9: Figure 10: Figure 11: Figure 12: Figure 13: Incremental cost per severe hypoglycaemic attack avoided over 6 years...44 ICER following changes in the pump price and cost of consumables...45 ICER following removal of the requirement for a hospital admission for pump training...45 Meta-analysis of the effect of CSII vs MDI on glycosylated haemoglobin in adults with type 1 diabetes: Base case unadjusted data - WMD (random effects model) Meta-analysis of the effect of CSII vs MDI on glycosylated haemoglobin in children and adolescents with type 1 diabetes: Base case unadjusted data - WMD (random effects model) Meta-analysis of the effect of CSII vs MDI on glycosylated haemoglobin in adults with type 2 diabetes: Base case unadjusted data - WMD (random effects model) Meta-analysis of the effect of CSII vs MDI on glycosylated haemoglobin in children and adolescents with type 1 diabetes: All studies, unadjusted data - WMD (random effects model) Meta-analysis of the effect of CSII vs MDI on glycosylated haemoglobin in adults with type 2 diabetes: All studies, unadjusted data - WMD (random effects model) Meta-analysis of the effect of CSII vs MDI on glycosylated haemoglobin in adults with type 1 diabetes: Base case adjusted data - WMD (random effects model) Meta-analysis of the effect of CSII vs MDI on glycosylated haemoglobin in children and adolescents with type 1 diabetes: Base case adjusted data - WMD (random effects model) Meta-analysis of the effect of CSII vs MDI on glycosylated haemoglobin in adults with type 2 diabetes: Base case adjusted data - WMD (random effects model) Meta-analysis of the effect of CSII vs MDI on glycosylated haemoglobin in children and adolescents with type 1 diabetes: All studies, adjusted data - WMD (random effects model) Meta-analysis of the effect of CSII vs MDI on glycosylated haemoglobin in adults with type 2 diabetes: All studies, adjusted data - WMD (random effects model)...131

14 xii List of Abbreviations and Acronyms AE BMI CI CIT CSII DQoL QOLCTQ EOT HbA 1c HDL ICER ITT LDL MDI NHMRC NHS NICE NPH nr ns QOL SD SF-12 SF-36 WMD adverse event body mass index confidence interval conventional insulin therapy continuous subcutaneous insulin infusion Diabetes Quality of Life Diabetes Quality of Life Clinical Trial Questionnaire end of treatment glycosylated haemoglobin A 1c high density lipoprotein incremental cost-effectiveness ratio intention-to-treat low density lipoprotein multiple daily injections National Health and Medical Research Council National Health Service National Institute for Health and Clinical Excellence neutral protamine Hagedorn not reported not significant quality of life standard deviation 12-item Short Form Health Survey 36-item Short Form Health Survey weighted mean difference

15 1 Introduction Objective The purpose of this systematic review update is to provide a summary of the recent evidence pertaining to the relative effectiveness, safety, and cost-effectiveness of CSII in patients with insulin-treated diabetes, when compared to optimised MDI. The systematic review update is inclusive of evidence relating to type 1 and type 2 diabetes. The cost-effectiveness analysis considers individuals with type 1 diabetes only. Insulin-dependent diabetes Diabetes is a chronic metabolic disorder characterised by hyperglycaemia due to impaired insulin secretion and/or impaired insulin action. There are two major types of diabetes: type 1 and type 2. People with type 1 diabetes generally require daily insulin injections to survive because the islet b cells in the pancreas (which produce insulin) have been destroyed through an autoimmune mechanism. Type 2 diabetes results from failure of insulin production to overcome reduced tissue sensitivity to insulin (known as insulin resistance). In the early stages, type 2 diabetes can be managed through diet and exercise alone. However, it is a progressive disease and nearly all individuals with type 2 diabetes will require oral glucose lowering drugs over time and most will eventually need insulin to maintain satisfactory blood glucose levels. An impaired insulin effect results in increased levels of glucose in the blood (hyperglycaemia), which can cause microvascular and macrovascular damage if prolonged. Common complications of diabetes include visual impairment, kidney failure, angina, myocardial infarction, stroke, foot ulceration, and erectile dysfunction. The principal goals of treatment for diabetes are therefore to prevent the acute and late complications of diabetes and thus improve quality of life and avoid premature diabetes-associated death. These goals may be achieved through better glycaemic control of blood glucose levels and through reductions in other macrovascular risk factors. There are four main types of insulin preparation, which are classified on the basis of their duration of action, onset of action, and peak action time: rapid-acting insulin analogues (eg, lispro, insulin aspart): onset min, peak min, duration 3-5 hr; used premeal short-acting insulins, also referred to as human soluble insulin or Regular insulin: onset min, peak 2-3 hr, duration 4-6 hr; used premeal intermediate-acting insulins (eg, neutral protamine Hagedorn (NPH) insulin): onset 2-4 hr, peak 4-8 hr, duration hr; used to control blood glucose between meals and during the night long-acting insulin analogues, also referred to as basal insulins (eg, glargine): onset 1-2 hr, peak none, duration 24 hr; given in the morning or at bedtime to control blood glucose all day

16 2 Conventional insulin therapy involved twice-daily injections of a mixture of slowacting and short-acting insulins (ie, meal-time and a basal insulin together). However, intensive therapy by multiple daily injection (MDI) of slow-acting and short-acting insulins (ie, 4-5 injections daily of meal-time insulin before the main meals and 1-2 injections of basal insulin) is now considered superior. The timing and frequency of insulin injections depend upon a number of factors, including the type of insulin, the amount and type of food eaten, the person's level of physical activity, experience of hyperglycaemia and hypoglycaemia, and the person s preference and appropriateness to his/her lifestyle. Living with diabetes requires the diligent monitoring of blood glucose levels, constant attention to diet and, in individuals receiving insulin therapy, multiple daily injections. Insulin and glucose intake have to be carefully balanced to avoid hyperglycaemia or episodes of hypoglycaemia, which can cause weakness, confusion, dizziness, unconsciousness, and seizures. The ongoing threat of short-term and long-term complications of diabetes can cause anxiety, fear and depression. Furthermore, the inflexibility of lifestyle often has a negative impact on quality of life. In adolescence, lifestyle and attitudes can make maintenance of tight blood glucose control more difficult. In younger children, good control of blood glucose is difficult to attain, partly because intermediate-acting insulins are absorbed too rapidly. Continuous subcutaneous insulin infusion Insulin pump therapy is technically referred to as continuous subcutaneous insulin infusion (CSII). CSII devices are external pumps comprising a programmable pump and insulin storage reservoir to which the patient is continuously connected. Insulin is administered to the patient via a needle or cannula inserted under the skin. The pump delivers insulin continuously at a constant or variable basal rate with an additional boost dose delivered at meal times. The objectives of CSII therapy include improved glycaemic control through lower mean blood glucose levels, less variation in blood glucose levels, and fewer episodes of hypoglycaemia. CSII also allows a greater degree of flexibility in lifestyle (activity and meal-planning). Structure of report This report is divided into sections. The next section describes the review s Methods and includes the search strategy, inclusion and exclusion criteria, the data extraction, appraisal and synthesis methods, and the methodological limitations of the evidence review. The results section considers the included appraised studies, and includes a meta-analysis of relevant outcomes where appropriate. Study characteristics and findings are reported in separate tables and synthesised in the text. This is followed by a section describing the methods and results of the economics evaluations. The final section summarises results, briefly discusses the limitations of the evidence base, and presents key conclusions. A Glossary and detailed appendices follow, including a list of included studies, all excluded papers annotated by reason for exclusion, the completed data extraction tables for included papers, and forest plots.

17 3 Methods The systematic review update was to be based on one of two systematic reviews provided by the requestor (Table 1). Although the literature search span of the Canadian review (Côté & St-Hilaire, 2005) is considerably more recent, it is not suitable for updating as the requestor has advised because it does not consider the use of CSII in people with type 2 diabetes. Thus, the basis of this update is the NHS (National Health Service) technology assessment report (Colquitt et al, 2004), which informed the National Institute for Health and Clinical Excellence (NICE) recommendations for the use of CSII in diabetes. Table 1: Recent systematic reviews, candidates for updating HTA organisation Country Title Literature search end date Agence d'evaluation des technologies et des modes d'intervention en santé ((AETMIS) Côté & St-Hilaire, 2005) Southampton Health Technology Assessments Centre under auspices of the NHS R&D HTA Programme (Colquitt et al, 2004) Québec, Canada UK Comparison of the insulin pump and multiple daily insulin Clinical and costeffectiveness of continuous subcutaneous insulin infusion for diabetes July 2004 May 2002 NICE recommended the use of insulin pump therapy as one option for people with type 1 diabetes provided that: multiple-dose insulin therapy (including using insulin glargine when it is appropriate) has failed, and the patient is willing and able to use insulin pump therapy effectively NICE considers that multiple-dose insulin therapy has failed when someone has been carefully trying to manage their diabetes but hasn t been able to keep their blood glucose levels within recommended levels without having disabling hypoglycaemia. This means that they have repeated and unpredictable hypoglycaemic episodes for which they need help from other people, and which make them anxious about the episodes occurring again and significantly spoil their way of life. The NICE recommendations regarding insulin pump therapy for type 1 diabetes are also valid for children, adolescents, pregnant women and women who are intending to become pregnant. However, pregnant women and women who are intending to become pregnant should only change to insulin pump therapy when under the care of the specialist team. NICE does not recommend insulin pump therapy for people who have type 2 diabetes and need to take insulin. It is noteworthy that the evidence upon which NICE based their recommendation for CSII was far from convincing in terms of reduction in levels of glycosylated haemoglobin (HbA 1c ), which is a standard indicator of the quality of glycaemic control over the past two to three months. In adults with type 1 diabetes, eight studies reported glycosylated haemoglobin after 10 weeks to 4 months of follow-up, and five provided sufficient data for inclusion in a meta-analysis. Using the random effects

18 4 model to account for heterogeneity between the trials, a non-significant reduction in glycosylated haemoglobin after up to four months of treatment with CSII compared with MDI was observed (P= 0.05). After six and 12 months of treatment with either CSII or MDI, a similar non-significant trend in favour of CSII was seen (P= 0.10 from four studies at six months, and P= 0.08 from three studies at 12 months). No relevant studies were available for children with type 1 diabetes, or adults with type 2 diabetes. Of two studies in adolescents with type 1 diabetes, one showed significantly lower glycosylated haemoglobin with CSII (9.3%) than with MDI (9.6%) at four months of follow-up (P< 0.05), whereas the other study found no difference between the treatments after six months of follow-up. The evidence for superiority of CSII over MDI was not overwhelming for other outcomes of relevance either. In adults with type 1 diabetes, only two of the included studies reported cholesterol levels after treatment with CSII or MDI and therefore the results in terms of the relative effect of treatment on lipid profile are inconclusive. The two studies in adolescents did not report lipid outcomes. Quality of life was reported in only one of the studies included in the NHS assessment. In this study (adult with type I diabetes), no significant differences between CSII and MDI were found overall or on any of the subscales of the Diabetes Quality of Life (DQOL) tool. Severe hypoglycaemic episodes differed little between treatments in nine of the twelve included studies of adults with type 1 diabetes. Likewise, the two studies of adolescents with type 1 diabetes reported no difference in the number of hypoglycaemic events between treatments. Cases of diabetic ketoacidosis were rare across all studies and therefore it was not possible to draw firm conclusions with regard to the relative incidence of ketoacidosis with CSII and MDI. The Appraisal Committee for NICE considered that the evidence from clinical trials comparing CSII therapy with MDI therapy showed that either CSII therapy is no more effective than MDI therapy, or if CSII therapy is more effective, then at best the difference between the two therapies is small. However, it was accepted that the comparisons combined evidence from studies using modern pump technology with studies using CSII technology that is now obsolete. In addition, many of the people enrolled in the trials were not from the group most likely to benefit from CSII therapy (ie, people with the most erratic control of their blood glucose levels). In making their recommendation, the Committee that for a small subgroup of people with type 1 diabetes who could not achieve adequate glycaemic control with MDI therapy, a much more satisfactory quality of life could be achieved using CSII therapy. Research questions The clinical question to be answered by this review was defined by staff from the Long Term Conditions Policy and Strategy team of the Clinical Services Directorate of New Zealand s Ministry of Health in conjunction with the reviewers. In general, the aim of this review was to evaluate the relative effectiveness, safety, and costeffectiveness of CSII in patients with insulin-treated diabetes, when compared to optimised MDI.

19 5 The primary research question to be addressed by this review was: Is subcutaneous insulin pump therapy effective, safe, and cost-effective compared with multiple daily injections? The review questions are defined according to the PICO (or PICOT) criteria: patient population intervention comparator outcomes time consideration For inclusion in the current review, the evidence had to fulfil the criteria outlined in Table 2 and Table 3. These criteria were developed a priori and described in the scoping protocol prepared prior to commencement of the review proper. Although the NHS technology assessment report (Colquitt et al, 2004) also included nonrandomised crossover studies, the current review includes randomised trials only to minimise bias. Table 2: Patient population Intervention Comparator Outcomes Table 3: Publication type Study design Study duration Sample size Criteria for determining study eligibility Insulin-treated diabetic patients (type 1 or type 2). Includes adults, children, adolescents, and pregnant women with pre-existing diabetes. Newly diagnosed patients are excluded. Gestational diabetes was excluded. Continuous subcutaneous insulin infusion (CSII), any manufacturer. Comparisons of conventional therapy, implantable pumps, and hospital inpatient pumps are excluded. Optimised multiple insulin injections (MDI), at least 3 injections per day. Efficacy outcomes: HbA 1c, lipid levels, quality of life (QOL) Safety outcomes: severe hypoglycaemic episodes, ketoacidotic episodes Nature of the evidence Studies published in the English language, including primary (original) research published as full original reports and secondary research (systematic reviews and meta-analyses) appearing in the published literature. Papers for which an abstract is not available for review via the bibliographic database are excluded. Those that provide at least Level II evidence according to the National Health and Medical Research Council (NHMRC) interim levels of evidence for intervention research questions (2005). This includes randomised controlled trials (Level II evidence) of crossover or parallel-group design, and systematic reviews of Level II evidence. At least 10 weeks on each treatment. At least 10 evaluable patients per study arm (or exposed to both treatments). It is noteworthy that the NHS technology assessment claims that comparison of CSII using analogues with MDI using soluble would introduce a confounding factor and thus comparisons of intensive therapy should only be made with the same type of insulin. Although there is a clear difference in the insulin profile of rapid-acting analogues and soluble insulin, the most appropriate comparator in practice is MDI using the insulin type most commonly used, which may well be short-acting rather then a rapid-acting analogue. In this review, studies of rapid-acting analogues in CSII with short-acting soluble insulin using MDI are included in additional all-inclusive analyses.

20 6 Literature search A systematic method of literature searching and selection was employed in the preparation of this review update. The NHS technology assessment report (Colquitt et al, 2004) upon which this update was based had a search date end of May/June For this update, searches were limited to English language material published from January 2002 onwards. The searches were completed on 27 August, Therefore, studies published after this date were not eligible for inclusion in the systematic review. The following databases were searched: Bibliographic databases Embase Medline Review databases Cochrane Database of Systematic Reviews Cochrane Central Register of Controlled Trials Database of Abstracts of Reviews of Effectiveness Health Technology Assessment database NHS Economic Evaluation database HTA Groups INAHTA website database: MSAC: ANZHSN: NZHTA: NICE: AHRQ/USPSTF: CADTH: Clinical Practice Guidelines National Guideline Clearing House database: The reference lists of key papers were searched to identify any peer-reviewed evidence that may have been missed in the literature search. In accordance with the Scoping Protocol, hand-searching was not undertaken and the grey literature and unpublished material such as conference abstracts were not searched due to the short time frame for this review. Search terms were searched for as keywords, exploded where possible, and as free text within the title and/or abstract, in the Embase and Medline databases. Variations on these terms were used for the Cochrane library and HTA website databases, modified to suit their keywords and descriptors. The search terms, search strategy and citations identified are presented in Table 4.

21 7 Table 4: Database EMBASE + MEDLINE Cochrane Library a Date searched 01 January August January August 2007 Search strategy for relevant clinical trials Search no. Search terms 1 'insulin *3 pump' AND [ ]/py 'insulin *3 pumps' AND [ ]/py 142 Citations 3 'insulin infusion'/exp 2,712 4 'pump *3 therapy' AND diabet* AND [ ]/py csii AND [ ]/py 'subcutaneous *5 insulin *5 infusion' AND [ ]/py 7 'continuous *5 insulin *5 infusion' AND [ ]/py 8 'external pump *5 insulin' AND [ ]/py 9 'external pump *5 diabetes' AND [ ]/py 10 'external pump *5 diabetic' AND [ ]/py 11 'external pumps *5 insulin' AND [ ]/py 12 'external pumps *5 diabetes' AND [ ]/py 13 'external pumps *5 diabetic' AND [ ]/py 14 #4 OR #5 OR #9 OR #10 OR #11 OR #12 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 15 #14 AND [english]/lim AND [humans]/lim AND [abstracts]/lim AND [ ]/py , Sub-total after exclusion of duplicate citations insulin NEAR pump*) OR csii OR ((continuous NEAR insulin) NEAR infusion) OR ((subcutaneous NEAR insulin) NEAR infusion) OR ((external AND pump*) AND (diabet* near insulin*)), from 2002 to Sub-total after exclusion of duplicate citations 142 Bibliographies of included studies and other sources 1 Non duplicate citations 726 a The search of the Cochrane Library includes Cochrane Central Register of Controlled Trials, Health Technology Assessment Database, Database of Abstract Reviews of Effect, Cochrane Database of Systematic Reviews, and NHS Economic Evaluation Database. Assessment of study eligibility Studies were selected for appraisal using a two-stage process. First, titles and abstracts (where available) identified from the search strategy were scanned and excluded as appropriate. Second, the full text articles were retrieved for the remaining studies and selected for inclusion and appraisal in the review if they fulfilled the pre-defined study selection criteria outlined below. Double-checking of the eligibility of studies by a second reviewer was not undertaken.

22 8 As mentioned earlier, non-english publications were excluded at the database searching stage. Citations were excluded for the following reasons: 1. Not a clinical study: including non-systematic reviews, case reports, animal studies, short notes, letters, editorials, conference abstracts, in-vitro studies, studies not deemed appropriate to the research question or nature of review 2. Wrong patient group: does not include subjects with diabetes (or only those with gestational diabetes 3. Wrong intervention: does not include CSII with a treatment duration of at least 10 weeks 4. Wrong comparator: does not include optimised MDI 5. Wrong outcomes: does not include the results relating to at least one of the identified outcomes of interest 6. Fewer than 10 evaluable patients per study arm at baseline 7. Not in English There were 726 non-duplicate studies identified by the search strategy. As detailed in Table 5, 32 full text articles were eligible for retrieval after excluding studies from the search titles and abstracts. Of full papers retrieved, 20 did not fulfil the inclusion criteria and were excluded. Therefore, 12 articles (referring to 11 studies) were fully appraised and are included in this report (listed in Appendix A). All excluded articles are presented in Appendix B, annotated by reason for exclusion based on the exclusion criteria detailed above. Reasons are presented hierarchically such that the first reason in the list that applied is reported. Other cited publications (eg, those providing background material) are presented in the References. Table 5: Application of selection criteria to citations Exclusion criteria Total citations 726 Title/abstract: Not a full publication of a clinical study: exclude non-systematic reviews, letters, editorials, notes and in-vitro studies. Not in patients with diabetes. Not CSII therapy for at least 10 weeks compared with MDI. Not report a relevant outcome. Not at least 10 evaluable patients per study arm. Not in English Full papers reviewed: 32 Full paper: Wrong study type (ie,, narrative review, conference abstract only, not a RCT) Wrong comparator Not at least 10 evaluable patients per study arm Literature search not beyond that of Colquitt et al, 2004 (for Level I evidence) Total included citations 12 Appraisal of included studies Dimensions of evidence Number The aim of this review was to find the highest quality evidence to answer the clinical question. In accordance with NHMRC guidance, the following dimensions of evidence were reviewed for each of the included studies (Table 6). It is important to

23 9 recognise that the value of a piece of evidence is determined by all of these dimensions, not just the level of evidence. Table 6: NHMRC Dimensions of evidence Dimension Strength of the evidence Level (see below) Reviewers definition The study design used, as an indication of the degree to which bias has been eliminated by the design alone. The levels reflect the effectiveness of the study design to answer the research question. Quality Statistical precision Size of effect Relevance of evidence The methods used to minimise bias within an individual study (ie,, other than design per se) An indication of the precision of the estimate of effect reflecting the degree of certainty about the existence of a true effect, as opposed to a effect due to chance Determines the magnitude of effect and whether this is of clinical importance The considers the relevance of the study to the specific research question and the context in which the information is likely to be applied, with regard to a) the nature of the intervention, b) the nature of the population and c) the definition of the outcomes. The evidence was assessed according to the dimensions outlined in Table 6 above. Each study was also assigned a level of evidence in accordance with the NHMRC (2005) interim levels of evidence (Table 7). The highest level of evidence available is a systematic review of randomised controlled trials, which are considered the study type least subject to bias. Individual randomised controlled trials (parallel-group and cross-over studies) also represent good evidence. This review update considered Level I and Level II evidence only. Lower levels of evidence (eg, non-randomised studies) remain subject to considerable bias and were thus excluded. Note that although Colquitt et al (2004) included non-randomised crossover studies, these were excluded from the current review update.

24 10 Table 7: NHMRC Interim Levels of Evidence (NHMRC 2005) for Evaluating Intervention Studies Level I * II III-1 III-2 III-3 IV Intervention A systematic review of level II studies A randomised controlled trial A pseudorandomised controlled trial (ie, alternate allocation or some other method) A comparative study with concurrent controls: Non-randomised, experimental trial Cohort study Case-control study Interrupted time series with a control group A comparative study without concurrent controls: Historical control study Two or more single arm study Interrupted time series without a parallel control group Case series with either post-test or pre-test/post-test outcomes * A systematic review will only be assigned a level of evidence as high as the studies it contains, excepting where those studies are of level II evidence. This also includes controlled before-and-after (pre-test/post-test) studies, as well as indirect comparisons (ie, utilise A vs B and B vs C, to determine A vs C). Comparing single arm studies ie, case series from two studies. Source: National Health and Medical Research Council (2005) Even within the levels of evidence stated above there is considerable variability in the quality of evidence. In accordance with NHMRC guidelines, it was necessary to consider the quality of each of the included studies. The characteristics and quality of each included study were assessed using a number of quality criteria, as shown in Table 8. Quality criteria for randomised controlled trials were identical to that reported in Colquitt et al (2004). No specific quality criteria were available from Colquitt et al (2004) for systematic reviews and therefore criteria were adapted from NHMRC Interim Levels of Evidence (NHMRC 2005) for Evaluating Intervention Studies. In accordance with the Scoping Protocol, no attempt was made to formulate a numeric score.

25 11 Table 8: Quality criteria for different levels of evidence Study type Systematic review RCT Quality criteria Was a clinical question clearly defined? a Was an adequate search strategy used? Were the inclusion criteria appropriate and applied in an unbiased way? Was a quality assessment of included studies undertaken? Were the characteristics and results of the individual studies appropriately summarised? Were the methods for pooling the data appropriate? Were sources of heterogeneity explored? Was the assignment to the treatment groups really random? Was the treatment allocation concealed? Were the groups similar at baseline in terms of prognostic factors? Were the eligibility criteria specified? Were the point estimates and measure of variability presented for the primary outcome measure? Did the analysis include an intention-to-treat analysis? Were withdrawals and dropouts completely described? Note: Quality criteria for RCTs were taken from Colquitt et al (2004). Quality criteria for systematic reviews were adapted from NHMRC Interim Levels of Evidence (NHMRC 2005) for Evaluating Intervention Studies. a This criterion was included in the current review but is not specified by the NHMRC. Data extraction Data was extracted onto specifically designed data extraction forms, and included information regarding study design, patient characteristics, details of intervention, relevant outcomes, study quality, and relevant results. Data was extracted by one reviewer. Completed data extraction forms containing detailed information regarding study characteristics and quality, together with a brief summary of study results, can be found in Appendix C. Data synthesis In addition to the level and quality of evidence of individual studies, the review will consider the body of evidence in total. This will involve consideration of the volume of evidence and its consistency. Included studies are reviewed and analysed according to patient population: (i) adults with type 1 diabetes, (ii) children and/or adolescents with type 1 diabetes, (iii) adults with type 2 diabetes, and (iv) pregnant women with diabetes. Outcome data will be presented in tabulated form for HbA 1c, severe hypoglycaemic events, and ketoacidotic events. Lipid outcomes and quality of life outcomes will be described narratively due to data limitations. Due to inadequacies in reporting, three different methods of analysis will be used to compare CSII with MDI in terms of HbA 1c. Difference in HbA 1c at endpoint, unadjusted for baseline levels: This method preferentially uses the reported HbA 1c levels at endpoint without consideration

26 12 of baseline levels. If unavailable, the endpoint value was calculated from the reported baseline and change from baseline. This approach was taken in the NHS technology assessment and relies on there being no difference in baseline levels between subjects treated with CSII and MDI. Difference in HbA 1c at endpoint, adjusted for baseline levels: If not reported, a crude adjustment was made by the reviewer to account for differences in HbA 1c levels at baseline. HbA 1c at endpoint in subjects treated with MDI were adjusted by the difference in baseline levels between CSII and MDI. Difference in change from baseline to endpoint: This method preferentially uses the change from baseline as reported in the publication. If unavailable, the change from baseline was calculated by the reviewer using baseline and endpoint values. When appropriate, a meta-analysis of evidence from RCTs will be performed using the methodology of the Cochrane Collaboration (Mulrow & Oxman, 1997). Metaanalysed data will be summarised as weighted mean difference (WMD) using the random-effects model. This approach is possible for HbA 1c at endpoint because the mean and standard deviation (SD) are often reported. If the SD is not reported, it will be calculated by the reviewer from the standard error, if available. Alternately, the baseline SD will be applied at endpoint. It is not possible to meta-analyse the difference at endpoint between MDI and CSII nor the difference in change from baseline to endpoint between MDI and CSII. This is because the variance of the difference is often not reported and can not be calculated using the available data. Data will therefore be averaged by the reviewer as a mean difference, shown with and without weighting based on the number of subjects at the end of study. Note that this approach does not account for duplicate data points for the two treatment phases of crossover design trials. For each method of analysis, a base case analysis will be undertaken with only those trials that compared like insulins (ie, rapid-acting insulin analogues were used in both the CSII and MDI arms). An additional, more inclusive, analysis will be undertaken with the inclusion of all trials, although these additional trials are arguably not entirely comparable to those of the base case. No attempt was made to meta-analyse data from the review update with data from the NHS assessment report (Colquitt et al, 2004). Limitations of the review methodology This review used a structured approach to review the literature. However, there were some inherent limitations with this approach. All types of study are subject to bias, with systematic reviews being subject to the same biases seen in the original studies they include, as well as biases specifically related to the systematic review process. Reporting biases are a particular problem related to systematic reviews and include publication bias, time-lag bias, multiple publication bias, language bias and outcome reporting bias (Egger et al 2001). A brief summary of the different types of reporting bias is shown in Table 9. Other biases can result if the methodology to be used in a review is not defined a priori (ie, before the review commences). Detailed knowledge of studies performed in the area of interest may influence the eligibility criteria for inclusion of studies in the review and may therefore result in biased

27 13 results. For example, studies with more positive results may be preferentially included in a review, thus biasing the results and overestimating treatment effect. Table 9: Reporting biases in systematic reviews a Type of bias Publication bias Time-lag bias Multiple publication bias Citation bias Language bias Outcome reporting bias a Adapted from Egger et al (2001). Definition and effect on results of review The publication or non-publication of research findings. Small, negative trials tend not to be published and this may lead to an overestimate of results of a review if only published studies are included. The rapid or delayed publication of research findings. Studies with positive results tend to be published sooner than studies with negative findings and hence results may be overestimated until the negative trials catch up. The multiple or singular publication of research findings. Studies with significant results tend to be published multiple times which increases the chance of duplication of the same data and may bias the results of a review. The citation or non-citation of research. Citing of trials in publications is not objective so retrieving studies using this method alone may result in biased results. Unsupported studies tend to be cited often which may also bias results. The publication of research findings in a particular language. Significant results are more likely to be published in English so a search limited to English-language journals may result in an overestimation of effect. The selective reporting of some outcomes but not others. Outcomes with favourable findings may be reported more. For example, adverse events have been found to be reported more often in unpublished studies. This may result in more favourable results for published studies. Some of these biases are potentially present in this review. Only data published in peer-reviewed journals is included. No attempt was made to include unpublished material, as such material typically has insufficient information upon which to base quality assessment, and it has not been subject to the scrutiny of the peer-review process. In addition, the search was limited to English-language publications only so language bias is a potential problem also. Outcome reporting bias and inclusion criteria bias are unlikely as the reviewers had no detailed knowledge of the topic literature, and the methodology used in the review and the scope of the review was defined a priori. The review scope was developed with the assistance of Ministry of Health staff to support policy and purchasing relevant to New Zealand. All studies included in this review were conducted outside New Zealand, and therefore, their generalisability to the New Zealand population and context may be limited and needs to be considered. This review was confined to an examination of the efficacy and safety of the interventions and did not consider ethical or legal considerations associated with these interventions. The studies were initially selected by examining the abstracts of these articles. Therefore, it is possible that some studies were inappropriately excluded prior to examination of the full text article. However, where detail was lacking ambiguous papers were retrieved as full text to minimise this possibility. Reasons for exclusion for every article included in the review are presented in Appendix B for transparency.

28 14 There are a number of caveats that must be considered when interpreting the results of the meta-analyses. In this review, several approaches have been taken to analyse the comparative data in an attempt to account for inadequacies in data reporting. However, of even greater concern is the potential bias introduced because of the crossover design of many of the included studies. In the majority of publications, a carry-over effect was not considered and in those studies that did consider carryover, the issue was not addressed appropriately. Furthermore, it was often unclear how dropouts and missing data were handled. In only one of the included studies (DeVries et al, 2002) did the authors choose to analyse data from the first treatment phase only due to a high dropout rate at crossover. Outcome data was rarely reported by treatment phase and therefore this approach was not feasible overall. It is worth noting that the NHS technology assessment (Colquitt et al, 2004) did not specifically address the issue of carryover in the included crossover studies, nor did it take into consideration baseline levels when comparing the effect of treatment on HbA 1c levels. Although treatment groups at baseline were generally well balanced, when the treatment effect is of small magnitude, as is the case with HbA 1c, a true measure of the change from baseline is imperative. In the current update, a number of studies did not report change from baseline to endpoint in HbA 1c, and in those cases it was estimated using the available data. Thus, although all efforts have been made to show whether a true difference exists between CSII and MDI, the results of the metaanalyses must be interpreted with caution. As mentioned above, the magnitude of the treatment effect is often small. For HbA 1c, the clinical significance of this change is at the discretion of the requestor. Data extraction, critical appraisal and report preparation was performed by a single reviewer. This review benefited from the advice provided by Dr Ray Kirk, however, it has not been exposed to wider peer review. For a detailed description of interventions and evaluation methods, and results used in the studies appraised, the reader is referred to the original papers cited. Evaluation of economic implications The current review included (i) a systematic search of the published literature to identify any relevant economic evaluations, and (ii) a simplistic economic evaluation of CSII, relative to the comparator, MDI. The search for published economic evaluations was undertaken on 29 January 2008 and included standard economic search terms and terms relating to insulin pump therapy. The search encompassed EMBASE and MEDLINE. The search terms and citations identified are presented in Table 10.

29 15 Table 10: Database EMBASE + MEDLINE Search strategy for economic evaluations Date searched < January 2008 Non duplicate citations 151 Search no. Search terms 1 ('insulin *3 pump') OR ('insulin *3 pumps') OR (csii) OR ('subcutaneous *5 insulin *5 infusion') OR ('continuous *5 insulin *5 infusion') OR ('external pump *5 insulin') OR ('external pump *5 diabetes') OR ('external pump *5 diabetic') OR (('pump *3 therapy') AND (diabet*)) OR ('external pumps *5 insulin') OR ('external pumps *5 diabetes') OR ('external pumps *5 diabetic') 2 ('cost effectiveness analysis'/exp OR 'cost effectiveness analysis') OR ('economic evaluation'/exp OR 'economic evaluation') OR ('health economics'/exp OR 'health economics') OR ('cost minimization analysis'/exp OR 'cost minimization analysis') OR ('cost minimisation analysis') OR ('cost utility analysis'/exp OR 'cost utility analysis') OR ('quality adjusted life year'/exp OR 'quality adjusted life year') OR ('qaly'/exp OR 'qaly') OR ('life year saved') Citations 3,420 3 #1 AND # #3 AND [english]/lim AND [humans]/lim #4 AND ([conference paper]/lim OR [letter]/lim OR [note]/lim) 6 #4 NOT # , An economic analysis was also undertaken to examine the cost-effectiveness of CSII compared with MDI for a patient with Type 1 diabetes. The economic model was based mainly on the method and approach presented in the NHS assessment report (Colquitt et al, 2004), with modification to inputs in order to populate the model with NZ data wherever available. Cost-effectiveness is presented as the incremental cost per severe hypoglycaemic attack avoided over six years (ie, the pump life-time). The total additional costs of using CSII can also be considered relative to the improvements seen in glycaemic control, and any reduction in diabetic complications that this may confer.

30 16

31 17 Results Overview Methodological information and results extracted from included studies are presented below, according to patient population: (i) adults with type 1 diabetes, (ii) children and/or adolescents with type 1 diabetes, (iii) adults with type 2 diabetes, and (iv) pregnant women with diabetes. More detailed information is available in Appendix C or in the original papers. Only data relevant to the current review is presented. Of the 12 papers identified as eligible for inclusion in the review, two papers were systematic reviews, and ten papers referred to nine original research studies. There were two publications from Weintrob and colleagues (2003, 2004) which referred to a single trial. The Weintrob et al (2003) publication is referred to hereafter because the 2004 paper from the same authors provided no additional study details or relevant outcomes. Clinical evidence: study characteristics and outcomes Adults with type 1 diabetes As shown in Table 11, the literature search conducted for this review update identified one systematic review (Retnakaran et al, 2004) and two RCTs (DeVries et al, 2002; Hoogma et al, 2006) which compared CSII with MDI in adults with type 1 diabetes. The Retnakaran review included three RCTs, two of which were included in the NHS technology assessment (Tsui et al, 2001; Hanaire-Broutin et al, 2000) and one which was identified in the literature search conducted for this review update (DeVries et al, 2002). The systematic review by Retnakaran and colleagues included only those studies that compared rapid-acting insulin analogues in CSII and MDI regimens. The literature search was conducted for the period 1982 to 2002, although the exact search date was not reported. The authors concluded that insulin pump therapy is associated with better glycaemic control, particularly in those individuals with higher baseline HbA 1c, and therefore may be uniquely advantageous in the high-risk population of patients with poor glycaemic control. It should be noted, however, that the trend toward better glycaemic control with CSII was modest and did not reach statistical significance. The study reported by DeVries et al (2002) was a multicentre, open, randomised crossover trial in 79 subjects with type 1 diabetes in persistent poor control while on at least three insulin injections per day. Study participants were treated in two sequential 16-week periods with rapid-acting insulin analogues with CSII then MDI, or vice versa. Due to a high drop-out rate at crossover, the authors treated and analysed the study as if it were parallel-design, using data from the first treatment period only. It is noteworthy that after randomisation or crossover, 9 subjects (11.4%) refused to start CSII therapy and seven subjects (8.9%) refused to start MDI. The study found that CSII resulted in a greater reduction of HbA 1c as compared with MDI, and improved stability reflected by a significantly lower SD in 24-hour glucose profiles in the CSII arm.

32 18 The study reported by Hoogma et al (2006) was a multicentre, open, randomised crossover trial in 272 subjects with type 1 diabetes on MDI for at least 6 months. Subjects received treatment with rapid-acting insulin analogues for six months in each of two treatment phases, each preceded by a two-month run-in/washout period. The authors claim that the study demonstrated the superiority of CSII over an NPH-based MDI regimen with respect to HbA 1c, blood glucose, particular aspects of quality of life, and a reduction in the incidence of hypoglycaemia.

33 19 Table 11: Summary of evidence for adults with type 1 diabetes Author & year [Level of evidence] Retnakaran 2004 [Level I] DeVries 2002 [Level II] Hoogma 2006 [Level II] Study type 3 x randomised trials (1 parallel-group and 2 crossover trials, 1 of which was analysed as parallel-group) N=79 (CSII n=39, MDI n=40), N=27 (CSII n=13, MDI n=14), N=41 Multicentre, open, randomised crossover trial, analysed as parallel-group for the first phase only due to a high drop-out rate at crossover N=79 (CSII-MDI n=39, MDI-CSII n=40) Multicentre, open, randomised crossover trial N=272 (CSII-MDI n=127, MDI-CSII n=129) Treatment duration Trial 1: 4 months Trial 2: 9 months Trial 3: 2 x 4 months 70 weeks in total, including 2 x 16- week treatment phases, a 14-week qualification phase and a 24-week follow-up phase 16 months in total, including 2 x 6- month treatment phases, each started with a 2- month run-in period Population Intervention Comparator Outcomes of relevance adults with type 1 diabetes (note: studies with newly diagnosed type 1 diabetes or pregnant patients were excluded) adults aged years with type 1 diabetes in persistent poor control (mean of all HbA 1c values 8.5% in previous 6 months) while on 3 insulin injections per day adults aged years with type 1 diabetes on MDI for at least 6 months CSII with rapidacting insulin analogues CSII with insulin aspart (rapidacting) CSII with insulin lispro (rapidacting) MDI with rapidacting insulin analogues MDI with insulin aspart (rapidacting) and NPH (intermediateacting) MDI with insulin lispro (rapidacting) and NPH (intermediateacting) HbA 1c ketoacidosis HbA 1c severe hypoglycaemia ketoacidosis QOL (SF-36) HbA 1c severe hypoglycaemia QOL (46-item DQoL, SF-12) Findings, CSII vs MDI treatment effect on HbA 1c at EOT: 0.34 (95% CI -0.09, 0.77) [random effects model], ns ketoacidotic episodes: 1 vs 1 change in HbA 1c from baseline to EOT (mean of weeks): -0.91% vs -0.07%, P= severe hypoglycaemic episodes: 3 vs 6 ketoacidotic episodes: 1 vs 1 change from baseline in QOL: general health +5.9 vs -1.2, P= 0.048; mental health +5.2 vs -0.6, P= mean HbA 1c at 8 months: 7.45% vs 7.67%, P< 0.001, HbA 1c at 6 months: ~7.51% vs ~7.64%, P< 0.05 severe hypoglycaemic episodes per patient per year: 0.2 vs 0.5, P< ketoacidotic episodes: 4 a vs 0 QOL at 8 months: DQoL 75 vs 71, P< 0.001; SF-12 physical health ns; improved mental health in CSII vs MDI P= Abbreviations: AE, adverse event; CI, confidence interval; CSII, continuous subcutaneous insulin infusion; DQoL, Diabetes Quality of Life; EOT, end of treatment; HbA 1c, glycosylated haemoglobin; MDI, multiple daily injections; NPH, neutral protamine hagedorn; ns, not significant; QOL, quality of life; SD, standard deviation; SF-12, 12-item Short Form Health Survey; SF-36, 36-item Short Form Health Survey a In total, 4 events occurred in during CSII; 2 during run-in and 2 during the treatment phase.

34 20 Children and/or adolescents with type 1 diabetes As shown in Table 12, the literature search conducted for this review update identified three RCTs, two of which compared the use of rapid-acting insulin analogues in CSII with short-acting insulin in MDI. One study (Doyle et al, 2004) used glargine as basal insulin in the MDI arm. The study reported by Cohen et al (2003) was a small open, randomised, crossover trial of 16 adolescents with type 1 diabetes treated with MDI 3-4 times a day. Subjects were treated for six months in each of two treatment periods with CSII with a rapidacting analogue or MDI with a short-acting insulin as premeal bolus. The authors concluded that CSII can serve as a good alternative to MDI in adolescents with type 1 diabetes. Although the study showed a trend of improvement in diabetic control with CSII compared with MDI, the difference did not reach statistical significance, perhaps due to small sample size. The study reported by Doyle et al (2004) was a 16-week single centre, open, randomised, parallel group trial of 32 children and adolescents aged 8-21 yrs with type 1 diabetes treated with insulin for at least 6 months and with screening HbA 1c %. Both treatment arms received a rapid-acting insulin analogue. The MDI arm also received long-acting insulin glargine. The authors concluded that a considerably greater improvement in HbA 1c levels was seen with CSII than with MDI & glargine. However, no single approach to treatment is ideal for every patient and the availability of multiple therapeutic options will allow clinicians who care for children with type 1 diabetes to choose the best treatment for an individual patient at a particular time. Weintrob and colleagues (2003) reported a single centre, open, randomised, crossover trial of 23 children and young adolescents aged 8-14 yrs with type 1 diabetes treated with insulin for at least two years. Participants received a rapid-acting analogue with CSII and a short- and intermediate-acting insulin with MDI. Treatment duration was 3.5 months in each of two treatment phases which were preceded by a two-week runin/washout period. An educational session was conducted three months before study onset. The authors found that patients treated intensively with CSII and MDI achieved similar metabolic control and have the same rate of adverse events. It is noteworthy that the main improvement in metabolic control (a significant reduction in HbA 1c of ~0.6%) was achieved in the period before the study, simply by intensifying patient education without a change in the diabetes treatment regimen. The authors recommended that both modes be made available to the diabetic team and patients to better tailor therapy, and that enrolling patients into a research study is an effective tool to improve diabetic control.

35 21 Table 12: Summary of evidence for children and/or adolescents with type 1 diabetes Author & year [Level of evidence] Cohen 2003 [Level II] Doyle 2004 [Level II] Weintrob 2003 [Level II] Study type Treatment duration Population Intervention Comparator Outcomes of relevance Open, randomised, crossover trial N=16 (CSII-MDI n=8, MDI-CSII n=8) Single centre, open, randomised, parallel group trial N=32 (CSII n=16, MDI n=16) Single centre, open, randomised, crossover trial N=23 (CSII-MDI n=11, MDI-CSII n=12) 12 months in total, including 2 x 6-month treatment phases 16 weeks. Instruction received 1-2 weeks prior to randomisation. 32 weeks, including 2 x 3.5- month treatment phases, each preceded by a 2-week run-in/washout period. An educational session was conducted 3 months before study onset. adolescents with type 1 diabetes for 2 yrs children and adolescents aged 8-21 yrs with type 1 diabetes treated with insulin for 6 months, naïve to glargine, and with screening HbA 1c % children and young adolescents aged 8-14 yrs with type 1 diabetes treated with insulin for 2 yrs CSII with lispro (rapid-acting) CSII with insulin aspart (rapidacting) CSII with insulin lispro (rapidacting) MDI with regular insulin (shortacting) and NPH (intermediateacting) MDI with insulin aspart (rapidacting) and glargine (longacting) MDI with regular insulin (shortacting) and NPH (intermediateacting) HbA 1c severe hypoglycaemia ketoacidosis QOL (DQOLY) HbA 1c severe hypoglycaemia ketoacidosis QOL (DQOLY) HbA 1c severe hypoglycaemia ketoacidosis QOL (DQOLY) Findings, CSII vs MDI mean HbA 1c at 6 months: 8.15% vs 8.57%, ns mean HbA 1c at 3 months: 8.19% vs 8.31% change in HbA 1c from baseline to 6 months: -0.43% vs +0.09%, ns severe hypoglycaemic events: 1 vs 4 ketoacidotic events: 1 vs 0 QOL (DQOLY): satisfaction subscale 82.7 vs 76.4, P<0.05; Impact scale and Worry scale, ns mean HbA 1c at 16 weeks: 7.2% vs 8.1%, P< 0.05 severe hypoglycaemic episodes: 0 vs 5 (in 4 subjects) ketoacidotic episodes: 1 vs 2 (in 1 subject) QOL (DQOLY): no difference mean HbA 1c at 3.5 months: 8.0% vs 8.1% change in HbA 1c from baseline to 3.5 months: +0.03% vs -0.23%, ns severe hypoglycaemic episodes: 1 vs 3, ns ketoacidotic episodes: 0 vs 0 QOL (DQOLY): ns Abbreviations: AE, adverse event; CSII, continuous subcutaneous insulin infusion; DQOLY, Diabetes Quality of Life in Youth; EOT, end of treatment; HbA 1c, glycosylated haemoglobin; MDI, multiple daily injections; NPH, neutral protamine hagedorn; ns, not significant; QOL, quality of life; SD, standard deviation NOTE: Studies shown in grey text make comparisons which are confounded (ie, rapid-acting analogues are used with CSII and short-acting insulin is used with MDI)

36 22 Adults with type 2 diabetes Four studies were identified that compared CSII with MDI in adults with type 2 diabetes (Table 13). Three studies compared rapid-acting analogues used with CSII and MDI, whilst the fourth study compared CSII using a rapid-acting insulin analogue with MDI using a short-acting soluble insulin as premeal bolus. One study (Herman et al, 2005) used glargine as basal insulin in the MDI arm. The study reported by Berthe et al (2007) was a two-centre, open, randomised, crossover trial of 17 subjects aged years with type 2 diabetes on conventional insulin therapy for more than six months but not optimally controlled. Subjects received a rapid-acting analogue in both treatment phases, each of 12 weeks duration. The authors concluded that the intensified insulin regimen using CSII allowed better glycaemic control than CIT or MDI, providing a better blood glucose profile and significantly greater reduction in HbA 1c levels. Herman and colleagues (2005) reported a two-centre, open, randomised, parallelgroup trial of 107 older adults aged 60 years or over with type 2 diabetes for at least one year and taking at least one insulin injection per day in the previous month. Subjects who experienced more than one episode of severe hypoglycaemia in the past year were excluded. Participants were treated for 12 months with either CSII using a rapid-acting analogue or MDI with a rapid-acting analogue together with glargine as basal insulin. The study showed no difference in efficacy between CSII and MDI. Although there was a trend toward a higher number of severe hypoglycaemic events in the MDI arm, this was largely related to one subject who experienced four events. The authors concluded that because MDI is less expensive than CSII, MDI may be preferred as an initial regimen for older patients with type 2 diabetes requiring intensive insulin therapy. The study reported by Raskin et al (2003) was a multicentre, open, randomised, parallel-group trial of 132 adults aged 35 years or older with type 2 diabetes for at least two years and at least one insulin dose per day for 6 months or more. Subjects with HbA 1c > 12% or with recurrent major hypoglycaemia were excluded. A rapidacting insulin analogue was used in both treatment arms. Treatment duration was 24 weeks, including an eight-week dose adjustment period. The authors concluded that CSII was as safe and effective as MDI therapy for patients with type 2 diabetes initiating intensive insulin therapy. Wainstein and colleagues (2005) reported a multicentre, open, randomised, crossover trial of 40 obese adults aged years with type 2 diabetes for at least six months, that is uncontrolled after treatment with diet, metformin, and high doses of insulin (divided into 2 or 3 daily injections). Subjects with HbA 1c > 15% were excluded. The study was designed with two 18-week treatment phases separated by a 12-week washout period during which subjects treated with MDI plus metformin. Subjects received a rapid-acting analogue in the CSII treatment phase and a short-acting insulin in the MDI phase. The authors concluded that CSII appeared to be superior to MDI in reducing HbA 1c and blood glucose in obese, uncontrolled, insulin-treated type 2 diabetic subjects. Although the number of major hypoglycaemic events were few and similar in both groups, the study was not powered to detect a difference in the frequency of major hypoglycaemic events by treatment groups.

37 23 Table 13: Summary of evidence for adults with type 2 diabetes Author & year [Level of evidence] Study type Treatment duration Population Intervention Comparator Outcomes of relevance Findings, CSII vs MDI Berthe 2007 [Level II] Two-centre, open, randomised, crossover trial N=17 (CSII-MDI n=7, MDI-CSII n=10) 30 weeks in total, including 2 x 12-week treatment phases and a 6-week run-in period with CIT adults aged years with type 2 diabetes on insulin for > 6 months but not optimally controlled (HbA 1c level 6.5% on 2 determinations) CSII with insulin lispro (rapidacting) MDI with premixed lispro-nph insulin (50% rapid-acting and intermediateacting) HbA 1c severe hypoglycaemia ketoacidosis lipid levels mean HbA 1c at 12 weeks: 7.7% vs 8.6%, P< 0.03 severe hypoglycaemic episodes: no self-reported episodes ketoacidotic episodes: no AEs reported lipids: ns Herman 2005 [Level II] Two-centre, open, randomised, parallelgroup trial N=107 (CSII n=53, MDI n=54) 12 months older adults aged 60 yrs with type 2 diabetes for 1 yr and taking 1 insulin injection per day in the previous month, with HbA 1c 7.0% and < 2 episodes of severe hypoglycaemia in the past year CSII with insulin lispro (rapidacting) MDI with insulin lispro (rapid-acting) and once daily insulin glargine (long-acting) HbA 1c severe hypoglycaemia QOL (DQOLCTQ, SF-36 physical and mental health scores) mean HbA 1c at 12 months: 6.6% vs 6.4%, P= 0.19 change in HbA 1c from baseline to 12 months: - 1.7% vs -1.6% Achievement of HbA 1c < 7.0% at 12 months: 75% vs 84%, P= 0.30 severe hypoglycaemic episodes: 4 vs 12 P= 0.49 change in QOL: ns Raskin 2003 [Level II] Multicentre, open, randomised, parallelgroup trial N=132 (CSII n=69, MDI n=63) 24 weeks in total, including a 8-week dose adjustment period and 16-week maintenance period adults aged 35 yrs with type 2 diabetes for 2 yrs and at least 1 insulin dose per day for 6 months, HbA 1c 6% and 12%, and no recurrent major hypoglycaemia CSII with insulin aspart (rapidacting) MDI with insulin aspart (rapid-acting) and NPH (intermediateacting) HbA 1c severe hypoglycaemia QOL (PHASE V Technologies Outcomes Information System) mean HbA 1c at 24 weeks: 7.6% vs 7.5% change in HbA 1c from baseline to 24 weeks: vs -0.46, ns severe hypoglycaemic episodes: 0 vs 0 QOL : no usable data

38 24 Table 13: Summary of evidence for adults with type 2 diabetes continued Author & year [Level of evidence] Wainstein 2005 [Level II] Study type Multicentre, open, randomised, crossover trial N=40 (CSII-MDI n=20, MDI-CSII n=20) Treatment duration 48 weeks in total, including 2 x 18-week treatment phases separated by a 12- week washout period during which subjects treated with MDI plus metformin. Randomisation preceded by 2-week run-in period during which subjects treated with insulin therapy plus metformin. Population Intervention Comparator Outcomes of relevance obese (BMI kg/m 2 ) adults aged yrs with type 2 diabetes for 6 months, uncontrolled after 3 months treatment with diet, metformin (850 mg 2-3 times daily) and high doses of insulin (> 1 unit/kg/day, divided into 2 or 3 daily injections), and with HbA 1c 15% CSII with insulin lispro (rapidacting) MDI with regular insulin (short-acting) and NPH (intermediateacting) HbA 1c severe hypoglycaemia lipid profile (total cholesterol, triglycerides, LDL, HDL) Findings, CSII vs MDI change in HbA 1c from baseline to 18 weeks [ITT cohort]: -0.8% vs +0.4%, P= change in HbA 1c from baseline to 18 weeks [completers cohort]: -0.8% vs -0.2%, P= 0.4 incidence of severe hypoglycaemia: 3 vs 2 lipid profile: ns Abbreviations: AE, adverse event; CIT, conventional insulin therapy; CSII, continuous subcutaneous insulin infusion; DQOLCTQ, Diabetes Quality of Life Clinical trial Questionnaire; EOT, end of treatment; HbA 1c, glycosylated haemoglobin; HDL, high density lipoprotein ; LDL, low density lipoprotein; MDI, multiple daily injections; NPH, neutral protamine hagedorn; ns, not significant; QOL, quality of life; SD, standard deviation; SF-36, 36-item Short Form Health Survey NOTE: Studies shown in grey text make comparisons which are confounded (ie, rapid-acting analogues are used with CSII and short-acting insulin is used with MDI)

39 25 Pregnant women with diabetes Only one paper, a Cochrane Review, was identified that compared CSII with MDI in pregnant women with diabetes (Table 14). The systematic review by Farrar and colleagues (2007) included two single-centre randomised, parallel-design trials, both of which included pregnant women with pre-existing diabetes. Although not clear, it appears that both studies compared short-acting insulin in both the CSII and MDI treatment arms. The authors concluded that there are insufficient data to draw conclusions in relation to best practice. Both methods of administration appear to have advantages and disadvantages and decisions regarding diabetes management in the context of pregnancy should be made according to individual needs.

40 26 Table 14: Summary of evidence for pregnant women with diabetes F Author & year [Level of evidence] Farrar 2007 [Level I] Study type 2 x single-centre randomised, paralleldesign trials N=29 N=31 Treatment duration first trimester to early postnatal period Population Intervention Comparator Outcomes of relevance pregnant women with pre-existing diabetes (type 1 or type 2) Trial 1: CSII with regular insulin (short-acting) Trial 2: CSII with insulin type not specified Trial 1: MDI with regular insulin (short-acting) Trial 2: MDI with regular insulin (short-acting) and intermediateacting insulin HbA 1c Findings, CSII vs MDI mean HbA 1c 2nd trimester: favours MDI, WMD 0.70% (95% CI %, 3.69%), P= 0.6 [1 study] mean HbA 1c 3rd trimester: favours MDI, WMD 0.10% (95% CI %, 2.58%), P= 0.9 [1 study] Abbreviations: CI, confidence interval; CSII, continuous subcutaneous insulin infusion; HbA 1c, glycosylated haemoglobin; MDI, multiple daily injections; WMD, weighted mean difference

41 27 Clinical evidence: results and meta-analyses Glycosylated haemoglobin HbA 1c levels at endpoint are shown in Table 15 and the change from baseline levels are shown in Table 16 according to patient population. WMD in endpoint HbA 1c and meta-analysis, where appropriate, is shown in Table 17 (base case) and Table 18 (all identified trials). The forest plots are presented in Appendix D. The mean difference between CSII and MDI in change from baseline in HbA 1c is shown in Table 19 (base case) and Table 20 (all identified trials), weighted by the number of subjects. Note that the results of the Retnakaran systematic review (2004) are not considered because two of the included trials were also included in the NHS technology assessment and the third is analysed separately in the current review. Adults with type 1 diabetes In the two RCTs that compared CSII with MDI in adults with type 1 diabetes (DeVries 2002 and Hoogma 2006), treatment with CSII was associated with better outcomes in terms of HbA 1c levels at all timepoints examined. HbA 1c levels at 3-4 months are meta-analysed in Table 17. However, despite the significant findings from the individual trials, meta-analysis using the random-effects model revealed a treatment effect in favour of CSII but no significant difference between CSII and MDI in terms of HbA 1c at 3-4 months (WMD -0.45%, 95% CI -1.04%, 0.14%). This is likely due to significant heterogeneity between the trials. The mean difference between CSII and MDI in change from baseline to endpoint in HbA 1c (Table 19) is 0.37% in favour of CSII. It is not possible to reliably determine the statistical significance of this estimate of treatment effect. Children and adolescents with type 1 diabetes As shown in Table 15 and Table 16, only one of the included studies that compared CSII and MDI in children and/or adolescents used a rapid-acting insulin analogue in both treatment arms. This study (Doyle 2004) showed a statistically significantly better outcome in terms of HbA 1c in patients treated with CSII compared with MDI, with mean HbA 1c levels in the CSII arm 0.8% to 0.9% lower than with MDI (P< 0.05). In the two trials that compared CSII using a rapid-acting analogue with MDI using short-acting soluble insulin, the results were not as clear cut. The Cohen 2003 study showed a non-significant trend in favour of CSII after three and six months of treatment. The results of the Weintrob 2003 study of adolescents with type 1 diabetes highlights the importance of careful consideration of baseline values. As shown in Table 15, a small difference in favour of CSII is seen between treatments at endpoint. However, when baseline HbA 1c levels are taken into consideration, this difference reversed in favour of MDI. Using the change from baseline to endpoint data reported in the publication (Table 16), a non-significant difference between treatments was seen in favour of MDI. Meta-analysis of all three trials of children and adolescents (Table 18) was in favour of MDI when adjusted for baseline HbA 1c levels but revealed no significant difference between treatments in terms of HbA 1c at endpoint (WMD -0.31%, 95% CI -0.79%,

42 %). The difference between CSII and MDI in terms of change from baseline HbA 1c, weighted by sample size, was 0.33% in favour of CSII. Adults with type 2 diabetes Three of the included studies that compared CSII with MDI in adults with type 2 diabetes used a rapid-acting insulin analogue with both treatment modalities. The Berthe 2007 study showed a statistically significantly better outcome in terms of HbA 1c in patients treated with CSII compared with MDI, with an absolute difference between treatments of 0.9% at endpoint (Table 15). The Herman 2005 study also showed a difference (albeit non-significant) in favour of CSII when baseline HbA 1c levels were taken into consideration (Table 15, Table 16, Table 17). Likewise, in the Raskin 2003 study the absolute change in HbA 1c from baseline to six months was greater with CSII compared with MDI, but the difference was of small magnitude and not statistically significant. Meta-analysis of data from these three trials showed no significant difference in treatments in terms of effect on HbA 1c at endpoint (Table 17). The weighted difference between treatments in change from baseline HbA 1c was 0.19% in favour of CSII (Table 19). The study reported by Wainstein et al (2005) compared CSI using rapid-acting analogue with MDI using short-acting soluble insulin. Although CSII had a greater effect on HbA 1c than MDI after four months of treatment (Table 15 and Table 16), this difference was not statistically significant (Table 18). When data from this trial were meta-analysed with the other three other trials, there was no difference between treatment modalities in terms of HbA 1c. The mean difference between treatments in change from baseline HbA 1c was 0.24%, in favour of CSII (Table 18). Pregnant women with diabetes The Farrar (2007) systematic review reported HbA 1c results from one of the included studies. After recruitment in first trimester, HbA 1c levels in both second and third trimester were lower in patients treated with MDI compared with CSII. However, this difference was not statistically significant (Table 14).

43 29 Table 15: Author & year Detailed data extraction from Level II evidence glycosylated haemoglobin at endpoint Number of subjects Mean (SD) HbA 1c Difference (CSII MDI) a Baseline CSII MDI P-value Unadjusted Adjusted Type I diabetes - adults DeVries 2002 Hoogma 2006 N=79 CSII N=39, end of phase 1 N=32 MDI N=40, end of phase 1 N=40 CSII 9.27% (1.4) MDI 9.25% (1.4) N=272, end of study N=223 CSII-MDI 8.2% (1.4) Type I diabetes children and/or adolescents Cohen 2003 Doyle 2004 Weintrob 2003 N=16, end of study N=12 CSII N=15 MDI N=13 N=32 CSII N=16, end of study N=16 MDI N=16, end of study N=15 MDI-CSII 8.3% (1.1) CSII ~7.93% (~1.1) c MDI ~7.81% (~1.2) c CSII 8.58% (0.82) MDI 8.48% (1.4) CSII 8.1% (1.2) MDI 8.2% (1.1) N=23, end of study N=23 CSII 8.0% (1.1) Type 2 diabetes - adults Berthe 2007 Herman 2005 MDI 8.3% (0.7) N=17, end of study N=17 CSII-MDI 8.6% (0.4) N=107 CSII N=53, end of study N=48 MDI N=54, end of study N=50 MDI-CSII 9.3% (2.1) CIT 9.0% (1.6) CSII 8.4% (1.1) MDI 8.1% (1.2) 3.7 months: 8.36% (1.4) b 9.18% (1.4) b = % -0.84% 4 months: ~7.47% (~1.0) c ~7.57% (~1.1) c nr ~-0.10% ~-0.22% 6 months: ~7.51% (~1.0) c ~7.64% (~1.1) c < 0.05 ~-0.13% ~-0.25% 8 months: 7.45% (~1.0) c 7.67% (~1.1) c < % -0.34% 3 months: 8.19% (0.96) 8.31% (1.04) nr -0.12% -0.22% 6 months: 8.15% (1.3) 8.57% (0.44) ns -0.42% -0.52% 3.7 months: 7.2% (1.0) 8.1% (1.2) < % -0.8% 3.5 months: 8.0% (0.7) 8.1% (0.8) nr -0.1% +0.2% 2.8 months: 7.7% (0.8) 8.6% (1.6) < % months: 6.6% (0.8) 6.4% (0.8) = % -0.1%

44 30 Table 15: Author & year Raskin 2003 Wainstein 2005 Detailed data extraction from Level II evidence glycosylated haemoglobin at endpoint continued Number of subjects N=132 CSII N=69, end of study N=60 MDI N=63, end of study N=55 Mean (SD) HbA 1c Difference (CSII MDI) a Baseline CSII MDI P-value Unadjusted Adjusted CSII 8.2% (1.4) MDI 8.0% (1.1) 5.5 months: 7.6% (1.22) 7.5% (1.17) nr +0.1% -0.1% N=40, end of study N=29 Completers 9.5% (1.5) d 4.1 months: 8.7 (1.5) d 9.3 (1.5) d nr -0.6% - Abbreviations: CSII, continuous subcutaneous insulin infusion; HbA 1c, glycosylated haemoglobin; MDI, multiple daily injections; nr, not reported; ns, not significant; SD, standard deviation NOTE: Study durations reported in weeks were converted to months assuming 30.4 days per month. Studies shown in grey text make comparisons which are confounded (ie, rapid- vs short-acting insulin) a The difference in mean HbA 1c levels is shown unadjusted and adjusted for mean HbA 1c at baseline. For the adjusted difference, the absolute difference in baseline levels was added to the MDI arm at endpoint. b Not reported in the publication. Calculated using the reported baseline value and reported change from baseline. SD at end of treatment is assumed to be identical to that at baseline. c Estimated from a figure in the publication. SEM was converted to SD using the following formula: SD = SE x N d Baseline HbA 1c refers to those subjects who completed the study. EOT mean HbA 1c levels are calculated from the change from baseline in the completers cohort using baseline SD.

45 31 Table 16: Author & year Detailed data extraction from Level II evidence change from baseline to endpoint in glycosylated haemoglobin Number of subjects Type I diabetes - adults DeVries 2002 Hoogma 2006 N=79 CSII N=39, end of phase 1 N=32 MDI N=40, end of phase 1 N=40 Difference in change Mean (SD) change in HbA 1c Baseline CSII MDI P-value a from baseline (CSII MDI) CSII 9.27% (1.4) MDI 9.25% (1.4) N=272, end of study N=223 CSII-MDI 8.2% (1.4) Type I diabetes children and/or adolescents Cohen 2003 Doyle 2004 Weintrob 2003 N=16, end of study N=12 CSII N=15 MDI N=13 N=32 CSII N=16, end of study N=16 MDI N=16, end of study N=15 MDI-CSII 8.3% (1.1) CSII ~7.93% (~1.1) c MDI ~7.81% (~1.2) c CSII 8.58% (0.82) MDI 8.48% (1.4) CSII 8.1% (1.2) MDI 8.2% (1.1) N=23, end of study N=23 CSII 8.0% (1.1) Type 2 diabetes adults Berthe 2007 Herman 2005 MDI 8.3% (0.7) N=17, end of study N=17 CSII-MDI 8.6% (0.4) N=107 CSII N=53, end of study N=48 MDI N=54, end of study N=50 MDI-CSII 9.3% (2.1) CIT 9.0% (1.6) CSII 8.4% (1.1) MDI 8.1% (1.2) 3.7 months: -0.91% (1.28) a -0.07% (0.70) a = % (95% CI -1.31, ) a 4 months: -0.46% b, c 6 months: -0.42% b, c 8 months: -0.48% b -0.24% b, c -0.17% b, c -0.14% b 3 months: -0.39% b -0.17% b nr 6 months: -0.43% a +0.09% a ns nr nr nr -0.22% b -0.25% b -0.34% b -0.22% b -0.52% b 3.7 months: -0.9% b -0.1% b nr -0.8% b 3.5 months: +0.03% (1.0) a -0.23% (1.0) a ns +0.26% b 2.8 months: -1.3% b -0.4% b < % b 2.8 months: -1.7% (1.0) a -1.6% (1.2) a = % b

46 32 Table 16: Author & year Raskin 2003 Wainstei n 2005 Detailed data extraction from Level II evidence change from baseline to endpoint in glycosylated haemoglobin continued Number of subjects N=132 CSII N=69, end of study N=60 MDI N=63, end of study N=55 Difference in change Mean (SD) change in HbA 1c Baseline CSII MDI P-value a from baseline (CSII MDI) CSII 8.2% (1.4) 5.5 months: -0.62% (1.11) a -0.46% (0.89) a ns -0.16% b MDI 8.0% (1.1) N=40, end of study N=29 Completers 9.5% (1.5) d 4.1 months: -0.8% (1.6) a, d [-0.8% (1.5) a, e ] -0.2% (1.2) a, d [0.4% (1.3) a, e ] = 0.4 c [= d ] -0.6% b, d -1.2% b, e Abbreviations: CI, confidence interval; CSII, continuous subcutaneous insulin infusion; HbA 1c, glycosylated haemoglobin; MDI, multiple daily injections; nr, not reported; ns, not significant; SD, standard deviation NOTE: Study durations reported in weeks were converted to months assuming 30.4 days per month. Studies shown in grey text make comparisons which are confounded (ie, rapid- vs short-acting insulin) a Reported in the study publication. b Calculated post-hoc using baseline and endpoint data. c Estimated from a figure in the publication. SEM was converted to SD using the following formula: SD = SE x N d Data taken from the completers cohort reported in the publication. e Data taken from the ITT (LOCF) cohort reported in the publication.

47 33 Table 17: Author & year Type 1 diabetes - adult At 3-4 months: Glycosylated haemoglobin at endpoint: Studies comparing the same insulin type with CSII and MDI a Unadjusted for baseline HbA 1c level b WMD (95% CI) P- value Adjusted for baseline HbA 1c level c I 2 WMD (95% CI) P- value DeVries (-1.47, -0.17) = (-1.49, -0.19) = Hoogma (-0.30, 0.10) = (-0.42, -0.02) = Meta-analysis At 6 months: (-1.08, 0.30) = % (-1.04, 0.14) = % Favours CSII, not significant Favours CSII, not significant DeVries (-0.33, 0.07) = (-0.45, -0.05) = At 8 months: Hoogma (-0.42, -0.02) = (-0.54, -0.14) < Type I diabetes - children and/or adolescents At 3-4 months: Doyle (-1.68, -0.12) = (-1.58, -0.02) = Type 2 diabetes - adults At 2-4 months: Berthe (-1.75, -0.05) = (-1.75, -0.05) = Herman (-0.12, 0.52) = (-0.42, 0.22) = Meta-analysis At 5-6 months: (-1.34, 0.79) = % (-1.16, 0.36) = % Favours CSII, not significant Favours CSII, not significant Raskin (-0.35, 0.55) = (-0.54, 0.34) = Any timepoint: Meta-analysis (-0.53, 0.42) = % (-0.55, 0.13) = % Favours CSII, not significant Favours CSII, not significant Abbreviations: CI, confidence interval; CSII, continuous subcutaneous insulin infusion; HbA 1c, glycolylated haemoglobin; MDI, multiple daily injections; WMD, weighted mean difference NOTE: An I2 greater than 50% indicates heterogeneity. a Base case analyses were conducted on all trials that compared CSII and MDI, both with a rapid-acting analogue b HbA 1c levels at endpoint are unadjusted for baseline levels, as per the NICE health technology assessment. c HbA 1c at endpoint is adjusted for baseline levels. The absolute difference in baseline levels between the 2 treatments was applied to the MDI arm as an absolute value. I 2 -

48 34 Table 18: Author & year Glycosylated haemoglobin at endpoint: All included studies, regardless of type of insulin a Unadjusted for baseline HbA 1c level b WMD (95% CI) P- value Type I diabetes children and/or adolescents At 3-4 months: Adjusted for baseline HbA 1c level c I 2 WMD (95% CI) P- value Cohen (-0.92, 0.68) = (-1.02, 0.58) = Doyle (-1.68, -0.12) = (-1.58, -0.02) = Weintrob (-0.53, 0.33) = (-0.23, 0.63) = Meta-analysis At 6 months: (-0.79, 0.16) = % (-0.81, 0.40) = % Favours CSII, not significant Favours CSII, not significant Cohen (-0.20, 0.36) = (-1.20, 0.36) = Type 2 diabetes - adults At 2-4 months: Berthe (-1.75, -0.05) = (-1.75, -0.05) = Herman (-0.12, 0.52) = (-0.42, 0.22) = Wainstein (-1.37, 0.17) = (-1.37, 0.17) = Meta-analysis Any timepoint d : Meta-analysis (-1.09, 0.39) = % (-0.91, 0.09) = % Favours CSII, not significant Favours CSII, not significant (-0.61, 0.29) = % (-0.56, 0.05) = % Favours CSII, not significant Favours CSII, not significant Abbreviations: CI, confidence interval; CSII, continuous subcutaneous insulin infusion; HbA 1c, glycolylated haemoglobin; MDI, multiple daily injections; WMD, weighted mean difference NOTE: An I2 greater than 50% indicates heterogeneity. a All trials were included in the analyses, including those that compared a rapid-acting analogue with short-acting insulin in CSII and MDI. b HbA 1c levels at endpoint are unadjusted for baseline levels, as per the NICE health technology assessment. c HbA 1c at endpoint is adjusted for baseline levels. The absolute difference in baseline levels between the 2 treatments was applied to the MDI arm as an absolute value. d Includes the following studies: Berthe 2007, Herman 2005, Wainstein 2005, Raskin 2003 I 2

49 35 Table 19: Change in glycosylated haemoglobin: Studies comparing the same insulin type with CSII and MDI a Author & year N Difference in change from baseline to endpoint (CSII MDI) Type I diabetes adults At 3-4 months: DeVries % Hoogma % Mean -0.53% Weighted mean -0.37% At 6 months: Favours CSII Hoogma % At 8 months: Hoogma % Type I diabetes children and/or adolescents At 3-4 months: Doyle % Type 2 diabetes - adults At 2-4 months: Berthe % Herman % Mean -0.50% Weighted mean -0.22% At 5-6 months: Favours CSII Raskin % Any timepoint b : Mean -0.39% Weighted mean -0.19% Favours CSII Abbreviations: CI, confidence interval; CSII, continuous subcutaneous insulin infusion; HbA 1c, glycolylated haemoglobin; MDI, multiple daily injections; WMD, weighted mean difference NOTE: The weighted mean was calculated using the number of subjects at end of study in each trial. This approach does not account for duplicate data points for the two treatment phases of crossover design trials. a Base case analyses were conducted on all trials that compared CSII and MDI, both with a rapid-acting analogue. b Includes the following studies: Berthe 2007, Herman 2005, Raskin 2003

50 36 Table 20: Change in glycosylated haemoglobin: All included studies, regardless of type of insulin a Author & year N Difference in change from baseline to endpoint (CSII MDI) Type I diabetes children and/or adolescents At 3-4 months: Cohen % Doyle % Weintrob % Mean -0.25% Weighted mean -0.33% At 6 months: Favours CSII Cohen % Type 2 diabetes - adults At 2-4 months: Berthe % Herman % Wainstein % Mean -0.53% Weighted mean -0.30% Any timepoint b : Favours CSII Mean -0.44% Weighted mean -0.24% Favours CSII Abbreviations: CI, confidence interval; CSII, continuous subcutaneous insulin infusion; HbA 1c, glycolylated haemoglobin; MDI, multiple daily injections; WMD, weighted mean difference NOTE: The weighted mean was calculated using the number of subjects at end of study in each trial. This approach does not account for duplicate data points for the two treatment phases of crossover design trials. a Base case analyses were conducted on all trials that compared CSII and MDI, both with a rapid-acting analogue. b Includes the following studies: Berthe 2007, Herman 2005, Wainstein 2005, Raskin 2003 Lipid levels Only two of the included studies reported the effect of treatment on lipid levels (Berthe et al, 2007; Wainstein et al, 2005). Both studies found no significant difference between CSII and MDI on lipid levels. Quality of life Quality of life was assessed using a variety of instruments across the trials. In general, quality of life data were poorly reported. Adults with type 1 diabetes Quality of life findings are briefly summarised in Table 20. In the study reported by DeVries et al (2002), a significant difference between treatments in favour of CSII was seen for the general health summary score of the SF-36 (change from baseline to

51 37 16 weeks, CSII vs MDI P= 0.048). Although there was a trend in favour of CSII in mental health, this failed to reach statistical significance (P= 0.050). In the Hoogma 2006 study, quality of life was assessed using the 46-item DQoL and SF-12. At endpoint (8 months) quality of life was significantly better after treatment with CSII compared to treatment with MDI (P< 0.001) using the DQoL. The SF-12 showed no difference between treatments in terms of physical health but improved mental health with CSII compared with MDI (P= 0.005). Children and/or adolescents with type 1 diabetes Quality of life was assessed in all three included trials using the DQOLY, which is a questionnaire designed specifically for youth. The Cohen 2003 study found a significant difference in favour of CSII in the satisfaction subscale (P<0.05), but no difference between treatments in the Impact scale and Worry scale. The studies by Doyle (2004) and Weintrob (2003) found no statistically significant difference between treatment modalities. Adults with type 2 diabetes Quality of life was assessed in two of the four trials that compared CSII with MDI in adults with type 2 diabetes. The study reported by Herman et al (2005) assessed quality of life using two instruments, the DQOL clinical trial questionnaire and the SF-36, and found no difference in quality of life in patients treated with CSII or MDI. Although the Raskin 2003 study assessed quality of life, albeit with a non-standard instrument, no true quality of life findings were reported in the publication. Pregnant women with diabetes The Farrar review (2007) made no attempt to evaluate quality of life. Severe hypoglycaemia Severe hypoglycaemia was reported as an outcome in all of the included RCTs. As shown in Table 21, the total number of events was generally low and therefore no attempt has yet been made to conduct a meta-analysis. In studies of type 1 diabetic adults and children/adolescents, the number of severe hypoglycaemic episodes was consistently higher during treatment with MDI compared with CSII. In the studies of adults with type 2 diabetes, two studies reported no events, one reported a higher frequency in the MDI arm and the other study reported a higher incidence of severe hypoglycaemia in the CSII arm. Note that an exclusion criterion in two of the studies was recurrent severe hypoglycaemia. No events occurred in one of these trials whilst the highest number of events (4 with CSII and 12 with MDI) occurred in the other. Ketoacidosis Ketoacidotic events were also uncommon (see Table 21) and therefore no firm conclusions can be drawn. Note that the frequency of ketoacidosis was not reported in three of the four trials in adults with type 2 diabetes.

52 38 Table 21: Data extraction from Level II evidence episodes of severe hypoglycaemia and ketoacidosis Author & year Number of subjects Treatment duration Severe hypoglycaemia Ketoacidosis (months) CSII MDI CSII MDI Type I diabetes - adults DeVries 2002 N=79 CSII N=39, end of phase 1 N=32 MDI N=40, end of phase 1 N=40 Hoogma 2006 N=272, end of study N= episodes per patient year Type I diabetes children and/or adolescents Cohen 2003 N=16, end of study N=12 CSII N=15 MDI N=13 Doyle 2004 N=32 CSII N=16, end of study N=16 MDI N=16, end of study N= episodes 6 episodes 1 episode 1 episode 0.5 episodes per patient year 4 episodes a 0 episodes 6 1 episode 4 episodes 1 episode 0 episodes episodes 5 episodes 1 episode 2 episodes Weintrob 2003 N=23, end of study N= episode 3 episodes 0 episodes 0 episodes Type 2 diabetes - adults Berthe 2007 N=17, end of study N= episodes 0 episodes 0 episodes 0 episodes Herman 2005 N=107 Raskin 2003 N=132 CSII N=53, end of study N=48 MDI N=54, end of study N=50 CSII N=69, end of study N=60 MDI N=63, end of study N= episodes 12 episodes nr nr episodes 0 episodes nr nr Wainstein 2005 N=40, end of study N= subjects 2 subjects nr nr Abbreviations: CI, confidence interval; CSII, continuous subcutaneous insulin infusion; HbA 1c, glycosylated haemoglobin; MDI, multiple daily injections; nr, not reported; ns, not significant; SD, standard deviation NOTE: Study durations reported in weeks were converted to months assuming 30.4 days per month. Studies shown in grey text make comparisons which are confounded (ie, rapid- vs short-acting insulin) a In total, 4 events occurred during the first CSII treatment phase; 2 during run-in and 2 during the treatment phase.

53 39 Economic considerations Results of the literature search The literature search identified five papers which were deemed eligible for the review. However, one of the identified papers has only the abstract available in English (Donlo et al, 2006) and therefore will not be discussed further. Summarised methods and results of the four remaining economic evaluations are presented in Table 22 and Table 23. All four studies address the cost-effectiveness of CSII compared to MDI for patients with Type 1 diabetes. All of the analyses were taken from the perspective of health care funder, which only included direct medical costs. Only one paper disaggregates its study population into the adult and adolescent cohorts (Cohen et al, 2007), while the remaining focus on average characteristics of the population of Type 1 diabetes patients. Table 22: Existing economic evaluations: methods Authors Year Model population Intervention Comparator Time horizon Scuffham P & Carr L 2003 Patients with insulindependent diabetes Roze S, Valentine W J, Zakrzewska KE & Palmer AJ Colquitt JL, Green C, Sidhu MK, Hartwell D & Waugh N Cohen N, Minshall ME, Sharon-Nash L, Zakrzewska K, Valentine WJ & Palmer AJ 2004 Patients with Type 1 diabetes in the UK 2004 Adults with Type 1 diabetes 2007 Adults and adolescents Type 1 Diabetes Mellitus patients CSII MDI 8 years CSII MDI lifetime CSII MDI 4 years CSII MDI lifetime All four studies reported results favouring insulin pump therapy and concluded that CSII could be a worthwhile investment. Two of the evaluations reached their conclusion based upon a cost-utility analysis that incorporated a reduction in diabetic complications and mortality as a result of improved glycaemic control with CSII (Roze et al, 2004; Cohen et al, 2007). Scuffham and Carr (2003) also conducted a cost-utility analysis, based mainly upon a reduction in severe hypoglycaemic events. Finally the National Health Service (NHS) assessment conducted for NICE (Colquitt et al, 2004) reported the cost-effectiveness as costs per severe hypoglycaemic events avoided. The authors have not found a satisfactory method of converting the observed benefits into quality-adjusted life-year (QALY), and hence the cost per QALY is not reported. However, it is clear from the results of the sensitivity analyses that the model results are reasonably dependent upon the model parameters associated with severe hypoglycaemic event rate and %HbA 1c.

54 40 Table 23: Existing economic evaluations: results Authors Year Base-case results Sensitivity analyses: HbA 1c Scuffham P & Carr L Roze S, Valentine W J, Zakrzewska KE & Palmer AJ Colquitt JL, Green C, Sidhu MK, Hartwell D & Waugh N Cohen N, Minshall ME, Sharon-Nash L, Zakrzewska K, Valentine WJ & Palmer AJ ,338 per QALY a Not incorporated in the model ,648 per QALY Base-case: -1.2% ,305-1,526 cost per severe hypoglycaemic event avoided 2007 Adult: A$74,147 per QALY Adolescent: A$74,661 per QALY Sensitivity: -0.51% = 61, Base-case (adult): - 1.2% Sensitivity: -0.51% =A$124,201 a Extracted from Table 5 One-way sensitivity analysis (Scuffham and Carr, 2003) Sensitivity analyses: severe Hypoglycaemic event rate Base-case: Sensitivity: 0.1 = 13,766 Base-case: no difference Sensitivity: 50% reduction = 20,104 Base-case (adult): no difference Sensitivity: 50% reduction =A$63,537 Background to the economic evaluation The objective of the current analysis is to examine the cost-effectiveness of CSII compared with MDI for a patient with type 1 diabetes. The economic model is based mainly on the method and approach presented in the NICE report (Colquitt et al, 2004), with modification to inputs in order to populate the model with New Zealand data wherever available. The section presents the additional costs associated with CSII, followed by the health benefits of this technology, the cost-effectiveness of CSII versus MDI, sensitivity analyses, and then the limitations of the analysis. Cost-effectiveness is presented as the incremental cost per severe hypoglycaemic attack avoided over six years (ie, the pump life-time). The total additional costs of using CSII can also be considered relative to the improvements seen in glycaemic control, and any reduction in diabetic complications that this may confer. This analysis did not attempt to quantify the improvement in the patient s quality of life that may be associated with the replacement of MDI with CSII. Costs incorporated in the model The cost analysis here aims to identify cost differences from switching to CSII from MDI. All costs are measured in 2007 New Zealand dollars (end of 2007 approximately), where required costs are inflated appropriately. The costs captured in these analyses include the cost of: (1) the insulin pump, (2) consumable items, (3) patient educational programmes, (4) patient management, (5) insulin costs, and (6) hypoglycaemic events. This report takes a whole of healthcare system perspective and, therefore, does not capture costs such as patient travel time, patient out of pocket expenses, and intangible costs. Insulin pumps last between four and eight years. In the base case, we assume that the life of the insulin pump is six years. The guaranteed life of a pump is four years in the

55 41 United Kingdom. Roche Diagnostics New Zealand currently offer a four year guarantee for their Accu-Check pumps. In the base-case of this analysis it is assumed that insulin pumps last for six years without breakdown and the associated costs of repair and replacement. Table 24: Item Costs of insulin pump and consumables Cost associated with purchase of an insulin pump: Unit cost a (NZ$) Source Insulin pump $5,625 b Ministry of Health (MoH) Costs of consumable items required: Consumables $1,800 per year MoH a GST inclusive b Accu-check Spirit insulin pump Patients who switch to CSII are required to undertake a one-off education programme to familiarise themselves with blood glucose management using the insulin pump. This training is extensive. There are no published information on the resource use and costs on pump training. New Zealand health authorities provided information on a typical pump training programme. It is acknowledged that the pump training programme could differ across districts health boards. The economic model has drawn on current practice in one district. The educational programme comprises of (1) a prepump training, (2) admission, (3) and follow-up after discharge. The pre-pump component entails a 2-hour meeting with a nurse, 10-hour meetings with a dietician, and a 2-hour meeting with a specialist. The pump candidates are then admitted to a hospital for a monitoring purpose for an average 2 to 3 days, the model assumed 2.5 days (20 hours). After discharge the patients receive an individual follow-up consisting of 6 hours of consultation with a specialist nurse, and 2 hours with a dietician. The cost estimates are shown in Table 25. Table 25: Cost of a patient education programme for CSII Input to educational programme Hours Cost per hour Cost per patient (NZ$) Pre-pump training: Nurse 2 $23 a $46 Dietician 10 $35 b $346 Specialist 2 $69 c $137 Admission: General admission 20 $70 d $1,398 Follow-up: Clinical specialist nurse 6 $35 e $208 Dietician 2 $35 $69 Estimated education cost per patient $2,203 a Registered nurse scale (Step 3) from District Health Boards/ New Zealand Nurses Organisation Multiemployer Nursing/ Midwifery collective agreement. b The clinical specialist nurse hourly rate is a proxy for dietician. c Medical and dental specialists salary scale, New Zealand District Health Boards - Senior Medical and Dental officers Collective agreement, d Hospital Throughput 2003/04 For District Health Boards and their Hospitals, MoH e Senior nurse scale (Grade 4) from District Health Boards/ New Zealand Nurses Organisation Multiemployer Nursing/ Midwifery collective agreement.

56 42 The NHS assessment report estimated that an extra outpatient visit to a specialist would be needed in addition to the patient s regular outpatient appointments as a result of the introduction of CSII. It is anticipated that the visit could occur at 3 months after commencing the pump therapy. Table 26 shows an estimated cost of a one-hour visit to an endocrinologist in the first year. Table 26: Cost of additional outpatient management Additional resources for patient management Additional cost (NZ$) One visit to a specialist $69 a a Medical and dental specialists salary scale, New Zealand District Health Boards - Senior Medical and Dental officers Collective agreement, The meta-analysis by Colquitt et al, 2004 showed that there is a reduction of units of insulin per day with the use of CSII compared to MDI. This reduction equates to a cost saving of $222 per year if fully realised (ie, not allowing for wastage), see Table 27. Table 27: Reduction in daily insulin dose units ( to -3.64) Reduction of insulin use with continuous subcutaneous insulin infusion Source Insulin cost Cost per insulin unit Colquitt et al, 2004 Humalog: 5 x 3-ml (100 units per ml) = $59.52 b $ $222 Annual cost reduction a (NZ$) a GST inclusive b Rapid acting insulin preparations, New Zealand pharmaceutical schedule, December It is postulated that a minor reduction in the number of severe hypoglycaemic events can be expected amongst patients using CSII compared to MDI. However, not all severe hypoglycaemic events have resource implications to healthcare providers because the majority of the events are managed by patients and their carers. Table 28 presents the cost estimates per one severe hypoglycaemic event (Colquitt et al, 2004). Table 28: Treatment Cost of managing a severe hypoglycaemic event Unit cost Proportion of events required treatment (%) Glucagon $25 a 100% $25 Outpatient attendance $156 b 10% $16 Paramedic/ambulance attendance $418 c 5% $21 Average cost per severe $62 hypoglycaemic event a New Zealand pharmaceutical schedule, December Average cost per patient with severe hypoglycaemic event (NZ$) b Inter-District Flow schedules, Operational Policy Framework, MoH c Cost of an ambulance attendance obtained from the Cost of Suicide to Society report, MoH

57 43 Table 29 presents the total incremental costs associated with the introduction of CSII. When excluding cost offsets from this calculation, the total additional cost of CSII compared to MDI, over this period is NZ$9,696. The total cost reduces to $9,412 when cost-offsets are included in the analysis. Table 29: Incremental costs associated with the introduction of CSII over year 1 Item Insulin Pump $5,625 Consumables $1,800 Additional general patient management $69 Additional patient education $2,203 Reduction in insulin usage ($222) Reduction in treatment costs for severe hypoglycaemic events ($62) Incremental Cost Total incremental cost for CSII in year 1 (with cost offsets) a $9,412 a This analysis does not capture the reduction in the use of needles and pens for MDI. While these are legitimate cost-offsets they are likely to be negligible and have little impact on the overall cost and costeffectiveness of CSII. Table 30 presents the total incremental costs associated with the introduction of CSII over six years (the approximated life of the pump). When excluding cost offsets from this calculation the total additional cost of CSII compared to MDI, over this period is $18,696 (undiscounted). The total cost reduces to $16,993 when cost-offsets are included in the analysis. Consumable items are the largest component, which accounts for more than 50% of the total cost. The essential components of the consumables consist of insulin cartridges, infusion sets, and batteries. Table 30: Incremental costs associated with the introduction of CSII over 6-years Item Incremental Cost Insulin Pump $5,625 Consumables $10,800 Additional general patient management $69 Additional patient education $2,203 Reduction in insulin usage ($1,332) Reduction in treatment costs for severe hypoglycaemic events ($371) Total incremental cost over 6 years (undiscounted) $16,993 Total incremental cost over 6 years (discounted) a $15,976 a Discount rate of 5% applied Health benefits incorporated in the economic model It is postulated that the use of CSII reduces the number of severe hypoglycaemic events compared with MDI. However, at this stage the evidence available to support this hypothesis is equivocal. Therefore, the cost effectiveness below should be considered as indicative only. That is, they illustrate the cost-effectiveness should be given reduction in severe hypoglycaemic events be achieved. The model does not incorporate any survival benefit secondary to reduced severe hypoglycaemic events.

58 44 Cost-effectiveness Table 31 presents the incremental cost per severe hypoglycaemic attack avoided per patient per annum, over a 6-year time horizon. This is presented graphically in Figure 1. If a total of 0.10 severe hypoglycaemic attacks were avoided per patient per year the incremental cost-effectiveness ratio (ICER) would be ~NZ$ 31,000. However, if every patient who moved from MDI to CSII therapy avoided one severe hypoglycaemic attack per year, it would decrease the ICER to around $3,000. Table 31: Incremental cost per severe hypoglycaemic event avoided per patient per annum No. of severe hypoglycaemic event avoided per patient per annum a ICER $30,533 $15,236 $10,137 $7,587 $6,057 $5,037 $4,309 $2,998 a Discount rate of 5% applied Figure 1: Incremental cost per severe hypoglycaemic attack avoided over 6 years $70,000 Incremental cost-effectiveness ratio $60,000 $50,000 I C E R $40,000 $30,000 $20,000 $10,000 $ Number of severe hypoglycaemic event avoided per patient per annum Sensitivity analyses The sensitivity analyses examine uncertainty of the key parameters. Figure 2 illustrates the impact of changing the pump price and cost of consumables. Figure 3 illustrates the impact of removing the requirement for a hospital admission for pump training.

59 45 Figure 2: ICER following changes in the pump price and cost of consumables $70,000 Incremental cost-effectiveness ratio $60,000 I C E R $50,000 $40,000 $30,000 $20,000 ICER: base case ICER: -10% decrease in cost of pump and consumables ICER: +10% increase in cost of pump and consumables $10,000 $ Number of severe hypoglycaemic event avoided per patient per annum Figure 3: ICER following removal of the requirement for a hospital admission for pump training $70,000 Incremental cost-effectiveness ratio $60,000 ICER: base case I C E R $50,000 $40,000 $30,000 $20,000 ICER: excluding admission component from educational program $10,000 $ Number of severe hypoglycaemic event avoided per patient per annum

60 46 Limitations of economic evaluation The analysis does not capture any quality of life gain associated with the use of pump rather than regular subcutaneous self injection, although this benefit remains equivocal (Tsui et al, 2001; Barnard and Skinner 2007). CSII also appears to provide a small improvement in glycaemic control (HbA 1c ) over MDI (~0.37% improvement in HbA 1c ). This benefit is not captured in the economic model. In the base-case it would cost a total of NZ$16,000 if this benefit were to be maintained over six years. Furthermore, the economic model does not include any reduction in long-term sequelae of diabetes that may occur due to improved glycaemic control (eg, diabetic retinopathy, amputation, peripheral vascular disease) and their associated costs, quality of life, and survival implications. The reader may wish to refer to the sensitivity analyses of Cohen et al, 2007, and Roze et al, 2004 (see Table 23) that reported the lifetime cost per QALY that would be expected with a change in HbA 1c of this magnitude. This exceeds NZ$100,000.

61 47 Summary and conclusions Summary of evidence for evidence review This report systematically reviewed the international evidence for the effectiveness and safety of CSII compared with MDI, published after the literature search which was conducted in the NHS technology assessment report (Colquitt et al, 2004). The main results are presented below. Adults with type 1 diabetes The literature search conducted for this review update identified one systematic review and two randomised trials that compared CSII with MDI in adults with type 1 diabetes. At all timepoints examined (4, 6, and 8 months), the two trials showed that treatment with CSII was associated with a greater reduction in HbA 1c levels, compared with treatment with MDI. Although the publications reported a statistically significant difference between CSII and MDI in terms of endpoint HbA 1c levels, meta-analysis of baseline adjusted data from the two trials at a common timepoint (four months) favoured CSII but failed to reach statistical significance. Quality of life endpoints were poorly reported but indicate that treatment with CSII may be associated with significantly improved quality of life compared with MDI. The effect of treatment on lipid levels was not reported in either trial. In terms of adverse events, episodes of severe hypoglycaemia were infrequent in both trials but were consistently lower during treatment with CSII compared with MDI. Ketoacidotic events were also uncommon but occurred more frequently during treatment with CSII than MDI. Children and/or adolescents with type 1 diabetes Three randomised trials that compared CSII with MDI in children and/or adolescents with type 1 diabetes were identified in the literature search update. In all three trials, HbA 1c levels were lower at endpoint after CSII than MDI, although the magnitude of the difference was small. Meta-analysis of baseline adjusted data from the three trials at a common timepoint (3-4 months) confirmed the trend in favour of CSII but did not reveal a significant difference between treatment modalities in terms of HbA 1c levels at endpoint. Quality of life was assessed in all three trials using a youth-specific questionnaire. Whilst two studies found no statistically significant difference between CSII and MDI, the third reported a significant difference in favour of CSII in the satisfaction subscale (P< 0.05), but not other subscales. The effect of treatment on lipid levels was not reported. In terms of safety, all three trials reported that episodes of severe hypoglycaemia were less frequent during treatment with CSII compared with MDI. Ketoacidotic events were uncommon with both treatment modalities and therefore no firm conclusions can be drawn. Adults with type 2 diabetes The literature search identified four randomised trials that compared CSII with MDI in adults with type 2 diabetes. In all four trials, the change from baseline in HbA 1c

62 48 levels was greater with CSII than MDI. Meta-analysis of data from the four trials (using the longest timepoint in each trial) confirmed the trend in favour of CSII but the difference was not statistically significant. One of the four trials in adults with type 2 diabetes reported quality of life outcomes and showed no difference between treatment modalities. Of the two studies that reported the effect of treatment on lipid levels, there was no significant difference between CSII and MDI. Overall, the total number of severe hypoglycaemic episodes across the four trials was higher in patients treated with MDI; however, this was driven by only one trial. Two of the trials reported no cases of severe hypoglycaemia and one trial reported more episodes in during treatment with CSII. There was insufficient evidence to draw any conclusions regarding the effect of treatment on the incidence of ketoacidosis. Pregnant women with diabetes The literature search identified one systematic review that compared CSII with MDI in pregnant women with diabetes. In both second and third trimester, HbA 1c levels were lower in women treated with MDI compared with CSII, but the difference was not significant. No other outcomes of relevance were reported in the review and therefore no firm conclusions can be drawn with respect to best practice in pregnant women with diabetes. Summary of results from economic evaluation It is postulated, however unproven, that CSII may reduce the number of severe hypoglycaemic attacks a patient experiences compared with MDI. If CSII were to reduce the number of hypoglycaemic attacks by 0.5 per patient per year, the incremental cost-effectiveness ratio would be ~NZ$6,000 per hypoglycaemic attack avoided over a 6-year time horizon. In addition, based on the clinical evidence the CSII pump appears to improve a patient s HbA 1c by around 0.37% compared to MDI after approximately four months of therapy. It is unknown, but not inconceivable that this benefit will be sustained in the long-term, bringing potential benefits of reduced disease sequelae in the long-term. These benefits come at an additional cost of approximately NZ$16,000 per patient over six years. Limitations of evidence base Systematic reviews are only as good as the quality of the information contained within the included studies. There are many biases that may impact on the internal validity of individual clinical trials such as selection bias, performance bias, detection bias and attrition bias (Egger et al, 2001). Furthermore, many of the included studies were crossover in design and the issue of carryover was not appropriately addressed in the primary publications. The current systematic review of the clinical evidence was limited to studies published after the literature search for the NHS technology assessment report (Colquitt et al, 2004). Meta-analysis of the updated literature with that of the Colquitt et al (2004) report was beyond the scope of this review update. Nevertheless, metaanalysis would not have been appropriate given that Colquitt et al (2004) did not consider differences in baseline levels between treatment arms. When the treatment

63 49 effect is of small magnitude, as is the case with HbA 1c, a true measure of the change from baseline is imperative. In the current update, a number of studies did not report change from baseline to endpoint in HbA 1c, and in those cases it was estimated using the available data. Thus, although all efforts have been made to show whether a true difference exists between CSII and MDI, the results of the meta-analyses must be interpreted with caution. Conclusions This report systematically reviewed the evidence for subcutaneous insulin pump therapy compared with multiple daily injections, published since the NHS assessment report for NICE. In general, the findings of the current review support the findings of the original NHS assessment report, that is, an improvement in glycaemic control that is of small magnitude and borderline statistical significance. When compared with optimised MDI, CSII results in a modest but potentially worthwhile improvement in glycosylated haemoglobin levels in all patient groups assessed (ie, adults with type 1 diabetes, children and adolescents with type 1 diabetes, and adults with type 2 diabetes). Due to the short duration of the clinical trials is not possible to evaluate the longer term benefits of such a difference in HbA 1c levels; however, there is an expectation that it would be reflected in a reduction in long-term complications. Although more immediate primary benefits from CSII may be associated with an impact on the incidence of severe hypoglycaemic events and improved quality of life (through greater flexibility of lifestyle), there is limited evidence to support this from the studies identified in this update. However, despite the limited evidence it is postulated that CSII may reduce the number of severe hypoglycaemic attacks a patient experiences compared with MDI. According to the results of the cost-effectiveness analysis conducted herein, it is estimated that if every patient who changed from MDI to CSII therapy was able to avoid one severe hypoglycaemic attack every two years (ie, 0.5 events per annum), the incremental cost per severe hypoglycaemic event would be approximately $6,000. The total incremental cost associated with the introduction of CSII compared to MDI for a patient with type 1 diabetes is approximately $16,000 over six years (the approximated life of the pump).

64 50 References Agence d'evaluation des technologies et des modes d'intervention en santé (AETMIS). Comparison of the insulin pump and multiple daily insulin injections in intensive therapy for type 1 diabetes. Report prepared by Brigitte Côté and Carole St- Hilaire (AETMIS 04-07). Montréal: AETMIS, 2005, xv-83 p. Barnard KD, Skinner TC. Qualitative study into quality issues surrounding insulin pumps use in type 1 diabetes. Practical Diabetes International 2007;24: Berthe E, Lireux B, Coffin C, Goulet-Salmon B, Houlbert D, Boutreux S et al (2007) Effectiveness of intensive insulin therapy by multiple daily injections and continuous subcutaneous infusion: A comparison study in type 2 diabetes with conventional insulin regimen failure. Horm Metab Res 39(3): Cohen D, Weintrob N, Benzaquen H, Galatzer A, Fayman G, Phillip M (2003) Continuous subcutaneous insulin infusion versus multiple daily injections in adolescents with type I diabetes mellitus: a randomized open crossover trial. Journal of pediatric endocrinology & metabolism: JPEM 16: Cohen N, Minshall ME, Sharon-Nash L, Zakrzewska K, Valentine WJ, Palmer AJ. Economic comparison in adult and adolescent Type 1 diabetes mellitus in Australia. Pharmacoeconomics 2007;25: Colquitt JL, Green C, Sidhu MK, Hartwell D, Waugh N. Clinical and costeffectiveness of continuous subcutaneous insulin infusion for diabetes. Health Technology Assessment 2004;8(43). DeVries JH, Snoek FJ, Kostense PJ, Masurel N, Heine RJ (2002) A randomized trial of continuous subcutaneous insulin infusion and intensive injection therapy in type 1 diabetes for patients with long-standing poor glycemic control. Diabetes Care 25(11): Donlo IC, Contreras DS, Barrios JMR, Mizrahi IL, Abat CC, Roze S. Cost-utility analysis of insulin pumps compared to multiple daily doses of insulin in patients with type 1 diabetes mellitus in Spin. Rev Esp Salud Pública 2006;80: Doyle EA, Weinzimer SA, Steffen AT, Ahern JAH, Vincent M, Tamborlane WV (2004) A randomized, prospective trial comparing the efficacy of continuous subcutaneous insulin infusion with multiple daily injections using insulin glargine. Diabetes Care 27(7): Egger, M., Dickersin, K. and Davey Smith, G. Problems and limitations in conducting systematic reviews. In Systematic Reviews in Health Care: Meta-analysis in Context. BMJ Publishing Group.London, UK Farrar D, Tuffnell DJ, West J (2007) Continuous subcutaneous infusion versus multiple daily injections of insulin for pregnant women with diabetes. Cochrane Database of Systematic Reviews, Issue 3, Art. No.: CD DOI: / CD pub2.

65 51 Herman WH, Ilag LL, Johnson SL, Martin CL, Sinding J, Al Harthi A et al (2005) A clinical trial of continuous subcutaneous insulin infusion versus multiple daily injections in older adults with type 2 diabetes. Diabetes Care 28(7): Hoogma RPLM, Hammond PJ, Gomis R, Kerr D, Bruttomesso D, Bouter KP et al (2006) Comparison of the effects of continuous subcutaneous insulin infusion (CSII) and NPH-based multiple daily insulin injections (MDI) on glycaemic control and quality of life: Results of the 5-nations trial. Diabetic Med 23(2): Mulrow CD and Oxman A (1997) Cochrane Collaboration Handbook [updated Sept 1997]. Oxford: The Cochrane Collaboration. NHMRC (1999) A guide to the development, implementation and evaluation of clinical practice guidelines. Canberra: NHMRC. NHMRC (2000a) How to review the evidence: systematic identification and review of the scientific literature. Canberra: NHMRC. NHMRC (2000b) How to use the evidence: assessment and application of scientific evidence. Canberra: NHMRC. NHMRC (2005) Interim Levels of Evidence. Canberra: NHMRC Raskin P, Bode BW, Marks JB, Hirsch IB, Weinstein RL, McGill JB et al (2003) Continuous subcutaneous insulin infusion and multiple daily injection therapy are equally effective in type 2 diabetes: A randomized, parallel-group, 24-week study. Diabetes Care 26(9): Retnakaran R, Hochman J, Devries JH, Hanaire-Broutin H, Heine RJ, Melki V et al (2004) Continuous subcutaneous insulin infusion versus multiple daily injections: The impact of baseline A 1c. Diabetes Care 27(11): Roze S, Valentine WJ, Zakrzewska KE, Palmer AJ. Health-economic comparison of continuous subcutaneous insulin infusion with multiple daily injection for the treatment of type 1 diabetes in the UK. Diabetic Medicine 2005;22: Scuffham P, Carr L. The cost effectiveness of continuous subcutaneous insulin infusion compared with multiple daily injection for the management of diabetes. Diabetic Medicine 2003;20: Tsui E, Barnie A, Ross S, Parkes R, Zinman B. Intensive insulin therapy with insulin lispro: a randomized trial of continuous subcutaneous insulin infusion versus multiple daily insulin injection. Diabetes Care 2001;24: Wainstein J, Metzger M, Boaz M, Minuchin O, Cohen Y, Yaffe A et al (2005) Insulin pump therapy vs. multiple daily injections in obese Type 2 diabetic patients. Diabetic Med 22(8):

66 52 Weintrob N, Benzaquen H, Galatzer A, Shalitin S, Lazar L, Fayman G et al (2003) Comparison of continuous subcutaneous insulin infusion and multiple daily injection regimens in children with type 1 diabetes: A randomized open crossover trial. Pediatrics 112(3 I): Weintrob N, Schechter A, Benzaquen H, Shalitin S, Lilos P, Galatzer A et al (2004) Glycemic patterns detected by continuous subcutaneous glucose sensing in children and adolescents with type 1 diabetes mellitus treated by multiple daily injections vs continuous subcutaneous insulin infusion. Arch Pediatr Adolesc Med 158(7):

67 53 Glossary Continuous subcutaneous insulin infusion (CSII): A portable device for people with diabetes that injects insulin at programmed intervals in order to regulate blood sugar levels. The device includes the pump itself (including controls, processing module, and batteries), a disposable reservoir for insulin (inside the pump), a disposable infusion set, including a cannula for subcutaneous insertion (under the skin) and a tubing system to interface the insulin reservoir to the cannula. An insulin pump is an alternative to multiple daily injections of insulin by insulin syringe or an insulin pen and allows for intensive insulin therapy when used in conjunction with blood glucose monitoring and carbohydrate counting. Cost effectiveness (CE): Involves the relationship between costs and effects, providing information on whether a technology is being delivered to those who would benefit from it with an optimal use of resources. It is expressed as a ratio of the effects (number of lives saved, number of disability days avoided) obtained for a specific cost (expressed in dollars). For example, the numerator may be the difference in lifetime costs between one intervention and another, while the denominator may be the difference in life expectancies associated with the two interventions. Low cost effectiveness ratios are desirable. Evidence based: Based on valid empirical information. Glycosylated haemoglobin, also known as haemoglobin A 1c (HbA 1c ): Haemoglobin to which glucose is bound. HbA 1c is widely used in clinical and research settings as a standard indicator of the quality of glycaemic control over the past two or three months. The glucose stays attached to haemoglobin for the life of the red blood cell (normally about 120 days), and therefore the level of HbA 1c reflects the average blood glucose level over the past 3 months. The normal level for HbA 1c is less than 7%. Red blood cells of individuals with poorly controlled diabetes have high levels of HbA 1c. Grey literature: That which is produced by all levels of government, academics, business and industry, in print and electronic formats, but which is not controlled by commercial publishers. Heterogeneous: A sample that is diverse in kind or nature; comprised of diverse patients/ subjects/individuals/communities that are unrelated or unlike each other. Homogeneous: A sample comprising the same kind of patients/ subjects/ individuals/ communities. Having the same kind of characteristics, being similar and relatively uniform. Meta-analysis: The process of using statistical methods to combine the results of different studies. Optimised multiple daily injections (MDI): An intensive therapeutic regimen for insulin-dependent diabetes, which attempts to mimic the pattern of small continuous basal insulin secretion of a working pancreas combined with larger insulin secretions

68 54 at mealtimes. Requires at least three daily injections of insulin by insulin syringe or an insulin pen. Randomised controlled trial: An epidemiologic experiment in which subjects in a population are randomly allocated into groups to receive or not receive an experimental preventive or therapeutic procedure, manoeuvre, or intervention. Randomised controlled trials are generally regarded as the most scientifically rigorous method of hypothesis testing available in epidemiology. Type 1 diabetes: Type 1 diabetes indicates that there has been a process of destruction of the beta cells of the pancreas, leading to insulin deficiency. Eventually, insulin is required for survival in order to prevent the development of ketoacidosis and death. There is usually a process of autoimmunity with autoantibodies, but these are not seen in all patients. The cause is unknown. Type 2 diabetes: Type 2 diabetes is more common, and is characterised by insulin resistance and insulin deficiency. The deficiency may be relative to insulin needs, rather than absolute, and there may be higher than normal production of insulin at some stages. Type 2 diabetes is linked to overweight and obesity and to physical inactivity.

69 55 Appendix A: Included Studies (1) Berthe E, Lireux B, Coffin C, Goulet-Salmon B, Houlbert D, Boutreux S et al (2007) Effectiveness of intensive insulin therapy by multiple daily injections and continuous subcutaneous infusion: A comparison study in type 2 diabetes with conventional insulin regimen failure. Horm Metab Res 39(3): (2) Cohen D, Weintrob N, Benzaquen H, Galatzer A, Fayman G, Phillip M (2003) Continuous subcutaneous insulin infusion versus multiple daily injections in adolescents with type I diabetes mellitus: a randomized open crossover trial. Journal of pediatric endocrinology & metabolism: JPEM 16: (3) DeVries JH, Snoek FJ, Kostense PJ, Masurel N, Heine RJ (2002) A randomized trial of continuous subcutaneous insulin infusion and intensive injection therapy in type 1 diabetes for patients with long-standing poor glycemic control. Diabetes Care 25(11): (4) Doyle EA, Weinzimer SA, Steffen AT, Ahern JAH, Vincent M, Tamborlane WV (2004) A randomized, prospective trial comparing the efficacy of continuous subcutaneous insulin infusion with multiple daily injections using insulin glargine. Diabetes Care 27(7): (5) Farrar D, Tuffnell DJ, West J (2007) Continuous subcutaneous infusion versus multiple daily injections of insulin for pregnant women with diabetes. Cochrane Database of Systematic Reviews, Issue 3, Art. No.: CD DOI: / CD pub2. (6) Herman WH, Ilag LL, Johnson SL, Martin CL, Sinding J, Al Harthi A et al (2005) A clinical trial of continuous subcutaneous insulin infusion versus multiple daily injections in older adults with type 2 diabetes. Diabetes Care 28(7): (7) Hoogma RPLM, Hammond PJ, Gomis R, Kerr D, Bruttomesso D, Bouter KP et al (2006) Comparison of the effects of continuous subcutaneous insulin infusion (CSII) and NPH-based multiple daily insulin injections (MDI) on glycaemic control and quality of life: Results of the 5-nations trial. Diabetic Med 23(2): (8) Raskin P, Bode BW, Marks JB, Hirsch IB, Weinstein RL, McGill JB et al (2003) Continuous subcutaneous insulin infusion and multiple daily injection therapy are equally effective in type 2 diabetes: A randomized, parallel-group, 24-week study. Diabetes Care 26(9): (9) Retnakaran R, Hochman J, Devries JH, Hanaire-Broutin H, Heine RJ, Melki V et al (2004) Continuous subcutaneous insulin infusion versus multiple daily injections: The impact of baseline A 1c. Diabetes Care 27(11): (10) Wainstein J, Metzger M, Boaz M, Minuchin O, Cohen Y, Yaffe A et al (2005) Insulin pump therapy vs. multiple daily injections in obese Type 2 diabetic patients. Diabetic Med 22(8): (11) Weintrob N, Benzaquen H, Galatzer A, Shalitin S, Lazar L, Fayman G et al (2003) Comparison of continuous subcutaneous insulin infusion and multiple daily injection

70 56 regimens in children with type 1 diabetes: A randomized open crossover trial. Pediatrics 112(3 I): (12) Weintrob N, Schechter A, Benzaquen H, Shalitin S, Lilos P, Galatzer A et al (2004) Glycemic patterns detected by continuous subcutaneous glucose sensing in children and adolescents with type 1 diabetes mellitus treated by multiple daily injections vs continuous subcutaneous insulin infusion. Arch Pediatr Adolesc Med 158(7):

71 57 Appendix B: Excluded Studies Annotated by Reason for Exclusion 1. (2003) Education for continuous subcutaneous insulin infusion pump users. The Diabetes educator 29: (2003) Insulin aspart and biphasic insulin aspart provide flexible and convenient administration. Drugs and Therapy Perspectives 19: (2003) Continuous subcutaneous insulin infusion. Diabetes Care 26:S (2004) Resource guide Insulin delivery. Diabetes forecast 57:RG , RG (2004) Continuous Subcutaneous Insulin Infusion. Diabetes Care 27:S (2004) Insulin therapy is associated with skin-related complications that influence glycaemic control. Drugs and Therapy Perspectives 20: (2004) Type 1 diabetes in adolescents: A challenging patient group to manage. Drugs and Therapy Perspectives 20: (2005) American Diabetes Association. Resource guide Insulin delivery. Diabetes forecast 58:RG16, RG19-RG16, RG HAYES and Inc. (2001) Insulin pumps, implantable (Brief record) HAYES and Inc. (2003) Insulin pumps, external (Brief record) HAYES and Inc. (2006) Inhaled insulin for type 1 diabetes (Brief record) National-Institute-for-Clinical-Excellence. (2003) Guidance on the use of continuous subcutaneous insulin infusion for diabetes (Structured abstract). NICE. Notes: Abstract/title: The current review update is based on the NHS technology assessment report that underpins this guidance 13. -The-National-Coordinating-Centre-for-Health-Technology-Assessment-. (2004) The clinical effectiveness and cost effectiveness of insulin pump therapy. Technology Assessment Report (project) (Brief record). NICE. Notes: Abstract/title: The current review update is based on this NHS technology assessment report for NICE 14. -Unidad-de-Evaluacion-de-Tecnologias-Sanitarias. (2003) Continuous subcutaneous insulin infusion for the treatment of diabetes mellitus: indications (Brief record). Notes: Abstract/title: Excluded. Not in english 15. Abid S, Mumtaz K, Jafri W, Hamid S, Abbas Z, Shah HA, and Khan AH. (2005) Pill-induced esophageal injury: Endoscopic features and clinical outcomes. Endoscopy 37: Abourizk NN, Vora CK, and Verma PK. (2004) Inpatient diabetology: The new frontier. Journal of General Internal Medicine 19: Acerini CL and Deeb A. (2004) New approaches to insulin therapy in children and adolescents with type 1 diabetes. British Journal of Diabetes and Vascular Disease 4: Admon G, Weinstein Y, Falk B, Weintrob N, Benzaquen H, Ofan R, Fayman G, Zigel L, Constantini N, and Phillip M. (2005) Exercise with and without an insulin pump among children and adolescents with type 1 diabetes mellitus. Pediatrics. 116:e348-e355. Notes: Abstract/title: Excluded. Wrong intervention 19. Agra Y, Pelayo M, Sacristan M, Sacristán A, Serra C, and Bonfill X. (2003) Chemotherapy versus best supportive care for extensive small cell lung cancer. Agra. Y, Pelayo. M., Sacristan. M., Sacristán. A, Serra. C, Bonfill. X. Chemotherapy versus. best supportive care for extensive. small cell lung cancer. Cochrane Database of Systematic Reviews: Reviews Issue. 4 John. Wiley. & Sons., Ltd. Chichester, UK DOI. : 10. Notes: Abstract/title: Excluded. Wrong patient group 20. Ahern JAH, Boland EA, Doane R, Ahern JJ, Rose P, Vincent M, and Tamborlane WV. (2002) Insulin pump therapy in pediatrics: A therapeutic alternative to safely lower HbA1c levels across all age groups. Pediatric Diabetes

72 58 3: Ahmed Z, Lockhart CH, Weiner M, and Klingensmith G. (2005) Advances in diabetic management: Implications for anesthesia. Anesthesia and Analgesia 100: Akalin S. (2006) How to start insulin treatment: Earlier or delayed insulin therapy. Diabetes Research and Clinical Practice 74:S17-S Akatsuka K, Wasaka T, Nakata H, Kida T, and Kakigi R. (2007) The effect of stimulus probability on the somatosensory mismatch field. Experimental Brain Research 181: Al Mallah M, Bazari RN, Jankowski M, and Hudson MP. (2007) Predictors and outcomes associated with gastrointestinal bleeding in patients with acute coronary syndromes. Journal of Thrombosis and Thrombolysis 23: Al Tureihi FIJ, Hassoun A, Wolf-Klein G, and Isenberg H. (2005) Albumin, length of stay, and proton pump inhibitors: Key factors in Clostridium difficile - Associated disease in nursing home patients. Journal of the American Medical Directors Association 6: Albisser AM, Harris R, I, Albisser JB, and Sperlich M. (2001) The impact of initiatives in education, selfmanagement training, and computer-assisted self-care on outcomes in diabetes disease management (Structured abstract). Diabetes Technology and Therapeutics 3: Albisser AM, Alejandro R, Meneghini LF, and Ricordi C. (2005) How good is your glucose control? Diabetes Technology and Therapeutics 7: Alemzadeh R, Loppnow C, Parton E, and Kirby M. (2003) Glucose sensor evaluation of glycemic instability in pediatric type 1 diabetes mellitus. Diabetes Technology and Therapeutics 5: Alemzadeh R, Ellis JN, Holzum MK, Parton EA, and Wyatt DT. (2004) Beneficial effects of continuous subcutaneous insulin infusion and flexible multiple daily insulin regimen using insulin glargine in type 1 diabetes. Pediatrics. 114:e91-e Alemzadeh R, Palma-Sisto P, Parton EA, and Holzum MK. (2005) Continuous subcutaneous insulin infusion and multiple dose of insulin regimen display similar patterns of blood glucose excursions in pediatric type 1 diabetes. Diabetes Technology and Therapeutics 7: Alemzadeh R, Palma SP, Parton EA, and Holzum MK. (2005) Continuous subcutaneous insulin infusion and multiple dose of insulin regimen display similar patterns of blood glucose excursions in pediatric type 1 diabetes. Diabetes technology & therapeutics 7: Alisky JM. (2006) Dexamethasone could improve myocardial infarction outcomes and provide new therapeutic options for non-interventional patients. Medical Hypotheses 67: Almbrand B, Johannesson M, Sjostrand B, Malmberg K, and Ryden L. (2000) Cost-effectiveness of intense insulin treatment after acute myocardial infarction in patients with diabetes mellitus: results from the DIGAMI study (Structured abstract). European Heart Journal 21: Amate-Blanco JM, Van den Eynde AM, Saz Z, and Conde-Olasagasti JL. (2000) Efficacy of insulin infusion pumps. Impact on the quality of life of certain patients. IPE-00/27 (Public report) (Structured abstract). Notes: Abstract/title: Excluded. Not in english 35. Andersen NH, Hansen TK, and Christiansen JS. (2007) Changes in glycaemic control are related to the systolic function in type 1 diabetes mellitus. Scandinavian Cardiovascular Journal 41: Anderson RE, Brismar K, Barr G, and Ivert T. (2005) Effects of cardiopulmonary bypass on glucose homeostasis after coronary artery bypass surgery. European journal of cardio thoracic surgery : official journal of the European Association for Cardio thoracic Surgery 28: Notes: Abstract/title: Excluded. Wrong intervention 37. Anim SM, Smyth R, and Howell C. (2005) Epidural versus non-epidural or no analgesia in labour. Anim Somuah. M., Smyth. R, Howell. C. Epidural. versus. non epidural. or. no analgesia in labour. Cochrane Database of Systematic Reviews: Reviews Issue. 4 John. Wiley. & Sons., Ltd. Chichester, UK DOI. : / CD pub2. Notes: Abstract/title: Excluded. Wrong patient group

73 Anthony S, Odgers T, and Kelly W. (2004) Health promotion and health education about diabetes mellitus. Journal of The Royal Society for the Promotion of Health 124: Apte MV and Wilson JS. (2003) Alcohol-induced pancreatic injury. Bailliere's Best Practice and Research in Clinical Gastroenterology 17: Apte MV, Pirola RC, and Wilson JS. (2004) Pancreatitis in the older adult. Geriatrics and Aging 7: Arcaro G, Cretti A, Balzano S, Lechi A, Muggeo M, Bonora E, and Bonadonna RC. (2002) Insulin causes endothelial dysfunction in humans: Sites and mechanisms. Circulation 105: Artal R. (2003) Exercise: The alternative therapeutic intervention for gestational diabetes. Clinical Obstetrics and Gynecology 46: Ashraf W, Wong DT, Ronayne M, and Williams D. (2004) Guidelines for preoperative administration of patients' home medications. Journal of Perianesthesia Nursing 19: Attali JR. (2006) CSII in type 2 diabetic patients. Diabetes Research and Clinical Practice 74:S116-S Au S, Courtney CH, Ennis CN, Sheridan B, Atkinson AB, and Bell PM. (2005) The effect of manipulation of basal pulsatile insulin on insulin action in Type 2 diabetes. Diabetic Medicine 22: Avenell A and Handoll HHG. (2006) Nutritional supplementation for hip fracture aftercare in older people. Avenell. A, Handoll. HHG. Nutritional supplementation. for hip. fracture. aftercare. in older. people. Cochrane Database of Systematic Reviews: Reviews Issue. 4 John. Wiley. & Sons., Ltd. Chichester, UK DOI. : / CD pub4. Notes: Abstract/title: Excluded. Wrong patient group 47. Bailey CJ, Del Prato S, Eddy D, Zinman B, Albetti G, Aschner PP, Blonde L, Felton AM, Goldstein B, Gomis R, Horton E, LaSalle J, Lee HK, Leiter L, Matthaei S, McGill M, Munro N, Nesto R, and Zimmet P. (2005) Earlier intervention in type 2 diabetes: The case for achieving early and sustained glycaemic control. International Journal of Clinical Practice 59: Barlow S, Crean J, Heizler A, Mulcahy K, and Springer J. (2005) Diabetes educators: Assessment of evolving practice. Diabetes Educator 31: Barnard KD, Lloyd CE, and Skinner TC. (2007) Systematic literature review: Quality of life associated with insulin pump use in type 1 diabetes. Diabetic Medicine 24: Notes: Abstract/title: Included. Full paper: Exclude. Wrong comparator. Level I evidence, no additional studies identified. 50. Barnett AH. (2006) Insulin glargine in the treatment of type 1 and type 2 diabetes. Vascular Health and Risk Management 2: Barrio Castellanos R. (2005) Long-acting insulin analogues (insulin glargine or determir) and continuous subcutaneous insulin infusion in the treatment of type 1 diabetes mellitus in the paediatric population. Journal of Pediatric Endocrinology and Metabolism 18: Battaglia MR, Alemzadeh R, Katte H, Hall PL, and Perlmuter LC. (2006) Brief report: Disordered eating and psychosocial factors in adolescent females with type 1 diabetes mellitus. Journal of Pediatric Psychology 31: Battcock T and Oswell A. (2005) The ageing oesophagus: Physiology and pathology. CME Journal Geriatric Medicine 7: Battelino T, Ursic-Bratina N, Bratanic N, Zerjav-Tansek M, Avbelj M, and Krzisnik C. (2004) The use of continuous subcutaneous insulin infusion (CSII) as the treatment of choice in children and adolescents with type 1 diabetes. Pediatric Endocrinology Reviews 1: Battelino T. (2006) Risk and benefits of continuous subcutaneous insulin infusion (CSII) treatment in school children and adolescents. Pediatric Diabetes 7: Baumgartner I. (2005) Systemic antiatherosclerotic treatment for the peripheral arterial occlusive disease patient. Expert Opinion on Pharmacotherapy 6:

74 Beaumont H and Boeckxstaens G. (2007) Recent developments in esophageal motor disorders. Current Opinion in Gastroenterology 23: Beck A, Salem K, Krischak G, Kinzl L, Bischoff M, and Schmelz A. (2005) Nonsteroidal anti-inflammatory drugs (NSAIDs) in the perioperative phase in traumatology and orthopedics. Effects on bone healing. Operative Orthopadie und Traumatologie 17: Begue RE, Gomez R, Compton T, and Vargas A. (2002) Effect of Helicobacter pylori eradication in the glycemia of children with type 1 diabetes: A preliminary study. Southern Medical Journal 95: Belhoula M, Ciébiéra JP, De La CA, Boisseau N, Coeurveille D, and Raucoules AM. (2003) Clonidine premedication improves metabolic control in type 2 diabetic patients during ophthalmic surgery. British journal of anaesthesia 90: Notes: Abstract/title: Excluded. Wrong intervention 61. Belicar PS, Vague P, and Lassmann-Vague V. (2003) Reproducibility of plasma insulin kinetics during intraperitoneal insulin treatment by programmable pumps. Diabetes and Metabolism 29: Beltrand J, Guilmin-Crepon S, Castanet M, Peuchmaur M, Czernichow P, and Levy-Marchal C. (2006) Insulin allergy and extensive lipoatrophy in child with type 1 diabetes. Hormone Research 65: Bendtson I. (2006) Continuous subcutaneous insulin infusion (CSII) - Danish experiences. Diabetes Research and Clinical Practice 74:S127-S Benedict B, Keyes R, and Sauls FC. (2004) The insulin pump as murder weapon: A case report. American Journal of Forensic Medicine and Pathology 25: Benhamou PY, Melki V, Boizel R, Perreal F, Quesada JL, Bessieres-Lacombe S, Bosson JL, Halimi S, and Hanaire H. (2007) One-year efficacy and safety of Web-based follow-up using cellular phone in type 1 diabetic patients under insulin pump therapy: the PumpNet study. Diabetes and Metabolism 33: Notes: Abstract/title: Excluded. Wrong comparator 66. Bent S, Padula A, and Avins AL. (2006) Brief communication: Better ways to question patients about adverse medical events. A randomized, controlled trial. Annals of internal medicine 144: Notes: Abstract/title: Excluded. Wrong patient group 67. Berhe T, Postellon D, Wilson B, and Stone R. (2006) Feasibility and safety of insulin pump therapy in children aged 2 to 7 years with type 1 diabetes: a retrospective study. Pediatrics. 117: Berlin KS, Davies WH, Jastrowski KE, Hains AA, Parton EA, and Alemzadeh R. (2006) Contextual assessment of problematic situations identified by insulin pump using adolescents and their parents. Families, Systems and Health 24: Berthe E, Lireux B, Coffin C, Goulet-Salmon B, Houlbert D, Boutreux S, Fradin S, and Reznik Y. (2007) Effectiveness of intensive insulin therapy by multiple daily injections and continuous subcutaneous infusion: A comparison study in type 2 diabetes with conventional insulin regimen failure. Hormone and Metabolic Research 39: Notes: Abstract/title: Included. 70. Beyan C, Kaptan K, Cetin T, and Nevruz O. (2002) Severe hyperglycemia as a complication of big ICE chemotherapy in a patient with acute myeloblastic leukemia. Haematologia 32: (case report) 71. Bharucha T, Brown J, McDonnell C, Gebert R, McDougall P, Cameron F, Werther G, and Zacharin M. (2005) Neonatal diabetes mellitus: Insulin pump as an alternative management strategy. Journal of paediatrics and child health. 41: (case report) 72. Bharucha T, Brown J, McDonnell C, Gebert R, McDougall P, Cameron F, Werther G, and Zacharin M. (2005) Neonatal diabetes mellitus: Insulin pump as an alternative management strategy. Journal of Paediatrics and Child Health 41: (case report) 73. Bierschbach JL, Cooper L, and Liedl JA. (2004) Insulin pumps: what every school nurse needs to know. The Journal of school nursing : the official publication of the National Association of School Nurses 20: (case report) 74. Biesenbach G, Grafinger P, and Raml A. (2006) Improvement of glycemic control after a 3-5 day insulin infusion in type 2-diabetic patients with insulin resistance can be maintained with glitazone therapy. Wiener Klinische Wochenschrift 118: Notes: Abstract/title: Excluded. Wrong comparator

75 Billington E, Fraser T, Tawashy A, and Tildesley HD. (2007) Carbohydrate counting vs. sliding scale for insulin dosage estimation. Canadian Journal of Diabetes 31: Notes: Abstract/title: Excluded. Wrong comparator 76. Bin-Abbas BS, Sakati NA, Raef H, and Al Ashwal AA. (2005) Continuous subcutaneous insulin infusion in type 1 diabetic Saudi children. A comparison with conventional insulin therapy. Saudi Medical Journal 26: Bin-Abbas BS, Al Fares A, Sakati NA, and Al Ashwal AA. (2006) Continuous subcutaneous insulin infusion in type 1 diabetic Saudi children: Two-year follow-up. Current Pediatric Research 10: Bin-Abbas BS, Al Fares A, Sakati NA, and Al Ashwal AA. (2006) Comparison of insulin pump and multiple daily injection regimens in type 1 diabetic patients. Current Pediatric Research 10: Blackstone R, Kieran J, Davis M, and Rivera L. (2007) Continuous perioperative insulin infusion therapy for patients with type 2 diabetes undergoing bariatric surgery. Surgical Endoscopy 21: Bode B, Weinstein R, Bell D, McGill J, Nadeau D, Raskin P, Davidson J, Henry R, Huang WC, and Reinhardt RR. (2002) Comparison of insulin aspart with buffered regular insulin and insulin lispro in continuous subcutaneous insulin infusion: A randomized study in type 1 diabetes. Diabetes Care 25: Notes: Abstract/title: Included. Full paper: Exclude. Wrong comparator (all subjects received CSII) 81. Bode BW, Tamborlane WV, and Davidson PC. (2002) Insulin pump therapy in the 21st century: Strategies for successful use in adults, adolescents, and children with diabetes. Postgraduate Medicine 111: Bode BW, Sabbah HT, Gross TM, Fredrickson LP, and Davidson PC. (2002) Diabetes management in the new millennium using insulin pump therapy. Diabetes/Metabolism Research and Reviews 18:S14-S Bode BW, Steed RD, Schleusener DS, and Strange P. (2005) Switch to multiple daily injections with insulin glargine and insulin lispro from continuous subcutaneous insulin infusion with insulin lispro: a randomized, open-label study using a continuous glucose monitoring system. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 11: Notes: Abstract/title: Excluded. Wrong intervention 84. Bode BW, Steed RD, Schleusener DS, and Strange P. (2005) Switch to multiple daily injections with insulin glargine and insulin lispro from continuous subcutaneous insulin infusion with insulin lispro: A randomized, open-label study using a continuous glucose monitoring system. Endocrine Practice 11: Notes: Abstract/title: Excluded. Wrong intervention 85. Bolli GB. (2002) Clinical strategies for controlling peaks and valleys: Type 1 diabetes. International Journal of Clinical Practice, Supplement -: Bolli GB. (2003) Rational use of insulin analogues in the treatment of Type 1 diabetes mellitus. Pediatric Endocrinology Reviews 1: Bolli GB, Capani F., Home P.D., Kerr D, Thomas R., Torlone E., and et al. (2004) Comparison of insulin aspart with buffered regular insulin and insulin lispro in continuous subcutaneous insulin infusion: a randomised, open, parallel study. American Diabetes Association455-P. Notes: Abstract/title: Included. Full paper: Exclude. Wrong study type (conference abstract only) 88. Bolli GB. (2006) Insulin treatment in type 1 diabetes. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 12 Suppl 1: Bolli GB. (2006) Long-term intervention studies using insulin in patients with type 1 diabetes. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 12 Suppl 1: Bolli GB. (2006) Insulin treatment in type 1 diabetes. Endocrine Practice 12: Bonhomme V, Hans P, and Brichant JF. (2006) Head trauma. Acta Anaesthesiologica Belgica 57: Bott OJ, Hoffmann I, Bergmann J, Kosche P, von Ahn C, Mattfeld DC, Schnell O, and Pretschner DP. (2006) Simulation based cost-benefit analysis of a telemedical system for closed-loop insulin pump therapy of diabetes. Studies in health technology and informatics 124: Boullu-Sanchis S, Ortega F, Chabrier G, Busch MS, Uhl C, Pinget M, and Jeandidier N. (2006) Efficacy of short term continuous subcutaneous insulin lispro versus continuous intravenous regular insulin in poorly controlled, hospitalized, type 2 diabetic patients. Diabetes and Metabolism 32: Notes: Abstract/title: Excluded. Wrong intervention

76 Boullu SS, Ortega F, Chabrier G, Busch MS, Uhl C, Pinget M, and Jeandidier N. (2006) Efficacy of short term continuous subcutaneous insulin lispro versus continuous intravenous regular insulin in poorly controlled, hospitalized, type 2 diabetic patients. Diabetes & metabolism 32: Notes: Abstract/title: Excluded. Wrong intervention 95. Boyce HW and Bakheet MR. (2005) Sialorrhea: A review of a vexing, often unrecognized sign of oropharyngeal and esophageal disease. Journal of Clinical Gastroenterology 39: Braun F, Broering D, and Faendrich F. (2007) Small intestine transplantation today. Langenbeck's Archives of Surgery 392: Brentnall TA. (2005) Management strategies for patients with hereditary pancreatic cancer. Current Treatment Options in Oncology 6: Broers S, Van Vliet KP, Everaerd W, Le Cessie S, and Radder JK. (2002) Modest contribution of psychosocial variables to hypoglycaemic awareness in Type 1 diabetes. Journal of Psychosomatic Research 52: Brunton SA, Davis SN, and Renda SM. (2006) Overcoming psychological barriers to insulin use in type 2 diabetes. Clinical Cornerstone 8:S19-S Brunton SA. (2007) Nocturnal hypoglycemia: Answering the challenge with long-acting insulin analogs. MedGenMed Medscape General Medicine 9. Notes: Abstract/title: Excluded. Wrong intervention 101. Bruttomesso D, Pianta A, Crazzolara D, Scaldaferri E, Lora L, Guarneri G, Mongillo A, Gennaro R, Miola M, Moretti M, Confortin L, Beltramello GP, Pais M, Baritussio A, Casiglia E, and Tiengo A. (2002) Continuous subcutaneous insulin infusion (CSII) in the veneto region: Efficacy, acceptability and quality of life. Diabetic Medicine 19: Bruttomesso D, Costa S, Crazzolara D, Di Bartolo P, Girelli A, Tiengo A, and Italian Study Group on Diffusion of CSII. (2006) Continuous subcutaneous insulin infusion (CSII) in Italy. Diabetes Research and Clinical Practice 74:S130- S Bucher P, Oulhaci W, Morel P, Ris F, and Huber O. (2007) Results of conservative treatment for perforated gastroduodenal ulcer in patients not eligible for surgical repair. Swiss Medical Weekly 137: Bui H and Daneman D. (2006) Type 1 diabetes in childhood. Medicine 34: Bulsara MK, Holman CDJ, Davis EA, and Jones TW. (2004) The impact of a decade of changing treatment on rates of severe hypoglycemia in a population-based cohort of children with type 1 diabetes. Diabetes Care 27: Bunn F, Alderson P, and Hawkins V. (2003) Colloid solutions for fluid resuscitation. Bunn. F., Alderson. P, Hawkins. V. Colloid solutions. for fluid resuscitation. Cochrane Database of Systematic Reviews: Reviews Issue. 1 John. Wiley. & Sons., Ltd. Chichester, UK DOI. : / CD Notes: Abstract/title: Excluded. Wrong patient group 107. Burdick J, Chase HP, Slover RH, Knievel K, Scrimgeour L, Maniatis AK, and Klingensmith GJ. (2004) Missed insulin meal boluses and elevated hemoglobin A1c levels in children receiving insulin pump therapy. Pediatrics. 113:e221-e Burt AL, Green S, Kwan I, Mugglestone M, and Thomas J. (2005) Intranasal insulin for type 1 diabetes mellitus. Burt. AL, Green. S, Kwan. I, Mugglestone. M., Thomas. J. Intranasal. insulin. for type. 1 diabetes mellitus. Cochrane Database of Systematic Reviews: Protocols Issue. 2 John. Wiley. & Sons., Ltd. Chichester, UK DOI. : / CD Notes: Abstract/title: Excluded. Wrong intervention 109. Burton WN, Morrison A, and Wertheimer AI. (2003) Pharmaceuticals and worker productivity loss: A critical review of the literature. Journal of Occupational and Environmental Medicine 45: Canani RB, Cirillo P, Roggero P, Romano C, Malamisura B, Terrin G, Passariello A, Manguso F, Morelli L, and Guarino A. (2006) Therapy with gastric acidity inhibitors increases the risk of acute gastroenteritis and communityacquired pneumonia in children. Pediatrics. 117:e817-e Canonico V, Fabietti PG, Benedetti MM, Federici MO, and Sarti E. (2006) Virtual type 1 diabetic patient for feedback control systems. Diabetes Research and Clinical Practice 74:S187-S190.

77 Cao Y and Lam L. (2002) Projections for insulin treatment for diabetics. Drugs of Today 38: Cao Y and Lam L. (2002) Projections for insulin treatment for diabetics. Drugs of today (Barcelona, Spain : 1998) 38: Caporali R, Cimmino MA, Sarzi-Puttini P, Scarpa R, Parazzini F, Zaninelli A, Ciocci A, and Montecucco C. (2005) Comorbid conditions in the AMICA study patients: Effects on the quality of life and drug prescriptions by general practitioners and specialists. Seminars in Arthritis and Rheumatism 35: Carroll MF and Schade DS. (2005) The dawn phenomenon revisited: implications for diabetes therapy. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 11: Castells S. (2002) Management of hyperglycemia in minority children with type 2 diabetes mellitus. Journal of Pediatric Endocrinology and Metabolism 15: Castera V, Dutour-Meyer A, Koeppel MC, Petitjean C, and Darmon P. (2005) Systemic allergy to human insulin and its rapid and long acting analogs: Successful treatment by continuous subcutaneous insulin lispro infusion. Diabetes and Metabolism 31: (case report) 118. Catargi B, Meyer L, Melki V, Renard E, and Jeandidier N. (2002) Comparison of blood glucose stability and HbA1C between implantable insulin pumps using U400 hoe 21pH insulin and external pumps using lispro in type 1 diabetic patients: A pilot study. Diabetes and Metabolism 28: Catargi B. (2004) Current status and future of implantable insulin pumps for the treatment of diabetes. Expert Review of Medical Devices 1: Cefalu WT. (2004) Evolving strategies for insulin delivery and therapy. Drugs 64: Chan NN and Hurel SJ. (2002) Potential impact of a new blood glucose monitoring device: The GlucoWatch(registered trademark) Biographer. Practical Diabetes International 19: Charkoudian N, Vella A, Reed AS, Minson CT, Shah P, Rizza RA, and Joyner MJ. (2002) Cutaneous vascular function during acute hyperglycemia in healthy young adults. Journal of Applied Physiology 93: Notes: Abstract/title: Excluded. Wrong intervention 123. Chase HP, Saib SZ, MacKenzie T, Hansen MM, and Garg SK. (2002) Post-prandial glucose excursions following four methods of bolus insulin administration in subjects with type 1 diabetes. Diabetic medicine : a journal of the British Diabetic Association 19:d-321. Notes: Abstract/title: Excluded. Wrong intervention 124. Chase HP, Saib SZ, MacKenzie T, Hansen MM, and Garg SK. (2002) Post-prandial post-prandial glucose excursions following four methods of bolus insulin administration in subjects with Type 1 diabetes. Diabetic Medicine 19: Notes: Abstract/title: Excluded. Wrong intervention 125. Chase HP, Pearson JA, Wightman C, Roberts MD, Oderberg AD, and Garg SK. (2003) Modem transmission of glucose values reduces the costs and need for clinic visits (Structured abstract). Diabetes Care 26: Notes: Abstract/title: Excluded. Wrong intervention 126. Chase HP, Roberts MD, Wightman C, Klingensmith G, Garg SK, Van Wyhe M, Desai S, Harper W, Lopatin M, Bartkowiak M, Tamada J, and Eastman RC. (2003) Use of the GlucoWatch biographer in children with type 1 diabetes. Pediatrics. 111: Notes: Abstract/title: Excluded. Wrong intervention 127. Chase HP, Horner B, McFann K, Yetzer H, Gaston J, Banion C, Fiallo-Scharer R, Slover R, and Klingensmith G. (2006) The use of insulin pumps with meal bolus alarms in children with type 1 diabetes to improve glycemic control. Diabetes Care 29: Notes: Abstract/title: Excluded. Wrong comparator 128. Chase JG, Shaw GM, Wong XW, Lotz T, Lin J, and Hann CE. (2006) Model-based glycaemic control in critical care-a review of the state of the possible. Biomedical Signal Processing and Control 1: Chassin LJ, Wilinska ME, and Hovorka R. (2005) Grading system to assess clinical performance of closed-loop glucose control. Diabetes Technology and Therapeutics 7: Chaubal MV and Roseman TJ. (2006) Drug delivery trends for parenteral therapeutics. Pharmaceutical Technology 30:

78 Chauhan N, Rani S, and Padh H. (2007) Pharmacogenetics: Genetic basis for rational drug therapy. Indian Journal of Pharmaceutical Sciences 69: Chawla PS and Kochar MS. (2004) What's new in clinical pharmacology and therapeutics. Wisconsin Medical Journal 103: Chen H, Ren A, Hu S, Mo W, Xin X, and Jia W. (2007) The significance of tumor necrosis factor-(alpha) in newly diagnosed type 2 diabetic patients by transient intensive insulin treatment. Diabetes Research and Clinical Practice 75: Chen HY, Wu KD, and Chen YM. (2006) Vasculitis-related Wunderlich's syndrome treated without surgical intervention. Clinical Nephrology 66: Chen WX, Zhang WF, Li B, Lin HJ, Zhang X, Chen HT, Gu ZY, and Li YM. (2006) Clinical manifestations of patients with chronic pancreatitis. Hepatobiliary and Pancreatic Diseases International 5: Chia CW and Saudek CD. (2004) Glucose sensors: Toward closed loop insulin delivery. Endocrinology and Metabolism Clinics of North America 33: Chico A, Vidal-Rios P, Subira M, and Novials A. (2003) The continuous glucose monitoring system is useful for detecting unrecognized hypoglycemias in patients with type 1 and type 2 diabetes but is not better than frequent capillary glucose measurements for improving metabolic control. Diabetes Care 26: Chirayath HH. (2006) Diabetes management in pregnancy. Reviews in Gynaecological and Perinatal Practice 6: Chlup R, Zapletalova J, Seckar P, Chlupova L, Tancosova S, and Reznickova M. (2004) Benefits of insulin aspart vs phosphate-buffered human regular insulin in persons with type 1 Diabetes treated by means of an insulin pump. Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia. 148: Chlup R, Zapletalová J, Seckar P, Chlupová L, Táncosová S, and Reznícková M. (2004) Benefits of insulin aspart vs phosphate-buffered human regular insulin in persons with type 1 Diabetes treated by means of an insulin pump. Biomedical papers. of the Medical Faculty. of the University Palacký., Olomouc., Czechoslovakia. 148: Notes: Abstract/title: Excluded. Wrong comparator 141. Chobot AP, Deja G, Marcinkowski A, Myrda A, Minkina-Pedras M, Jarosz-Chobot P, and Otto-Buczkowska E. (2007) Treatment of type 1 diabetes mellitus revealed below 7 years of age in the Diabetes Center of Silesia, Poland. Endokrynologia, Diabetologia i Choroby Przemiany Materii Wieku Rozwojowego 13: Chu LY. (2005) Controlled release systems for insulin delivery. Expert Opinion on Therapeutic Patents 15: Clay PG, Dong BJ, Sorensen SJ, Tseng A, Romanelli F, and Antoniou T. (2006) Advances in human immunodeficiency virus therapeutics. Annals of Pharmacotherapy 40: Cohen D, Weintrob N, Benzaquen H, Galatzer A, Fayman G, and Phillip M. (2003) Continuous subcutaneous insulin infusion versus multiple daily injections in adolescents with type I diabetes mellitus: a randomized open crossover trial. Journal of pediatric endocrinology & metabolism : JPEM. 16: Notes: Abstract/title: Included Cohen ND and Shaw JE. (2007) Diabetes: Advances in treatment. Internal Medicine Journal 37: Cohen R, Pinheiro JS, Correa JL, and Schiavon CA. (2006) Laparoscopic Roux-en-Y gastric bypass for BMI <35 kg/m2: a tailored approach. Surgery for Obesity and Related Diseases 2: Colberg SR and Walsh J. (2002) Pumping insulin during exercise: What healthcare providers and diabetic patients need to know. Physician and Sportsmedicine 30: Colquitt J, Royle P, and Waugh N. (2003) Are analogue insulins better than soluble in continuous subcutaneous insulin infusion? Results of a meta-analysis. Diabetic Medicine 20: Notes: Abstract/title: Excluded. Wrong comparator 149. Colquitt J, Clegg A, Loveman E, Royle P, and Sidhu MK. (2005) Surgery for morbid obesity. Colquitt. J, Clegg. A, Loveman. E, Royle. P, Sidhu. MK. Surgery for morbid. obesity. Cochrane Database of Systematic Reviews: Reviews Issue. 4 John. Wiley. & Sons., Ltd. Chichester, UK DOI. : / CD pub2. Notes: Abstract/title: Excluded. Wrong patient group

79 Colquitt JL, Green C, Sidhu MK, Hartwell D, and Waugh N. (2004) Clinical and cost-effectiveness of continuous subcutaneous insulin infusion for diabetes (Structured abstract). Health Technology Assessment 8: Notes: Abstract/title: The current review update was based on this NHS technology assessment report for NICE 151. Colquitt JL, Green C, Sidhu MK, Hartwell D, and Waugh N. (2004) Clinical and cost-effectiveness of continuous subcutaneous insulin infusion for diabetes. Health Technology Assessment 8:iii-95. Notes: Abstract/title: The current review update was based on this NHS technology assessment report for NICE 152. Colwell JA. (2006) Aspirin for the primary prevention of cardiovascular events. Drugs of Today 42: Compagno LM. (2005) Caring for adults with thalassemia in a pediatric world. Annals of the New York Academy of Sciences 1054: Conley R, Gupta SK, and Sathyan G. (2006) Clinical spectrum of the osmotic-controlled release oral delivery system (OROS*), an advanced oral delivery form. Current Medical Research and Opinion 22: Notes: Abstract/title: Excluded. Wrong patient group 155. Connery LE and Coursin DB. (2004) Assessment and therapy of selected endocrine disorders. Anesthesiology Clinics of North America 22: Connor H. (2004) Practical Diabetes International: Past, present and future. Practical Diabetes International 21: Conrad SC, McGrath MT, and Gitelman SE. (2002) Transition from multiple daily injections to continuous subcutaneous insulin infusion in type 1 diabetes mellitus. Journal of Pediatrics 140: Cook CB, Boyle ME, Cisar NS, Miller-Cage V, Bourgeois P, Roust LR, Smith SA, and Zimmerman RS. (2005) Use of continuous subcutaneous insulin infusion (insulin pump) therapy in the hospital setting: Proposed guidelines and outcome measures. Diabetes Educator 31: (case report) 159. Coppola A, Cimino E, Conca P, De Simone C, Tufano A, Tarantino G, Cerbone AM, and Di Minno G. (2006) Long-term prophylaxis with intermediate-purity factor VIII concentrate (Haemate P) in a patient with type 3 von Willebrand disease and recurrent gastrointestinal bleeding. Haemophilia 12: (case report) 160. Correa-de-Araujo R, Miller GE, Banthin JS, and Trinh Y. (2005) Gender differences in drug use and expenditures in a privately insured population of older adults. Journal of Women's Health 14: Coskun F, Topeli A, and Sivri B. (2005) Patients admitted to the emergency room with upper gastrointestinal bleeding: Factors influencing recurrence or death. Advances in Therapy 22: Cosson E, Bringuier AF, Paries J, Guillot R, Vaysse J, Attali JR, Feldmann G, and Valensi P. (2005) Fas/Fasligand pathway is impaired in patients with type 2 diabetes. Influence of hypertension and insulin resistance. Diabetes and Metabolism 31: Cote B and St Hilaire C. (2004) Comparison of the insulin pump and multiple daily insulin injections in intensive therapy for type 1 diabetes (Structured abstract). AETMIS. Notes: Abstract/title: This was one of the reviews on which the current review update was to be based 164. Cote B and St Hilaire C. (2005) Comparison of the insulin pump and multiple daily insulin injections in intensive therapy for type 1 diabetes (Provisional record). Notes: Abstract/title: This was one of the reviews on which the current review update was to be based 165. Couper JJ and Prins JB. (2003) 2: Recent advances in therapy of diabetes. Medical Journal of Australia 179: Cox DJ, Penberthy JK, Zrebiec J, Weinger K, Aikens JE, Frier B, Stetson B, DeGroot M, Trief P, Schaechinger H, Hermanns N, Gonder-Frederick L, and Clarke W. (2003) Diabetes and driving mishaps: Frequency and correlations from a multinational survey. Diabetes Care 26: Crispino P, Pica R, Angelucci E, Consolazio A, Rivera M, Cassieri C, and Paoluzi P. (2007) Hematological malignancies in chronic inflammatory bowel diseases: Report of five cases and review of the literature. International Journal of Colorectal Disease 22: Cyna AM, Andrew M, Emmett RS, Middleton P, and Simmons SW. (2006) Techniques for preventing hypotension during spinal anaesthesia for caesarean section. Cyna. AM, Andrew. M., Emmett. RS., Middleton. P, Simmons. SW. Techniques for preventing. hypotension. during. spinal anaesthesia for caesarean. section. Cochrane Database of Systematic Reviews: Reviews Issue. 4 John. Wiley. & Sons., Ltd. Chichester, UK DOI. : Notes: Abstract/title: Excluded. Wrong patient group

80 Daley KB, Wodrich DL, and Hasan K. (2006) Classroom attention in children with type 1 diabetes mellitus: The effect of stabilizing serum glucose. Journal of Pediatrics 148: Dalton MF, Klipfel L, and Carmichael K. (2006) Safety issues: Use of continuous subcutaneous insulin infusion (CSII) pumps in hospitalized patients. Hospital Pharmacy 41: Daneman D. (2002) Islet cell transplantation and other new technologies for treating type 1 diabetes: A paediatric view. Hormone Research 57: Daniel GW and Malone DC. (2007) Characteristics of older adults who meet the annual prescription drug expenditure threshold for medicare medication therapy management programs. Journal of Managed Care Pharmacy 13: Danne T, Deiss D, Hopfenmuller W, von Schutz W, and Kordonouri O. (2002) Experience with insulin analogues in children. Hormone Research 57: Danne T, Battelino T, Kordonouri O, Hanas R, Klinkert C, Ludvigsson J, Barrio R, Aebi C, Gschwend S, Mullis PE, Schumacher U, Zumsteg U, Morandi A, Rabbone I, Cherubini V, Toni S, de Beaufort C, Hindmarsh P, Sumner A, van Waarde WM, van den Berg N, and Phillip M. (2005) A cross-sectional international survey of continuous subcutaneous insulin infusion in 377 children and adolescents with type 1 diabetes mellitus from 10 countries. Pediatric Diabetes 6: Danne T, von Schutz W, Lange K, Nestoris C, Datz N, and Kordonouri O. (2006) Current practice of insulin pump therapy in children and adolescents - The Hannover recipe. Pediatric Diabetes 7: Daugherty KK. (2004) Review of Insulin Therapy. Journal of Pharmacy Practice 17: Davis T and Edelman SV. (2004) Insulin therapy in type 2 diabetes. Medical Clinics of North America 88: Day C, Archer H, and Bailey CJ. (2003) Recent advances in insulin therapy. British Journal of Cardiology 10: de Galan BE. (2004) Insulin pump therapy, should we consider it more often? Netherlands Journal of Medicine 62: DeFelippis MR, Bell MA, Heyob JA, and Storms SM. (2006) In vitro stability of insulin lispro in continuous subcutaneous insulin infusion. Diabetes Technology and Therapeutics 8: DeFelippis MR, Bell MA, Heyob JA, and Storms SM. (2006) In vitro stability of insulin lispro in continuous subcutaneous insulin infusion. Diabetes technology & therapeutics. 8: Deiss D, Hartmann R, Hoeffe J, and Kordonouri O. (2004) Assessment of glycemic control by continuous glucose monitoring system in 50 children with type 1 diabetes starting on insulin pump therapy. Pediatric Diabetes 5: Dejkhamron P, Menon RK, and Sperling MA. (2007) Childhood diabetes mellitus: Recent advances & future prospects. Indian Journal of Medical Research 125: Devries JH, Snoek FJ, Kostense PJ, Masurel N, and Heine RJ. (2002) A randomized trial of continuous subcutaneous insulin infusion and intensive injection therapy in type 1 diabetes for patients with long-standing poor glycemic control. Diabetes Care 25: Notes: Abstract/title: Included Devries JH, Eskes SA, Snoek FJ, Pouwer F, van Ballegooie E, Spijker AJ, Kostense PJ, Seubert M, and Heine RJ. (2002) Continuous intraperitoneal insulin infusion in patients with 'brittle' diabetes: Favourable effects on glycaemic control and hospital stay. Diabetic Medicine 19: Devries JH, Wentholt IME, Masurel N, Mantel I, Poscia A, Maran A, and Heine RJ. (2004) Nocturnal hypoglycaemia in type 1 diabetes - Consequences and assessment. Diabetes/Metabolism Research and Reviews 20:S43-S Devries JH, Snoek FJ, and Heine RJ. (2004) Persistent poor glycaemic control in adult Type 1 diabetes. A closer look at the problem. Diabetic Medicine 21:

81 Di Bartolo P, Pellicano F, Scaramuzza A, Fabbri T, Melandri P, Miselli V, Casetti T, and Cannata F. (2006) Aspart and lispro insulin, is there any difference when used with an insulin pump treatment? Diabetes Research and Clinical Practice 74:S119-S Diabetes PT. (2002) Effects of insulin in relatives of patients with type 1 diabetes mellitus. The New England journal of medicine 346: Notes: Abstract/title: Excluded. Wrong intervention 190. DiMeglio LA, Boyd SR, Pottorff TM, Cleveland JL, Fineberg N, and Eugster EA. (2004) Preschoolers are not miniature adolescents: A comparison of insulin pump doses in two groups of children with type 1 diabetes mellitus. Journal of Pediatric Endocrinology and Metabolism 17: DiMeglio LA, Pottorff TM, Boyd SR, France L, Fineberg N, and Eugster EA. (2004) A randomized, controlled study of insulin pump therapy in diabetic preschoolers. Journal of Pediatrics 145: Notes: Abstract/title: Included. Full paper: Exclude. Wrong comparator (< 3 injections per day in 15 of 17 subjects) 192. Dinneen SF. (2006) Management of type 1 diabetes. Medicine 34: Djalilian AR and Nussenblatt RB. (2002) Immunosuppression in uveitis. Ophthalmology Clinics of North America 15: Doyle EA, Weinzimer SA, Steffen AT, Ahern JAH, Vincent M, and Tamborlane WV. (2004) A randomized, prospective trial comparing the efficacy of continuous subcutaneous insulin infusion with multiple daily injections using insulin glargine. Diabetes Care 27: Notes: Abstract/title: Included Doyle EA, Steffen AT, and Tamborlane WV. (2005) Case study: Contrasting challenges of insulin pump therapy in a toddler and adolescent with type 1 diabetes. Diabetes Educator 31: (case report) 196. Drummond A, Kwok S, Morgan J, and Durrington PN. (2002) Costs of aspirin and statins in general practice. QJM - Monthly Journal of the Association of Physicians 95: Dudde R, Vering T, Piechotta G, and Hintsche R. (2006) Computer-aided continuous drug infusion: setup and test of a mobile closed-loop system for the continuous automated infusion of insulin. IEEE transactions on information technology in biomedicine : a publication of the IEEE Engineering in Medicine and Biology Society. 10: Dufaitre-Patouraux L, Riveline JP, Renard E, Melki V, Belicar-Schaepelynck P, Selam JL, Guerci B, Millot L, Brun JM, Fermon C, Catargi B, Gin H, Jeandidier N, Lejeune PJ, Lassmann-Vague V, Charpentier G, Rudoni S, Fontaine P, Mestre B, Martin P, Rocher-Mingret L, Vague P, Apostol D, Bringer J, Benamo E, Sola A, Haardt MJ, Slama G, Grulet H, Leborgne C, Estour B, Boivin S, Meyer L, Pinget M, and Hanaire-Broutin H. (2006) Continuous intraperitoneal insulin infusion does not increase the risk of organ-specific autoimmune disease in type 1 diabetic patients: Results of a multicentric, comparative study. Diabetes and Metabolism 32: Dufaitre PL, Riveline JP, Renard E, Melki V, Belicar SP, Selam JL, Guerci B, Millot L, Brun JM, Fermon C, Catargi B, Gin H, Jeandidier N, Lejeune PJ, and Lassmann V, V. (2006) Continuous intraperitoneal insulin infusion does not increase the risk of organ-specific autoimmune disease in type 1 diabetic patients: results of a multicentric, comparative study. Diabetes & metabolism 32: Notes: Abstract/title: Excluded. Wrong comparator 200. Dunn CJ, Plosker GL, Keating GM, McKeage K, and Scott LJ. (2003) Insulin glargine: An updated review of its use in the management of diabetes mellitus. Drugs 63: Durand-Gonzalez KN, Guillausseau N, Anciaux ML, Hentschel V, and Gayno JP. (2003) Allergy to insulin in a woman with gestational diabetes mellitus: Transient efficiency of continuous subcutaneous insulin lispro infusion. Diabetes and Metabolism 29: (case report) 202. Duvillard L, Florentin E, Lalanne-Mistrich ML, Petit JM, Baillot-Rudoni S, Brun-Pacaud A, Brun JM, Gambert P, and Verges B. (2005) Normal metabolism of apolipoprotein B100-containing lipoproteins despite qualitative abnormalities in type 1 diabetic men. Diabetologia 48: Einhorn D. (2004) Advances in diabetes for the millennium: insulin treatment and glucose monitoring. MedGenMed [electronic resource] : Medscape general medicine. 6: Einhorn D. (2004) Advances in diabetes for the millennium: Insulin treatment and glucose monitoring CME. MedGenMed Medscape General Medicine 6:8p.

82 Eisenbarth GS. (2007) Update: Update in type 1 diabetes. Journal of Clinical Endocrinology and Metabolism 92: El Kamar FG and Posner JB. (2004) Brain metastases. Seminars in Neurology 24: El Zahaby HM, El Din BMN, and Ismail M. (2003) Glucose-insulin-potassium infusion for myocardial protection in non-diabetic patients undergoing off-pump coronary artery bypass surgery. Egyptian Journal of Anaesthesia 19: Eugster EA and Francis G. (2006) Position statement: Continuous subcutaneous insulin infusion in very young children with type 1 diabetes. Pediatrics. 118:e1244-e1249. Notes: Abstract/title: Included. Full paper: Exclude. Wrong study type (review not systematic) 209. Evans M. (2005) Avoiding hypoglycaemia when treating type 1 diabetes. Diabetes, Obesity and Metabolism 7: Everett J. (2004) The role of insulin pumps in the management of diabetes. Nursing times 100: Fabietti PG, Canonico V, Orsini Federici M, Sarti E, and Massi Benedetti M. (2006) Model based study on monitoring ketone bodies to improve safety in intensive insulin therapy. International Journal of Artificial Organs 29: Fahlen M, Eliasson B, and Oden A. (2005) Optimization of basal insulin delivery in Type 1 diabetes: A retrospective study on the use of continuous subcutaneous insulin infusion and insulin glargine. Diabetic Medicine 22: Fanelli CG and Rossetti P. (2006) Counterregulatory responses in CSII. Diabetes Research and Clinical Practice 74:S108-S Farrar D, Tuffnell DJ, and West J. (2007) Continuous subcutaneous insulin infusion versus multiple daily injections of insulin for pregnant women with diabetes. Farrar. D, Tuffnell. DJ., West J. Continuous. subcutaneous. insulin. infusion versus. multiple daily. injections. of insulin. for pregnant. women with. diabetes. Cochrane Database of Systematic Reviews: Reviews Issue. 3 John. Wiley. & Sons., Ltd. Chichester, UK DOI. Notes: Abstract/title: Included Fayolle C, Brun JF, Bringer J, Mercier J, and Renard E. (2006) Accuracy of continuous subcutaneous glucose monitoring with the GlucoDay(registered trademark) in type 1 diabetic patients treated by subcutaneous insulin infusion during exercise of low versus high intensity. Diabetes and Metabolism 32: Federici MO and Benedetti MM. (2006) Ketone bodies monitoring. Diabetes Research and Clinical Practice 74:S77-S Feltbower RG, Campbell FM, Bodansky HJ, Stephenson CR, and McKinney PA. (2006) Insulin pump therapy in childhood diabetes - Cost implications for Primary Care Trusts. Diabetic Medicine 23: Feltbower RG, Campbell FM, Bodansky HJ, Stephenson CR, and McKinney PA. (2006) Insulin pump therapy in childhood diabetes: cost implications for Primary Care Trusts (Provisional record). Diabetic Medicine 23: Fenter TC, Naslund MJ, Shah MB, Eaddy MT, and Black L. (2006) The cost of treating the 10 most prevalent diseases in men 50 years of age or older. American Journal of Managed Care 12:S90-S Fisher LK. (2006) The selection of children and adolescents for treatment with continuous subcutaneous insulin infusion (CSII). Pediatric Diabetes 7: Flesch M and Erdmann E. (2006) The problem of polypharmacy in heart failure. Current Cardiology Reports 8: Flood T. (2006) Advances in insulin delivery systems and devices: Beyond the vial and syringe. Insulin 1: Notes: Abstract/title: Included. Full paper: Exclude. Wrong comparator. Level I evidence, no additional studies identified Folgueira MAAK, Brentani H, Katayama MLH, Patrao DFC, Carraro DM, Netto MM, Barbosa EM, Caldeira JRF, Abreu APS, Lyra EC, Kaiano JHL, Mota LD, Maciel MS, Dellamano M, Caballero OLSD, and Brentani MM. (2006) Gene expression profiling of clinical stages II and III breast cancer. Brazilian Journal of Medical and Biological Research 39:

83 Fonseca VA, Theuma P, Mudaliar S, Leissinger CA, Clejan S, and Henry RR. (2006) Diabetes treatments have differential effects on nontraditional cardiovascular risk factors. Journal of Diabetes and its Complications 20: Notes: Abstract/title: Included. Full paper: Exclude. Wrong comparator (not optimised MDI) 225. Fox LA, Buckloh LM, Smith SD, Wysocki T, and Mauras N. (2005) A randomized controlled trial of insulin pump therapy in young children with type 1 diabetes. Diabetes Care 28: Notes: Abstract/title: Included. Full paper: Exclude. Wrong comparator (2 or 3 injections per day rather than at least 3 per day) 226. Fox LA, Beck R, Steffes M, Chase P, Coffey J, Wysocki T, Buckingham B, Weinzimer S, Tamborlane W, Kollman C, and Ruedy K. (2007) Relative accuracy of the BD Logic(registered trademark) and FreeStyle(registered trademark) blood glucose meters. Diabetes Technology and Therapeutics 9: Fox RI. (2005) Sjogren's syndrome. Lancet 366: Fox RI and Liu AY. (2006) Sjogren's syndrome in dermatology. Clinics in Dermatology 24: Franklin VL, Torrance T, Peebles M, Wilkie R, and Greene S. (2003) Life-threatening autoimmunity with diabetes: Management with an insulin pump. Pediatric Diabetes 4: (case report) 230. Franz MJ. (2004) Prioritizing diabetes nutrition recommendations based on evidence. Minerva Medica 95: Fujimoto S, Matsushima A, Yoshitani K, Oya M, Shimono D, Takeda T, Kurose T, Yamada Y, and Seino Y. (2003) Type-1 diabetes mellitus with insufficient serum immunoreactive insulin elevation after subcutaneous NPHinsulin injection. Diabetes Research and Clinical Practice 60: (case report) 232. Furnary AP, Gao G, Grunkemeier GL, Wu Y, Zerr KJ, Bookin SO, Floten HS, and Starr A. (2003) Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. Journal of Thoracic and Cardiovascular Surgery 125: Furnary AP, Wu Y, and Bookin SO. (2004) Effect of hyperglycemia and continuous intravenous insulin infusions on outcomes of cardiac surgical procedures: the Portland Diabetic Project. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 10 Suppl 2: Furnary AP. (2006) Rationale for glycemic control in cardiac surgical patients: the Portland Diabetic Project (Structured abstract). Insulin. 1:S24-S Gabbe SG and Graves CR. (2003) Management of diabetes mellitus complicating pregnancy. Obstetrics and Gynecology 102: Gandhi GY, Nuttall GA, Abel MD, Mullany CJ, Schaff HV, O'Brien PC, Johnson MG, Williams AR, Cutshall SM, Mundy LM, Rizza RA, and McMahon MM. (2007) Intensive intraoperative insulin therapy versus conventional glucose management during cardiac surgery: a randomized trial. Annals of internal medicine 146: Notes: Abstract/title: Excluded. Wrong intervention 237. Ganesh R, Suresh N, and Ramesh J. (2006) Diabetic ketoacidosis in children. National Medical Journal of India 19: Garcia-Garcia E, Galera R, Aguilera P, Cara G, and Bonillo A. (2007) Long-term use of continuous subcutaneous insulin infusion compared with multiple daily injections of glargine in pediatric patients. Journal of pediatric endocrinology & metabolism : JPEM 20: Garcia-Garcia E, Galera R, Aguilera P, Cara G, and Bonillo A. (2007) Long-term use of continuous subcutaneous insulin infusion compared with multiple daily injections of glargine in pediatric patients. Journal of Pediatric Endocrinology and Metabolism 20: García GE, Galera R, Aguilera P, Cara G, and Bonillo A. (2007) Long-term use of continuous subcutaneous insulin infusion compared with multiple daily injections of glargine in pediatric patients. Journal of pediatric endocrinology & metabolism : JPEM. 20: Garg R, Johnston V, McNally PG, Davies MJ, and Lawrence IG. (2007) U-500 insulin: Why, when and how to use in clinical practice. Diabetes/Metabolism Research and Reviews 23: Garg S and Jovanovic L. (2006) Relationship of fasting and hourly blood glucose levels to HbA1c values: Safety, accuracy, and improvements in glucose profiles obtained using a 7-day continuous glucose sensor. Diabetes Care

84 70 29: Garg SK, Walker AJ, Hoff HK, D'Souza AO, Gottlieb PA, and Chase HP. (2004) Glycemic Parameters with Multiple Daily Injections Using Insulin Glargine Versus Insulin Pump. Diabetes Technology and Therapeutics 6: Garg SK, Ellis SL, and Ulrich H. (2005) Insulin glulisine: A new rapid-acting insulin analogue for the treatment of diabetes. Expert Opinion on Pharmacotherapy 6: Garg SK and Ulrich H. (2006) Achieving goal glycosylated hemoglobin levels in type 2 diabetes mellitus: Practical strategies for success with insulin therapy. Insulin 1: Garmo A, Pettersson-Frank B, and Ehrenberg A. (2004) Treatment effects and satisfaction in diabetic patients changing from multiple daily insulin injections to CSII. Practical Diabetes International 21: George J, Vuong T, Bailey MJ, Kong DCM, Marriott JL, and Stewart K. (2006) Development and validation of the medication-based disease burden index. Annals of Pharmacotherapy 40: Gibril F and Jensen RT. (2004) Zollinger-Ellison syndrome revisited: Diagnosis, biologic markers, associated inherited disorders, and acid hypersecretion. Current Gastroenterology Reports 6: Gimenez M, Conget I, Nicolau J, Pericot A, and Levy I. (2007) Outcome of pregnancy in women with type 1 diabetes intensively treated with continuous subcutaneous insulin infusion or conventional therapy. A case-control study. Acta Diabetologica 44: Gin H, Renard E, Melki V, Boivin S, Schaepelynck-Belicar P, Guerci B, Selam JL, Brun JM, Riveline JP, Estour B, Catargi B, Martin JF, Gilly F, Mestre B, Lassmann-Vague V, Vague P, Bringer J, Grulet H, Leborgne C, Millot L, Jeandidier N, Pinget M, and Hanaire-Broutin H. (2003) Combined improvements in implantable pump technology and insulin stability allow safe and effective long term intraperitoneal insulin delivery in type 1 diabetic patients: The EVADIAC experience. Diabetes and Metabolism 29: Giuliano EA. (2004) Nonsteroidal anti-inflammatory drugs in veterinary ophthalmology. Veterinary Clinics of North America - Small Animal Practice 34: Giurini JM, Cook EA, and Cook JJ. (2007) Diabetes: The Latest Trends in Glycemic Control. Clinics in Podiatric Medicine and Surgery 24: Giusti M, Sidoti M, Augeri C, Rabitti C, and Minuto F. (2004) Effect of short-term treatment with low dosages ot the proton-pump inhibitor omeprazole on serum chromogranin A levels in man. European Journal of Endocrinology 150: Glandt M, Hagopian W, and Herold KC. (2003) Treatment of Type 1 Diabetes with Anti-CD3 Monoclonal Antibody. Reviews in Endocrine and Metabolic Disorders 4: Glaser NS, Iden SB, Green BD, Bennett C, Hood JK, Styne DM, and Goodlin JB. (2004) Benefits of an insulin dosage calculation device for adolescents with type 1 diabetes mellitus. Journal of pediatric endocrinology & metabolism : JPEM. 17: Notes: Abstract/title: Excluded. Wrong comparator 256. Glaser NS, Iden SB, Green-Burgeson D, Bennett C, Hood-Johnson K, Styne DM, and Goodlin-Jones B. (2004) Benefits of an insulin dosage calculation device for adolescents with type 1 diabetes mellitus. Journal of Pediatric Endocrinology and Metabolism 17: Notes: Abstract/title: Excluded. Wrong comparator 257. Glister BC and Vigersky RA. (2003) Perioperative management of type 1 diabetes mellitus. Endocrinology and Metabolism Clinics of North America 32: Gloyn AL, Cummings EA, Edghill EL, Harries LW, Scott R, Costa T, Temple IK, Hattersley AT, and Ellard S. (2004) Permanent neonatal diabetes due to paternal germline mosaicism for an activating mutation of the KCNJ11 gene encoding the Kir6.2 subunit of the (beta)-cell potassium adenosine triphosphate channel. Journal of Clinical Endocrinology and Metabolism 89: (case report) 259. Goffin L, Lolin K, Janssen F, Schurmans T, and Dorchy H. (2006) Insulin-dependent diabetes mellitus as long term complication of haemolytic-uraemic syndrome. Diabetes and Metabolism 32: (case report)

85 Golla K, Epstein JB, Rada RE, Sanai R, Messieha Z, and Cabay RJ. (2004) Diabetes mellitus: An updated overview of medical management and dental implications. General Dentistry 52: Gonder-frederick LA, Fisher CD, Ritterband LM, Cox DJ, Hou L, Dasgupta AA, and Clarke WL. (2006) Predictors of fear of hypoglycemia in adolescents with type 1 diabetes and their parents. Pediatric Diabetes 7: Gonzalez-Michaca L, Ahumada M, and Ponce-de-Leon S. (2002) Insulin subcutaneous application vs. continuous infusion for postoperative blood glucose control in patients with non-insulin-dependent diabetes mellitus. Archives of Medical Research 33: Notes: Abstract/title: Excluded. Wrong intervention 263. Gonzalez C, Santoro S, Salzberg S, Di Girolamo G, and Alvarinas J. (2005) Insulin analogue therapy in pregnancies complicated by diabetes mellitus. Expert Opinion on Pharmacotherapy 6: Gonzalez JL. (2002) Management of diabetes in pregnancy. Clinical Obstetrics and Gynecology 45: González ML, Ahumada M, and Ponce dl. (2002) Insulin subcutaneous application vs. continuous infusion for postoperative blood glucose control in patients with non-insulin-dependent diabetes mellitus. Archives of Medical Research 33: Notes: Abstract/title: Excluded. Wrong intervention 266. Gottlieb PA, Frias JP, Peters KA, Chillara B, and Garg SK. (2002) Optimizing insulin therapy in pregnant women with type 1 diabetes mellitus. Treatments in Endocrinology 1: Grant P. (2007) A new approach to diabetic control: Fuzzy logic and insulin pump technology. Medical Engineering and Physics 29: Green DJ, Walsh JH, Maiorana A, Burke V, Taylor RR, and O'Driscoll JG. (2004) Comparison of resistance and conduit vessel nitric oxide-mediated vascular function in vivo: Effects of exercise training. Journal of Applied Physiology 97: Notes: Abstract/title: Excluded. Wrong intervention 269. Gross TM, Kayne D, King A, Rother C, and Juth S. (2003) A bolus calculator is an effective means of controlling postprandial glycemia in patients on insulin pump therapy. Diabetes technology & therapeutics 5: Notes: Abstract/title: Excluded. Wrong intervention 270. Gross TM, Kayne D, King A, Rother C, and Juth S. (2003) A bolus calculator is an effective means of controlling postprandial glycemia in patients on insulin pump therapy. Diabetes Technology and Therapeutics 5: Notes: Abstract/title: Excluded. Wrong intervention 271. Groudine SB and Phan B. (2005) Significant hyperkalemia after discontinuation of an insulin pump. Journal of Clinical Anesthesia 17: (case report) 272. Grudell ABM, Mueller PS, and Viggiano TR. (2006) Black esophagus: Report of six cases and review of the literature, Diseases of the Esophagus 19: Grundy SM. (2006) Drug therapy of the metabolic syndrome: Minimizing the emerging crisis in polypharmacy. Nature Reviews Drug Discovery 5: Guerci B, Benichou M, Floriot M, Bohme P, Fougnot S, Franck P, and Drouin P. (2003) Accuracy of an electrochemical sensor for measuring capillary blood ketones by fingerstick samples during metabolic deterioration after continuous subcutaneous insulin infusion interruption in type 1 diabetic patients. Diabetes Care 26: Guerci B, Floriot M, Bohme P, Durain D, Benichou M, Jellimann S, and Drouin P. (2003) Clinical performance of CGMS in type 1 diabetic patients treated by continuous subcutaneous insulin infusion using insulin analogs. Diabetes Care 26: Guerci B. (2006) Acute complications of insulin pump therapy. Diabetes Research and Clinical Practice 74:S104-S Guilhem I, Leguerrier AM, Lecordier F, Poirier JY, and Maugendre D. (2006) Technical risks with subcutaneous insulin infusion. Diabetes and Metabolism 32: Gurvits GE, Shapsis A, Lau N, Gualtieri N, and Robilotti JG. (2007) Acute esophageal necrosis: A rare syndrome. Journal of Gastroenterology 42: Gustafson PA, Zarro DL, Palanzo DA, Manley NJ, Montesano RM, Quinn M, Elmore BA, and Castagna JM. (2002) Conventional approach to glucose management for diabetic patients undergoing coronary artery bypass surgery.

86 72 Perfusion 17: Guvener M, Pasaoglu I, Demircin M, and Oc M. (2002) Perioperative hyperglycemia is a strong correlate of postoperative infection in type II diabetic patients after coronary artery bypass grafting. Endocrine Journal 49: Haddad N, Sanchez J, and Temple IK. (2007) Transient neonatal diabetes mellitus: A case report and review of the literature. Endocrinologist 17: (case report) 282. Hainer TA. (2006) Managing older adults with diabetes. Journal of the American Academy of Nurse Practitioners. 18: Hale DE and Kiess W. (2004) Insulins and oral hypoglycemic medications. Pediatric Endocrinology Reviews 2: Hall EJ and Sykes NP. (2004) Analgesia for patients with advanced disease: 2. Postgraduate Medical Journal 80: Halvorson M, Carpenter S, Kaiserman K, and Kaufman FR. (2007) A Pilot Trial in Pediatrics with the Sensor- Augmented Pump: Combining Real-Time Continuous Glucose Monitoring with the Insulin Pump. Journal of Pediatrics 150: Hammond P. (2004) Continuous subcutaneous insulin infusion: Short-term benefits apparent, long-term benefits speculative. British Journal of Diabetes and Vascular Disease 4: Hammond P, Boardman S, and Greenwood R. (2006) ABCD position paper on insulin pumps. Practical Diabetes International 23: Hanaire H. (2006) Continuous glucose monitoring and external insulin pump: Towards a subcutaneous closed loop. Diabetes and Metabolism 32: Hanas R. (2002) Selection for and initiation of continuous subcutaneous insulin infusion: Proceedings from a workshop. Hormone Research 57: Hanas R and Ludvigsson J. (2006) Hypoglycemia and ketoacidosis with insulin pump therapy in children and adolescents. Pediatric Diabetes 7: Hanas R and Adolfsson P. (2006) Insulin pumps in pediatric routine care improve long-term metabolic control without increasing the risk of hypoglycemia. Pediatric Diabetes 7: Hanney SR, Home PD, Frame I, Grant J, Green P, and Buxton MJ. (2006) Identifying the impact of diabetes research. Diabetic Medicine 23: Harmel AP and Mathur R. (2004) Similar A1C outcomes in type 1 diabetic patients undergoing intensive diabetes management with preprandial rapid-acting insulin and either CSII or glargine. Diabetes Care 27: Notes: Abstract/title: Included. Full paper: Exclude. Wrong study type (not randomised) 294. Harris SB, Leiter LA, Yale JF, Chiasson JL, Kleinstiver P, and Sauriol L. (2007) Out-of-pocket costs of managing hyperglycemia and hypoglycemia in patients with type 1 diabetes and insulin-treated type 2 diabetes. Canadian Journal of Diabetes 31: Harsch IA, Stocker S, Radespiel-Troger M, Hahn EG, Konturek PC, Ficker JH, and Lohmann T. (2002) Traffic hypoglycaemias and accidents in patients with diabetes mellitus treated with different antidiabetic regimens. Journal of Internal Medicine 252: Hathout EH, McClintock T, Sharkey J, Kytsenko D, Hartwick N, Hadley-Scofield M, Torgeson S, and Mace JW. (2003) Glycemic, auxologic, and seasonal aspects of continuous subcutaneous insulin infusion therapy in children and young adults with type 1 diabetes. Diabetes Technology and Therapeutics 5: Hatipoglu B, Soni S, and Espinosa V. (2006) Glycemic control with continuous subcutaneous insulin infusion with use of U-500 insulin in a pregnant patient. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 12: (case report)

87 Hatipoglu B, Soni A, and Espinosa V. (2006) Glycemic control with continuous subcutaneous insulin infusion with use of U-500 insulin in a pregnant patient. Endocrine Practice 12: (case report) 299. Hatton J, Kryscio R, Ryan M, Ott L, and Young B. (2006) Systemic metabolic effects of combined insulin-like growth factor-i and growth hormone therapy in patients who have sustained acute traumatic brain injury. Journal of Neurosurgery 105: Notes: Abstract/title: Excluded. Wrong patient group 300. Haycox A. (2004) Insulin aspart: an evidence-based medicine review (Structured abstract). Clinical Drug Investigation 24: Notes: Abstract/title: Excluded. Wrong intervention 301. Haycox A. (2004) Insulin aspart: An evidence-based medicine review. Clinical Drug Investigation 24: Notes: Abstract/title: Excluded. Wrong intervention 302. Heller S. (2003) Insulin lispro: A useful advance in insulin therapy. Expert Opinion on Pharmacotherapy 4: Heptulla RA, Allen HF, Gross TM, and Reiter EO. (2004) Continuous glucose monitoring in children with type 1 diabetes: Before and after insulin pump therapy. Pediatric Diabetes 5: Heptulla RA, Rodriguez LM, Bomgaars L, and Raymond MW. (2005) The role of amylin and glucagon in the dampening of glycemic excursions in children with type 1 diabetes. Diabetes 54: Notes: Abstract/title: Excluded. Wrong intervention 305. Herman WH, Ilag LL, Johnson SL, Martin CL, Sinding J, Al Harthi A, Plunkett CD, LaPorte FB, Burke R, Brown MB, Halter JB, and Raskin P. (2005) A clinical trial of continuous subcutaneous insulin infusion versus multiple daily injections in older adults with type 2 diabetes. Diabetes Care 28: Notes: Abstract/title: Included Hermanns N, Scheff C, Kulzer B, Weyers P, Pauli P, Kubiak T, and Haak T. (2007) Association of glucose levels and glucose variability with mood in type 1 diabetic patients. Diabetologia 50: Hernando ME, Gomez EJ, Gili A, Gomez M, Garcia G, and del Pozo F. (2004) New trends in diabetes management: mobile telemedicine closed-loop system. Studies in health technology and informatics 105: Herndon DN. (2003) Nutritional and pharmacological support of the metabolic response to injury. Minerva anestesiologica 69: Herndon DN and Tompkins RG. (2004) Support of the metabolic response to burn injury. Lancet 363: Hess-Fischl A. (2004) Practical Management of Patient with Diabetes in Critical Care: From a Diabetes Educator's Perspective. Critical Care Nursing Quarterly 27: Hilberg T, Eichler E, Glaser D, Prasa D, Sturzebecher J, and Gabriel HHW. (2003) Blood coagulation and fibrinolysis before and after exhaustive exercise in patients with IDDM. Thrombosis and Haemostasis 90: Hirsch IB. (2004) Treatment of patients with severe insulin deficiency: What we have learned over the past 2 years. American Journal of Medicine 116:17S-22S Hirsch IB. (2005) Intensifying insulin therapy in patients with type 2 diabetes mellitus. American Journal of Medicine 118:21S-26S Hirsch IB, Bode BW, Garg S, Lane WS, Sussman A, Hu P, Santiago OM, and Kolaczynski JW. (2005) Continuous subcutaneous insulin infusion (CSII) of insulin aspart versus multiple daily injection of insulin aspart/insulin glargine in type 1 diabetic patients previously treated with CSII. Diabetes Care 28: Notes: Abstract/title: Excluded. Wrong intervention 315. Hissa MN, Hissa ASR, Bruin VMS, and Fredrickson LP. (2002) Comparison between continuous subcutaneous insulin infusion in type 1 diabetes mellitus: 18-month follow-up. Endocrine Practice 8: Hoffmann KM, Furukawa M, and Jensen RT. (2005) Duodenal neuroendocrine tumors: Classification, functional syndromes, diagnosis and medical treatment. Best Practice and Research in Clinical Gastroenterology 19: Hollander P. (2002) Insulin therapy in type 2 diabetes. Current Opinion in Endocrinology and Diabetes 9:

88 Holterhus PM, Odendahl R, Oesingmann S, Lepler R, Wagner V, Hiort O, and Holl R. (2007) Classification of distinct baseline insulin infusion patterns in children and adolescents with type 1 diabetes on continuous subcutaneous insulin infusion therapy. Diabetes Care 30: Holzinger A, Bonfig W, Kusser B, Eggermann T, Muller H, and Munch HG. (2006) Use of long-term microdialysis subcutaneous glucose monitoring in the management of neonatal diabetes: A first case report. Biology of the Neonate 89: (case report) 320. Home P. (2006) Global Guideline for Type 2 Diabetes: Recommendations for standard, comprehensive, and minimal care. Diabetic Medicine 23: Hoogma RP and Schumicki D. (2006) Safety of insulin glulisine when given by continuous subcutaneous infusion using an external pump in patients with type 1 diabetes. Hormone and metabolic research. Hormon. und Stoffwechselforschung. Hormones et métabolisme. 38: Notes: Abstract/title: Excluded. Wrong comparator 322. Hoogma RPLM, Spijker AJM, Doorn-Scheele M, van Doorn TT, Michels RPJ, van Doorn RG, Levi M, and Hoekstra JBL. (2004) Quality of life and metabolic control in patients with diabetes mellitus type I treated by continuous subcutaneous insulin infusion or multiple daily insulin injections. Netherlands Journal of Medicine 62: Hoogma RPLM, Hammond PJ, Gomis R, Kerr D, Bruttomesso D, Bouter KP, Wiefels KJ, De La Calle H, Schweitzer DH, Pfohl M, Torlone E, Krinelke LG, and Bolli GB. (2006) Comparison of the effects of continuous subcutaneous insulin infusion (CSII) and NPH-based multiple daily insulin injections (MDI) on glycaemic control and quality of life: Results of the 5-nations trial. Diabetic Medicine 23: Notes: Abstract/title: Included Hoogma RPLM, Hoekstra JB, Michels BP, and Levi M. (2006) Comparison between multiple daily insulin injection therapy (MDI) and continuous subcutaneous insulin infusion therapy (CSII), results of the five nations study. Diabetes Research and Clinical Practice 74:S144-S Hoogma RPLM and Schumicki D. (2006) Safety of insulin glulisine when given by continuous subcutaneous infusion using an external pump in patients with type 1 diabetes. Hormone and Metabolic Research 38: Notes: Abstract/title: Excluded. Wrong comparator 326. Horvath K, Jeitler K, Berghold A, Ebrahim SH, Gratzer TW, Plank J, Kaiser T, Pieber TR, and Siebenhofer A. (2007) Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus. Horvath. K., Jeitler. K., Berghold. A, Ebrahim. SH, Gratzer. TW, Plank. J, Kaiser. T, Pieber. TR., Siebenhofer. A. Long acting. insulin. analogues. versus. NPH. insulin. for type. 2 diabetes mellitus. Cochrane Database of Systematic Reviews: Reviews Issue. 2 John. Wi. Notes: Abstract/title: Excluded. Wrong comparator 327. Hoskison KT and Wortmann RL. (2007) Management of gout in older adults: Barriers to optimal control. Drugs and Aging 24: Hovorka R, Chassin LJ, Wilinska ME, Canonico V, Akwi JA, Federici MO, Massi-Benedetti M, Hutzli I, Zaugg C, Kaufmann H, Both M, Vering T, Schaller HC, Schaupp L, Bodenlenz M, and Pieber TR. (2004) Closing the loop: The adicol experience. Diabetes Technology and Therapeutics 6: Hovorka R, Canonico V, Chassin LJ, Haueter U, Massi-Benedetti M, Federici MO, Pieber TR, Schaller HC, Schaupp L, Vering T, and Wilinska ME. (2004) Nonlinear model predictive control of glucose concentration in subjects with type 1 diabetes. Physiological Measurement 25: Hovorka R, Wilinska ME, Chassin LJ, and Dunger DB. (2006) Roadmap to the artificial pancreas. Diabetes Research and Clinical Practice 74:S178-S Hovorka R. (2006) Continuous glucose monitoring and closed-loop systems. Diabetic Medicine 23: Howlett KF, Watt MJ, Hargreaves M, and Febbraio MA. (2003) Regulation of glucose kinetics during intense exercise in humans: Effects of a- and beta-adrenergic blockade. Metabolism: Clinical & Experimental 52: Notes: Abstract/title: Excluded. Wrong intervention 333. Hruska LA, Smith JM, Hendy MP, Fritz VL, McAdams S, and Rusche J. (2005) Continuous insulin infusion reduces infectious complications in diabetics following coronary surgery. Journal of Cardiac Surgery 20: Huang L, Quartin A, Jones D, and Havlir DV. (2006) Intensive care of patients with HIV infection. New England Journal of Medicine 355: Hunger-Dathe W, Braun A, Muller UA, Schiel R, Femerling M, and Risse A. (2003) Insulin Pump Therapy in Patients with Type 1 Diabetes Mellitus: Results of the Nationwide Quality Circle in Germany (ASD)

89 75 Experimental and Clinical Endocrinology and Diabetes 111: Hwu CM, Hsiao CF, Grove J, Hung YJ, Chuang LM, Chen YT, Curb JD, Chen YDI, Rodriguez B, and Ho LT. (2007) Surrogate estimates of insulin sensitivity in subjects with hypertension. Journal of Human Hypertension 21: Ilavajady S, Jayalakshmi TS, Kaul HL, and Dureja GP. (2002) Comparison of continuous glucose insulin potassium infusion with subcutaneous administration of insulin in perioperative control of diabetes mellitus. Journal of Anaesthesiology Clinical Pharmacology 18: Notes: Abstract/title: Excluded. Wrong intervention 338. Inductivo-Yu I, Adams A, Gish RG, Wakil A, Bzowej NH, Frederick RT, and Bonacini M. (2007) Mycophenolate Mofetil in Autoimmune Hepatitis Patients Not Responsive or Intolerant to Standard Immunosuppressive Therapy. Clinical Gastroenterology and Hepatology 5: Inoue K, Yamashita T, Harada T, and Nakamura S. (2002) Role of human SII cortices in sensorimotor integration. Clinical Neurophysiology 113: Iscoe KE, Campbell JE, Jamnik V, Perkins BA, and Riddell MC. (2006) Efficacy of continuous real-time blood glucose monitoring during and after prolonged high-intensity cycling exercise: Spinning with a continuous glucose monitoring system. Diabetes Technology and Therapeutics 8: Jackson A, Ternand C, Brunzell C, Kleinschmidt T, Dew D, Milla C, and Moran A. (2003) Insulin glargine improves hemoglobin Alc in children and adolescents with poorly controlled type 1 diabetes. Pediatric Diabetes 4: Jackson R and Pencharz PB. (2003) Cystic fibrosis. Bailliere's Best Practice and Research in Clinical Gastroenterology 17: Jankovec Z, Cechurova D, Krcma M, Lacigova S, Zourek M, and Rusavy Z. (2006) National Register of patients with insulin pump treatment in the Czech Republic. Diabetes Research and Clinical Practice 74:S135-S Jarosz-Chobot P, Nowakowska M, and Polanska J. (2007) Seeking the factors predisposing to local skin inflammatory state development in children with type 1 diabetes (T1DM) treated with continuous subcutaneous insulin infusion (CSII). Experimental and Clinical Endocrinology and Diabetes 115: Jeandidier N, Boullu S, Busch-Brafin MS, Chabrier G, Sapin R, Gasser F, and Pinget M. (2002) Comparison of antigenicity of Hoechst 21PH insulin using either implantable intraperitoneal pump or subcutaneous external pump infusion in type 1 diabetic patients. Diabetes Care 25: Jeha GS, Karaviti LP, Anderson B, Smith EO, Donaldson S, Mcgirk TS, and Haymond MW. (2005) Insulin pump therapy in preschool children with type 1 diabetes mellitus improves glycemic control and decreases glucose excursions and the risk of hypoglycemia. Diabetes Technology and Therapeutics 7: Johansson UB, Adamson U, Lins PE, and Wredling R. (2005) Patient management of long-term continuous subcutaneous insulin infusion. Journal of Advanced Nursing 51: Jones SM, Quarry JL, Caldwell-Mcmillan M, Mauger DT, and Gabbay RA. (2005) Optimal insulin pump dosing and postprandial glycemia following a pizza meal using the continuous glucose monitoring system. Diabetes Technology and Therapeutics 7: Jones SM, Quarry JL, Caldwell MM, Mauger DT, and Gabbay RA. (2005) Optimal insulin pump dosing and postprandial glycemia following a pizza meal using the continuous glucose monitoring system. Diabetes technology & therapeutics 7: Notes: Abstract/title: Excluded. Wrong intervention 350. Jorneskog G, Hansson LO, Wallen NH, Yngen M, and Blomback M. (2003) Increased plasma fibrin gel porosity in patients with Type I diabetes during continuous subcutaneous insulin infusion. Journal of thrombosis and haemostasis : JTH 1: Juliusson PB, Graue M, Wentzel-Larsen T, and Sovik O. (2006) The impact of continuous subcutaneous insulin infusion on health-related quality of life in children and adolescents with type 1 diabetes. Acta Paediatrica, International Journal of Paediatrics 95: Juurlink DN, Herrmann N, Szalai JP, Kopp A, and Redelmeier DA. (2004) Medical illness and the risk of suicide in the elderly. Archives of Internal Medicine 164:

90 Kaal ECA and Vecht CJ. (2004) The management of brain edema in brain tumors. Current Opinion in Oncology 16: Kahl S and Malfertheiner P. (2004) Exocrine and endocrine pancreatic insufficiency after pancreatic surgery. Best Practice and Research in Clinical Gastroenterology 18: Kalergis M, De Grandpre E, and Andersons C. (2005) The role of the glycemic index in the prevention and management of diabetes: A review and discussion. Canadian Journal of Diabetes 29: Kamalakannan D, Baskar V, Barton DM, and Abdu TAM. (2003) Diabetic ketoacidosis in pregnancy. Postgraduate Medical Journal 79: Kamalakannan D, Baskar V, and Singh BM. (2004) Severe and disabling diabetic autonomic neuropathy: A case report. Journal of Diabetes and its Complications 18: (case report) 358. Kamboj MK, Zhou P, Malofsky WJ, Franklin B, Shah B, David R, and Kohn B. (2005) Hemorrhagic pituitary apoplexy in an 18 year-old male presenting as non-ketotic hyperglycemic coma (NKHC). Journal of Pediatric Endocrinology and Metabolism 18: (case report) 359. Kamboj MK. (2005) Diabetes on the college campus. Pediatric Clinics of North America 52: Kamoi K, Miyakoshi M, and Maruyama R. (2004) A quality-of-life assessment of intensive insulin therapy using insulin lispro switched from short-acting insulin and measured by an ITR-QOL questionnaire: A prospective comparison of multiple daily insulin injections and continuous subcutaneous insulin infusion. Diabetes Research and Clinical Practice 64: Kamoi K, Tanaka M, Ikarashi T, and Miyakoshi M. (2006) Effect of the 2004 Mid Niigata Prefecture earthquake on glycemic control in type 1 diabetic patients. Diabetes Research and Clinical Practice 74: kan D, Yurtseven N, Tuygun AK, Aksoy P, and Canik S. (2006) [The effects of insulin given prior to release of cross-clamp on coronary sinus lactate levels in coronary artery surgery]. Anadolu. kardiyoloji. dergisi : AKD. = the Anatolian. journal of cardiology 6: Notes: Abstract/title: Excluded. Wrong intervention 363. Kantarceken B, Bulbuloglu E, Yuksel M, and Cetinkaya A. (2004) Dysphagia lusorium in elderly: A case report. World Journal of Gastroenterology 10: (case report) 364. Kapellen TM, Heidtmann B, Bachmann J, Ziegler R, Grabert M, and Holl RW. (2007) Indications for insulin pump therapy in different age groups - An analysis of 1567 children and adolescents. Diabetic Medicine 24: Karl DM. (2004) The use of bolus insulin and advancing insulin therapy in type 2 diabetes. Current Diabetes Reports 4: Kaufman FR, Austin J, Neinstein A, Jeng L, Halvorson M, Devoe DJ, and Pitukcheewanont P. (2002) Nocturnal hypoglycemia detected with the continuous glucose monitoring system in pediatric patients with type 1 diabetes. Journal of Pediatrics 141: Kazlauskaite R, Fogelfeld L, and Orlowski JM. (2003) Insulin therapy in type 2 diabetes. Disease-a-Month 49: Kee CA, Tomalty JA, Cline J, Novick RJ, and Stitt L. (2006) Change in practice patterns in the management of diabetic cardiac surgery patients. Canadian journal of cardiovascular nursing = Journal canadien en soins. infirmiers. cardio vasculaires. 16: Kee CA, Tomalty JA, Cline J, Novick RJ, and Stitt L. (2006) Change in practice patterns in the management of diabetic cardiac surgery patients. Canadian journal of cardiovascular nursing = Journal canadien en soins infirmiers cardio-vasculaires. 16: Keene JR, Kaltman SI, and Kaplan HM. (2002) Treatment of patients who have type 1 diabetes mellitus: physiological misconceptions and infusion pump therapy. The Journal of the American Dental Association 133: Keene KS, Rich TA, Penberthy DR, Shepard RC, Adams R, and Jones RS. (2005) Clinical experience with chronomodulated infusional 5-fluorouracil chemoradiotherapy for pancreatic adenocarcinoma. International Journal of

91 77 Radiation Oncology Biology Physics 62: Kessler L, Passemard R, Oberholzer J, Benhamou PY, Bucher P, Toso C, Meyer P, Penfornis A, Badet L, Wolf P, Colin C, Morel P, and Pinget M. (2002) Reduction of blood glucose variability in type 1 diabetic patients treated by pancreatic islet transplantation: Interest of continuous glucose monitoring. Diabetes Care 25: Khan Ghilzai NM. (2003) New developments in insulin delivery. Drug Development and Industrial Pharmacy 29: Kim KY, Schumacher HR, Hunsche E, Wertheimer AI, and Kong SX. (2003) A literature review of the epidemiology and treatment of acute gout. Clinical Therapeutics 25: King AB and Armstrong D. (2003) A comparison of basal insulin delivery: continuous subcutaneous insulin infusion versus glargine. Diabetes Care 26:1322. Notes: Abstract/title: Included. Full paper: Excluded. Wrong study type (not randomised) 376. Kirk SE. (2003) Insulin pump therapy for type 2 diabetes. Current Diabetes Reports 3: Klonoff DC. (2003) Technological advances in the treatment of diabetes mellitus: Better bioengineering begets benefits in glucose measurement, the artificial pancreas, and insulin delivery. Pediatric Endocrinology Reviews 1: Knee TS, Seidensticker DF, Walton JL, Solberg LM, and Lasseter DH. (2003) A novel use of U-500 insulin for continuous subcutaneous insulin infusion in patients with insulin resistance: a case series. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 9: (case report) 379. Knee TS, Seidensticker DF, Walton JL, Solberg LM, and Lasseter DH. (2003) A novel use of U-500 insulin for continuous subcutaneous insulin infusion in patients with insulin resistance: a case series (Provisional record). Endocrine Practice 9: Kofoed KF, Carstensen S, Hove JD, Freiberg J, Bangsgaard R, Holm S, Rabol A, Hesse B, Arendrup H, and Kelbaek H. (2002) Low whole-body insulin sensitivity in patients with ischaemic heart disease is associated with impaired myocardial glucose uptake predictive of poor outcome after revascularisation. European Journal of Nuclear Medicine 29: Kordonouri O, Hartmann R, Lauterborn R, Barnekow C, Hoeffe J, and Deiss D. (2006) Age-specific advantages of continuous subcutaneous insulin infusion as compared with multiple daily injections in pediatric patients: one-year follow-up comparison by matched-pair analysis. Diabetes Care 29: Notes: Abstract/title: Included. Full paper: Excluded. Wrong study type (not randomised) 382. Korytkowski M, DiNardo M, Donihi AC, Bigi L, and De Vita M. (2006) Evolution of a Diabetes Inpatient Safety Committee. Endocrine Practice 12: Koschwanez HE and Reichert WM. (2007) In vitro, in vivo and post explantation testing of glucose-detecting biosensors: Current methods and recommendations. Biomaterials 28: Krebs J. (2005) PHARMAC and long-acting insulin analogues: a poor man's insulin pump--but not available to the poor man. The New Zealand medical journal. 118:U Krebs J. (2005) PHARMAC and long-acting insulin analogues: A poor man's insulin pump - But not available to the poor man. New Zealand Medical Journal 118:5p Kruger DF, White K, Galpern A, Mann K, Massirio A, McLellan M, and Stevenson J. (2003) Effect of modem transmission of blood glucose data on telephone consultation time, clinic work flow, and patient satisfaction for patients with gestational diabetes mellitus. Journal of the American Academy of Nurse Practitioners. 15: Notes: Abstract/title: Excluded. Wrong intervention 387. Kruger DF, White K, Galpern A, Mann K, Massirio A, McLellan M, and Stevenson J. (2003) Effect of modem transmission of blood glucose data on telephone consultation time, clinic work flow, and patient satisfaction for patients with gestational diabetes mellitus. Journal of the American Academy of Nurse Practitioners 15: Kuhn-Velten WN, Genesius H, and Wiefels KJ. (2002) Measurement of accidental urinary insulin loss from a dislocated intraperitoneal insulin catheter. Diabetes and Metabolism 28: (case report) 389. Kyle PM. (2006) Drugs and the fetus. Current Opinion in Obstetrics and Gynecology 18:93-99.

92 Lane WS. (2006) Use of U-500 regular insulin by continuous subcutaneous insulin infusion in patients with type 2 diabetes and severe insulin resistance. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 12: Langer G, Schloemer G, Knerr A, Kuss O, and Behrens J. (2003) Nutritional interventions for preventing and treating pressure ulcers. Langer. G, Schloemer. G, Knerr. A, Kuss. O., Behrens. J. Nutritional interventions for preventing. and treating. pressure ulcers. Cochrane Database of Systematic Reviews: Reviews Issue. 4 John. Wiley. & Sons., Ltd. Chichester, UK DOI. : / CD Notes: Abstract/title: Excluded. Wrong patient group 392. Lapolla A, Dalfra MG, Masin M, Bruttomesso D, Piva I, Crepaldi C, Tortul C, Dalla Barba B, and Fedele D. (2003) Analysis of outcome of pregnancy in type 1 diabetics treated with insulin pump or conventional insulin therapy. Acta Diabetologica 40: Larsen J, Ford T, Lyden E, Colling C, Mack-Shipman L, and Lane J. (2004) What is hypoglycemia in patients with well-controlled type 1 diabetes treated by subcutaneous insulin pump with use of the continuous glucose monitoring system? Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 10: Lassmann-Vague V and Schaepelynck-Belicar P. (2006) The EVADIAC experience. Diabetes Research and Clinical Practice 74:S164-S Lavack AM and Kropp F. (2003) Smoking among university students in Canada and South Korea: Linking diffusion theory with consumer susceptibility to interpersonal influence. Health Marketing Quarterly 20: Lawson ML, Pacaud D, Lawrence SE, Daneman D, and Dean HJ. (2005) 2003 Canadian clinical practice guidelines for the management of diabetes in children and adolescents. Paediatrics and Child Health 10:5A-16A Le TH, Ostergard DR, Bhatia NN, and Huggins ME. (2005) Newer pharmacologic options in management of overactive bladder syndrome. Current Opinion in Obstetrics and Gynecology 17: Lee A, Cooper MG, Craig JC, Knight JF, and Keneally JP. (2007) Effects of nonsteroidal anti-inflammatory drugs on postoperative renal function in adults with normal renal function. Lee. A, Cooper. MG., Craig. JC, Knight. JF, Keneally. JP. Effects of nonsteroidal. anti inflammatory drugs on postoperative. renal function in adults. with. normal. renal function. Cochrane Database of Systematic Reviews: Reviews Issue. 2 John. Wiley. & Sons., Lt. Notes: Abstract/title: Excluded. Wrong patient group 399. Lee DK, Jin Y, and Kashani A. (2003) Better glucose control by insulin continuous infusion in a medical intensive care unit - a randomized trial [abstract]. American Thoracic Society 99th. International ConferenceA112. Notes: Abstract/title: Excluded. Wrong comparator 400. Lee SW, Im R, and Magbual R. (2004) Current Perspectives on the Use of Continuous Subcutaneous Insulin Infusion in the Acute Care Setting and Overview of Therapy. Critical Care Nursing Quarterly 27: Lee SW, Cao M, Sajid S, Hayes M, Choi L, Rother C, and de Leon R. (2004) The dual-wave bolus feature in continuous subcutaneous insulin infusion pumps controls prolonged post-prandial hyperglycaemia better than standard bolus in type 1 diabetes. Diabetes, Nutrition and Metabolism - Clinical and Experimental 17: Lee SW, Cao M, Sajid S, Hayes M, Choi L, Rother C, and de León R. (2004) The dual-wave bolus feature in continuous subcutaneous insulin infusion pumps controls prolonged post-prandial hyperglycaemia better than standard bolus in Type 1 diabetes. Diabetes, nutrition & metabolism 17: Notes: Abstract/title: Excluded. Wrong intervention 403. Lei Y, Xiang AF, and Dai L. (2002) The efficiency of a continuous infusion of regular insulin by syringe pump in diabetic acute complication. Journal of Nursing Science 17: Lell WA, Nielsen VG, McGiffin DC, Schmidt FE, Kirklin JK, and Stanley AW. (2002) Glucose-insulin-potassium infusion for myocardial protection during off-pump coronary artery surgery. The Annals of thoracic surgery 73: Notes: Abstract/title: Excluded. Wrong patient group 405. Lenhard MJ. (2006) A new look at patient selection criteria for continuous subcutaneous insulin infusion (CSII). Diabetes Research and Clinical Practice 74:S140-S Lepore G, Dodesini AR, Nosari I, and Trevisan R. (2003) Both continuous subcutaneous insulin infusion and a multiple daily insulin injection regimen with glargine as basal insulin are equally better than traditional multiple daily insulin injection treatment. Diabetes Care 26: Notes: Abstract/title: Included. Full paper: Excluded. Wrong study type (not randomised)

93 Lepore G, Dodesini AR, Nosari I, and Trevisan R. (2004) Effect of continuous subcutaneous insulin infusion vs multiple daily insulin injection with glargine as basal insulin: An open parallel long-term study. Diabetes, Nutrition and Metabolism - Clinical and Experimental 17: Levetan C, Want LL, Weyer C, Strobel SA, Crean J, Wang Y, Maggs DG, Kolterman OG, Chandran M, Mudaliar SR, and Henry RR. (2003) Impact of pramlintide on glucose fluctuations and postprandial glucose, glucagon, and triglyceride excursions among patients with type 1 diabetes intensively treated with insulin pumps. Diabetes Care 26: Li JY, Sun S, and Wu SJ. (2006) Continuous insulin infusion improves postoperative glucose control in patients with diabetes mellitus undergoing coronary artery bypass surgery. Texas. Heart Institute journal / from. the Texas. Heart Institute of St. Luke's. Episcopal. Hospital, Texas. Children's. Hospital 33: Notes: Abstract/title: Excluded. Wrong intervention 410. Li JY, Sun S, and Wu SJ. (2006) Continuous insulin infusion improves postoperative glucose control in patients with diabetes mellitus: Undergoing coronary artery bypass surgery. Texas Heart Institute Journal 33: Notes: Abstract/title: Excluded. Wrong intervention 411. Li MZ, Zhang SX, and Wang JM. (2003) A clinical study on treatment of comatose cerebral hemorrhage patients with hyperglycemia by continuous intravenous injection of insulin with micropump. Journal of Binzhou. Medical College 26: Notes: Abstract/title: Excluded. Wrong patient group 412. Li Y, Xu W, Liao Z, Yao B, Chen X, Huang Z, Hu G, and Weng J. (2004) Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients is associated with improvement of (beta)-cell function. Diabetes Care 27: Li YB, Liu J, Liao ZH, Liao Y, Deng WP, and Weng JP. (2005) [The comparison of insulin aspart and human soluble insulin used in insulin pump therapy in newly diagnosed type 2 diabetic patients]. Chung Hua i Hsueh Tsa Chih [Chinese Medical Journal] 85: Notes: Abstract/title: Excluded. Wrong intervention 414. Liakishev AA. (2006) [Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. Results of the DCCT/EDIC study]. Kardiologiia. 46:73. Notes: Abstract/title: Excluded. Wrong intervention 415. Liberatore J, Perlman K, Buccino J, Artiles-Sisk A, and Daneman D. (2004) Continuous subcutaneous insulin infusion pump treatment in children with type 1 diabetes mellitus. Journal of Pediatric Endocrinology and Metabolism 17: Liebl A. (2002) Challenges in optimal metabolic control of diabetes. Diabetes/Metabolism Research and Reviews 18:S36-S Lindner O, Klein E, Franzke K, Petzoldt R, and Burchert W. (2004) Scintigraphic Monitoring of Catheter-Port Systems in Type I Diabetics with Continuous Insulin Therapy. Experimental and Clinical Endocrinology and Diabetes 112: Linkeschova R, Raoul M, Bott U, Berger M, and Spraul M. (2002) Less severe hypoglycaemia, better metabolic control and improved quality of life in Type 1 diabetes mellitus with continuous subcutaneous insulin infusion (CSII) therapy; an observational study of 100 consecutive patients followed for a mean of 2 years. Diabetic Medicine 19: Lisowski LA, Verheijen PM, De Smedt MMC, Visser GHA, and Meijboom EJ. (2003) Altered fetal circulation in type-1 diabetic pregnancies. Ultrasound in Obstetrics and Gynecology 21: Litton J, Rice A, Friedman N, Oden J, Lee MM, and Freemark M. (2002) Insulin pump therapy in toddlers and preschool children with type 1 diabetes mellitus. Journal of Pediatrics 141: Liu JP, Gluud LL, Als NB, and Gluud C. (2004) Artificial and bioartificial support systems for liver failure. Liu JP, Gluud. LL, Als Nielsen. B, Gluud. C. Artificial and bioartificial. support systems. for liver failure. Cochrane Database of Systematic Reviews: Reviews Issue. 1 John. Wiley. & Sons., Ltd. Chichester, UK DOI. : / CD pub2. Notes: Abstract/title: Excluded. Wrong patient group 422. Liuzzo JP, Ambrose JA, and Diggs P. (2005) Proton-pump inhibitor use by coronary artery disease patients is associated with fewer chest pain episodes, emergency department visits and hospitalizations. Alimentary Pharmacology and Therapeutics 22: Liuzzo JP, Ambrose JA, and Diggs P. (2005) Proton pump inhibitors for patients with coronary artery disease associated with reduced chest pain, emergency department visits, and hospitalizations. Clinical Cardiology 28:

94 Lo A, Egidi MF, Gaber LW, Amiri HS, Vera S, Nezakatgoo N, and Gaber AO. (2004) Comparison of sirolimusbased calcineurin inhibitor-sparing and calcineurin inhibitor-free regimens in cadaveric renal transplantation. Transplantation 77: Logtenberg SJJ, van Ballegooie E, Israel-Bultman H, van Linde A, and Bilo HJG. (2007) Glycaemic control, health status and treatment satisfaction with continuous intraperitoneal insulin infusion. Netherlands Journal of Medicine 65: Lombardo F, Salzano G, Messina MF, and De Luca F. (2005) Compliance and administration methods in management of type 1 diabetes. Acta bio-medica de L'Ateneo parmense : organo della Societa di medicina e scienze naturali di Parma. 76 Suppl 3: Loveman E, Royle P, and Waugh N. (2003) Specialist nurses in diabetes mellitus. Loveman. E, Royle. P, Waugh. N. Specialist. nurses in diabetes mellitus. Cochrane Database of Systematic Reviews: Reviews Issue. 2 John. Wiley. & Sons., Ltd. Chichester, UK DOI. : / CD Notes: Abstract/title: Excluded. Wrong intervention 428. Low KG, Massa L, Lehman D, and Olshan JS. (2005) Insulin pump use in young adolescents with type 1 diabetes: A descriptive study. Pediatric Diabetes 6: Ludvigsson J and Isacson E. (2003) Clinical use of glucose sensors in the treatment of diabetes in children and adolescents. Practical Diabetes International 20: Ludvigsson J and Hanas R. (2003) Continuous subcutaneous glucose monitoring improved metabolic control in pediatric patients with type 1 diabetes: a controlled crossover study. Pediatrics. 111: Notes: Abstract/title: Excluded. Wrong intervention 431. Lundstrom S and Furst CJ. (2006) The use of corticosteroids in Swedish palliative care. Acta Oncologica 45: Lynch ME and Watson CPN. (2006) The pharmacotherapy of chronic pain: A review. Pain Research and Management 11: Notes: Abstract/title: Excluded. Wrong patient group 433. MacGregor DA, Zvara DA, Treadway J, Ibdah JA, Maloney JD, Kon ND, and Riley RD. (2004) Late presentation of esophageal injury after transesophageal echocardiography. Anesthesia and Analgesia 99: (case report) 434. Mack-Fogg JE, Orlowski CC, and Jospe N. (2005) Continuous subcutaneous insulin infusion in toddlers and children with type 1 diabetes mellitus is safe and effective. Pediatric Diabetes 6: MacLeod KM. (2004) Hypoglycaemia in diabetes. Clinical Medicine, Journal of the Royal College of Physicians of London 4: Magee L, Shrim A, and Koren G. (2006) Diagnosis and management of nausea and vomiting in pregnancy. Fetal and Maternal Medicine Review 17: Malmberg K. (2004) Role of insulin-glucose infusion in outcomes after acute myocardial infarction: the diabetes and insulin-glucose infusion in acute myocardial infarction (DIGAMI) study. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 10 Suppl 2: Notes: Abstract/title: Excluded. Wrong comparator 438. Maron R, Levine D, Dobbs TE, and Geisler WM. (2006) Two cases of pott disease associated with bilateral psoas abscesses: Case report. Spine 31:E561-E564. (case report) 439. Marrero DG, Crean J, Zhang B, Kellmeyer T, Gloster M, Herrmann K, Rubin R, Fineberg N, and Kolterman O. (2007) Effect of adjunctive pramlintide treatment on treatment satisfaction in patients with type 1 diabetes. Diabetes Care 30: Notes: Abstract/title: Included. Full paper: Exclude. Wrong comparator (compares intensive therapy with placebo vs pramlintide). Wrong outcomes (patient satisfaction only) 440. Masoudi FA, Baillie CA, Wang Y, Bradford WD, Steiner JF, Havranek EP, Foody JM, and Krumholz HM. (2005) The complexity and cost of drug regimens of older patients hospitalized with heart failure in the United States, Archives of Internal Medicine 165: Mastrototaro JJ, Cooper K, and Shah R. (2006) Early clinical experience with an integrated continuous glucose sensor/insulin pump platform. Diabetes Research and Clinical Practice 74:S156-S159.

95 Mastrototaro JJ, Cooper KW, Soundararajan G, Sanders JB, and Shah RV. (2006) Clinical experience with an integrated continuous glucose sensor/insulin pump platform: A feasibility study. Advances in Therapy 23: Matheu V, Perez E, Hernandez M, Diaz E, Darias R, Gonzalez A, Garcia JC, Sanchez I, Feliciano L, Caballero A, and de la Torre F. (2005) Insulin allergy and resistance successfully treated by desensitisation with Aspart insulin. Clinical and Molecular Allergy 3:18p. (case report) 444. Matta MP, Melki V, Bessiere-Lacombe S, and Hanaire-Broutin H. (2004) What are capillary blood ketone levels in type 1 diabetic patients using CSII in normal conditions of insulin delivery? Diabetes and Metabolism 30: Matyka K, Ford-Adams M, and Dunger DB. (2002) Hypoglycaemia and counterregulation during childhood. Hormone Research 57: Mauras N, Chase PH, Fiallo-Scharer R, Fisher JH, Tallant B, Tsalikian E, Tansey MJ, Larson LF, Coffey J, Wysocki T, Mauras N, Fox LA, Bird K, Lofton KL, Buckingham BA, Wilson DM, Block JM, Clinton P, Weinzimer SA, Tamborlane WV, Doyle EA, Sikes K, Beck RW, Ruedy KJ, Kollman C, Xing D, Kalajian A, Stockdale CR, Steffes MW, Bucksa JM, Nowicki ML, Van Hale CA, Makky V, Singh R, Grave GD, Linder B, Winer KK, Becker DM, Cox C, Ryan CM, White NH, and White PC. (2007) Impaired overnight counterregulatory hormone responses to spontaneous hypoglycemia in children with type 1 diabetes. Pediatric Diabetes 8: McCall AL, Cox DJ, Crean J, Gloster M, and Kovatchev BP. (2006) A novel analytical method for assessing glucose variability: Using CGMS in type 1 diabetes mellitus. Diabetes Technology and Therapeutics 8: McGahan L. (2002) Continuous glucose monitoring in the management of diabetes mellitus (Structured abstract) McGahan L. (2002) Continuous glucose monitoring in the management of diabetes mellitus. Issues in emerging health technologies -: McGirt MJ, Mavropoulos JC, McGirt LY, Alexander MJ, Friedman AH, Laskowitz DT, and Lynch JR. (2003) Leukocytosis as an independent risk factor for cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Journal of Neurosurgery 98: McIntyre M and Haw C. (2007) How much medicine is prescribed for the side effects of psychotropics? Hospital Pharmacist 14: McKeage K and Goa KL. (2002) Spotlight on insulin glargine in type 1 and 2 diabetes mellitus. Treatments in Endocrinology 1: McMahon SK, Airey FL, Marangou DA, McElwee KJ, Carne CL, Clarey AJ, Davis EA, and Jones TW. (2005) Insulin pump therapy in children and adolescents: Improvements in key parameters of diabetes management including quality of life. Diabetic Medicine 22: McMahon SK, Ferreira LD, Ratnam N, Davey RJ, Youngs LM, Davis EA, Fournier PA, and Jones TW. (2007) Glucose requirements to maintain euglycemia after moderate-intensity afternoon exercise in adolescents with type 1 diabetes are increased in a biphasic manner. The Journal of clinical endocrinology and metabolism 92: Notes: Abstract/title: Excluded. Wrong intervention 455. Meas T, Taboulet P, Sobngwi E, and Gautier JF. (2005) Is capillary ketone determination useful in clinical practice? In which circumstances? Diabetes and Metabolism 31: Mednick L, Cogen FR, and Streisand R. (2004) Satisfaction and quality of life in children with type 1 diabetes and their parents following transition to insulin pump therapy. Children's Health Care 33: Meece JD and Campbell RK. (2002) Insulin lispro update. The Diabetes educator 28:d-277. Notes: Abstract/title: Included. Full paper: Exclude. Wrong study type (review not systematic) 458. Mehler PS, Crews C, and Weiner K. (2004) Bulimia: Medical complications. Journal of Women's Health 13: Melville B. (2005) The insulin pump: Why not use it for every type I diabetic patient? Critical Care Nursing Quarterly 28: Meo SA, Al Drees AM, Shah SFA, Arif M, and Al Rubean K. (2005) Lung function in type 1 Saudi diabetic patients. Saudi Medical Journal 26:

96 Mesejo A, Acosta JA, Ortega C, Vila J, Fernández M, Ferreres J, Sanchis JC, and López F. (2003) Comparison of a high-protein disease-specific enteral formula with a high-protein enteral formula in hyperglycemic critically ill patients. Clinical Nutrition 22: Notes: Abstract/title: Excluded. Wrong intervention 462. Meyer L, Bohme P, Delbachian I, Lehert P, Cugnardey N, Drouin P, and Guerci B. (2002) The benefits of metformin therapy during continuous subcutaneous insulin infusion treatment of type 1 diabetic patients. Diabetes Care 25: Notes: Abstract/title: Excluded. Wrong comparator 463. Minkina PM, Jarosz CP, ecka TE, and Deja G. (2005) [Assessment of metabolic control and safety of continuous subcutaneous insulin infusion in prepubertal children with type 1 diabetes mellitus]. Endokrynologia., diabetologia i choroby. przemiany. materii. wieku. rozwojowego. : organ Polskiego Towarzystwa Endokrynologów. Dzieci. &#281. ;cych. 11: Misso ML, O'Connor DA, Egberts KJ, and Shaw J. (2005) Continuous subcutaneous insulin infusion (CSII) versus multiple insulin injections for type 1 diabetes mellitus. Misso. ML., O'Connor. DA., Egberts. KJ, Shaw. J. Continuous. subcutaneous. insulin. infusion versus. multiple insulin. injections. for type. 1 diabetes mellitus. Cochrane Database of Systematic Reviews: Protocols Issue. 1 John. Wiley. & Sons., Ltd. Chichester, UK. (protocol only) 465. Mlcak P, Fialova J, Trnkova K, and Chlup R. (2004) A Continuous Glucose Monitoring System (CGMS) - a promising approach for improving metabolic control in persons with type 1 Diabetes mellitus treated by insulin pumps. Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia. 148: Mokshagundam SPL. (2004) Perioperative Management of Diabetes Mellitus. Critical Care Nursing Quarterly 27: Monjezi S and Lyle RR. (2006) Neurofeedback treatment of type I diabetes mellitus: Perceptions of quality of life and stabilization of insulin treatment - Two case studies. Journal of Neurotherapy 10: (case report) 468. Monnier L, Colette C, Lapinski H, and Boniface H. (2004) Self-monitoring of blood glucose in diabetic patients: From the least common denominator to the greatest common multiple. Diabetes and Metabolism 30: Moore KB, Saudek CD, Greene A, and Dackiw A. (2006) Implantable insulin pump therapy: An unusual presentation of a catheter-related complication. Diabetes Technology and Therapeutics 8: (case report) 470. Moore KB, Saudek CD, Greene A, and Dackiw A. (2006) Implantable insulin pump therapy: an unusual presentation of a catheter-related complication. Diabetes technology & therapeutics. 8: (case report) 471. Moreland EC, Tovar A, Zuehlke JB, Butler DA, Milaszewski K, and Laffel LMB. (2004) The impact of physiological, therapeutic and psychosocial variables on glycemic control in youth with type 1 diabetes mellitus. Journal of Pediatric Endocrinology and Metabolism 17: Moyes V, Driver R, Croom A, Mirakian R, and Chowdhury TA. (2006) Insulin allergy in a patient with Type 2 diabetes successfully treated with continuous subcutaneous insulin infusion. Diabetic Medicine 23: (case report) 473. Mozdzan M, Mozdzan M, Loba J, Markuszewski L, and Ruxer J. (2006) [Effect of short-term intensive insulin therapy on daily insulin requirement in poorly controlled type 2 diabetes patients]. Wiadomo. &#347. ;ci. lekarskie. 59: Notes: Abstract/title: Excluded. Wrong intervention 474. Mozdzan M, Ruxer J, Loba J, Siejka A, and Markuszewski L. (2006) Safety of various methods of intensive insulin therapy in hospital condition assessed by hypoglycaemic episodes detected with the use of continuous glucose monitoring system. Advances in medical sciences 51: Notes: Abstract/title: Excluded. Wrong intervention 475. Muis MJ, Bots ML, Bilo HJG, Hoogma RPLM, Hoekstra JBL, Grobbee DE, and Stolk RP. (2006) Determinants of daily insulin use in Type 1 diabetes. Journal of Diabetes and its Complications 20: Muroi R, Yagyu H, Kobayashi H, Nagata M, Sato N, Ideno J, Fujita N, Ando A, Okada K, Takiyama Y, Nagasaka S, Miyajima H, Nakano I, and Ishibashi S. (2006) Early onset insulin-dependent diabetes mellitus as an initial manifestation of aceruloplasminaemia. Diabetic Medicine 23: (case report) 477. Murray KJ and Lovell DJ. (2002) Advanced therapy for juvenile arthritis. Bailliere's Best Practice and Research in Clinical Rheumatology 16: Myers VH, Boyer BA, Herbert JD, Barakat LP, and Scheiner G. (2007) Fear of hypoglycemia and self reported posttraumatic stress in adults with type I diabetes treated by intensive regimens. Journal of Clinical Psychology in

97 83 Medical Settings 14: Nabhan ZM, Rardin L, Meier J, Eugster EA, and DiMeglio LA. (2006) Predictors of glycemic control on insulin pump therapy in children and adolescents with type I diabetes. Diabetes Research and Clinical Practice 74: Nagai T, Negishi T, Imamura M, and Mori M. (2005) Metformin use in an obese diabetic patient from weeks 1 to 21 of pregnancy. Kitakanto Medical Journal 55: (case report) 481. Nahata L. (2006) Insulin therapy in pediatric patients with type I diabetes: Continuous subcutaneous insulin infusion versus multiple daily injections. Clinical Pediatrics 45: Nakata H, Inui K, Wasaka T, Tamura Y, Tran TD, Qiu Y, Wang X, Nguyen TB, and Kakigi R. (2004) Movements modulate cortical activities evoked by noxious stimulation. Pain 107: Nanda K, Cook LA, Gallo MF, and Grimes DA. (2002) Terbutaline pump maintenance therapy after threatened preterm labor for preventing preterm birth. Nanda. K., Cook. LA, Gallo. MF., Grimes. DA. Terbutaline. pump. maintenance. therapy after. threatened. preterm. labor. for preventing. preterm. birth. Cochrane Database of Systematic Reviews: Reviews Issue. 4 John. Wiley. & Sons., Ltd. Chichester, UK DOI. : /. Notes: Abstract/title: Excluded. Wrong patient group 484. New R. (2004) Oral insulin therapy. EBR - European Biopharmaceutical Review -: NHS Q, I. (2003) The use of subcutaneous insulin infusion for diabetes(insulin pump therapy) (Brief record) Nielsen S, Kain D, Szudzik E, Dhindsa S, Garg R, and Dandona P. (2005) Use of continuous subcutaneous insulin infusion pump in patients with type 2 diabetes mellitus. Diabetes Educator 31: (case report) 487. Nimri R, Weintrob N, Benzaquen H, Ofan R, Fayman G, and Phillip M. (2006) Insulin pump therapy in youth with type 1 diabetes: a retrospective paired study. Pediatrics. 117: Noczynska A, Kaluzny M, Wasik-Kuprianowicz A, and Filipowski H. (2004) Insulin pump therapy in children and adolescents with type 1 diabetes - Personal observations. Advances in Clinical and Experimental Medicine 13: Norgaard K. (2003) A nationwide study of continuous subcutaneous insulin infusion (CSII) in Denmark. Diabetic Medicine 20: Novak B and Metelko Z. (2003) New trends in insulin therapy. Diabetologia Croatica 32: Nuboer R and Bruining GJ. (2006) Cost-effectiveness of continuous subcutaneous insulin infusion (CSII) in children: Illusion or delusion? Pediatric Diabetes 7: O'Neil KJ, Jonnalagadda SS, Hopkins BL, and Kicklighter JR. (2005) Quality of life and diabetes knowledge of young persons with type 1 diabetes: Influence of treatment modalities and demographics. Journal of the American Dietetic Association 105: Oduneye F. (2002) Insulin pumps, conventional and intensive multiple injection insulin therapy for type 1 diabetes mellitus (Structured abstract). in Foxcroft DR, Muthu V (Eds) STEER: Succinct and Timely Evaluated Evidence Reviews. Wessex Institute for Health Research & Development, University of Southampton [WWW document] URL signpoststeer. org/ 2(4). Notes: Abstract/title: Included. Full paper: Excluded. Level I evidence with literature search to November Olinder AL, Kernell A, and Smide B. (2006) Treatment with CSII in two infants with neonatal diabetes mellitus. Pediatric Diabetes 7: (case report) 495. Olivieri I, Palazzi C, Peruz G, and Padula A. (2005) Management issues with elderly-onset rheumatoid arthritis: An update. Drugs and Aging 22: Orsini-Federici M, Akwi JA, Canonico V, Celleno R, Ferolla P, Pippi R, Tassi C, Timi A, and Benedetti MM. (2006) Early detection of insulin deprivation in continuous subcutaneous insulin infusion-treated patients with type 1 diabetes. Diabetes Technology and Therapeutics 8: Oswald G, Kinch A, and Ruddy E. (2004) Transfer to a patient centred, carbohydrate counting and insulin matching programme in a shortened time frame. Practical Diabetes International 21:

98 Otto-Buczkowska E, Dworzecki T, and Mazur U. (2007) Alterations of blood glucose homeostasis in critically ill children - Hyperglycemia. Endokrynologia, Diabetologia i Choroby Przemiany Materii Wieku Rozwojowego 13: Owens DR. (2002) New horizons - Alternative routes for insulin therapy. Nature Reviews Drug Discovery 1: Ozmen B and Boyvada S. (2002) Can self-monitoring blood glucose control decrease glycated hemoglobin levels in diabetes mellitus. Endocrinologist 12: Pace F, Molteni P, and Wiklund I. (2006) Outcome research in gastroenterology: The case of gastroesophageal reflux disease (GERD). Drug Development Research 67: Palerm CC, Zisser H, Bevier WC, Jovanovic L, and Doyle III FJ. (2007) Prandial insulin dosing using run-to-run control: Application of clinical data and medical expertise to define a suitable performance metric. Diabetes Care 30: Pankowska E, Skorka A, Szypowska A, and Lipka M. (2005) Memory of insulin pumps and their record as a source of information about insulin therapy in children and adolescents with type 1 diabetes. Diabetes Technology and Therapeutics 7: Pankowska E, Szypowska A, Lipka M, and Skorka A. (2007) Sustained metabolic control and low rates of severe hypoglycaemic episodes in preschool diabetic children treated with continuous subcutaneous insulin infusion. Acta Paediatrica, International Journal of Paediatrics 96: Papadogias D, Makras P, Griniatsos I, Kaltsas G, and Grossman AB. (2006) Advances in the detection and management of neuroendocrine (carcinoid and pancreatic islet cell) tumours. Current Opinion in Endocrinology and Diabetes 13: Park S and Choi SB. (2002) Effects of (alpha)-tocopherol supplementation and continuous subcutaneous insulin infusion on oxidative stress in Korean patients with type 2 diabetes. American Journal of Clinical Nutrition 75: Notes: Abstract/title: Excluded. Wrong comparator 507. Park S and Choi SB. (2002) Effects of alpha-tocopherol supplementation and continuous subcutaneous insulin infusion on oxidative stress in Korean patients with type 2 diabetes. The American journal of clinical nutrition 75: Notes: Abstract/title: Excluded. Wrong comparator 508. Park S and Choi SB. (2003) Induction of long-term normoglycemia without medication in Korean type 2 diabetes patients after continuous subcutaneous insulin infusion therapy. Diabetes/Metabolism Research and Reviews 19: Patni P, Varghese D, Balekar N, and Jain D. (2006) Needle-free insulin drug delivery. Indian Journal of Pharmaceutical Sciences 68: Peragallo-Dittko V. (2002) Evolving strategies in insulin replacement therapy. Drug Benefit Trends 14: Pereira CT and Herndon DN. (2005) The pharmacologic modulation of the hypermetabolic response to burns. Advances in Surgery 39: Perkins BA and Riddell MC. (2006) Type 1 diabetes and exercise: Using the insulin pump to maximum advantage. Canadian Journal of Diabetes 30: Petrovski G, Dimitrovski C, and Milenkovic T. (2007) Clinical utility of continuous subcutaneous insulin infusion in patients with type 1 diabetes: A Macedonian report. Diabetologia Croatica 35: Peyrot M and Rubin RR. (2005) Validity and reliability of an instrument for assessing health-related quality of life and treatment preferences: The insulin delivery system rating questionnaire. Diabetes Care 28: Pfutzner J, Forst T, Butzer R, Forst S, Weber MM, Pfutzner AH, and Pfutzner A. (2006) Performance of the continuous glucose monitoring system (CGMS) during development of ketosis in patients on insulin pump therapy. Diabetic Medicine 23: Pichon RA, Augustovski F, Cernadas C, Ferrante D, Regueiro A, and Garcia MS. (2004) Diabetes mellitus treatment with insulin pump: clinical effectiveness - indications (Brief record). Notes: Abstract/title: Excluded. Not in english

99 Pickup J and Keen H. (2002) Continuous subcutaneous insulin infusion at 25 years: evidence base for the expanding use of insulin pump therapy in type 1 diabetes. Diabetes Care 25: Pickup J, Mattock M, and Kerry S. (2002) Glycaemic control with continuous subcutaneous insulin infusion compared with intensive insulin injections in patients with type 1 diabetes: Meta-analysis of randomised controlled trials. British Medical Journal 324: Notes: Abstract/title: Included. Full paper: Exclude. Level I evidence with literature search to Pickup JC, Kidd J, Burmiston S, and Yemane N. (2005) Effectiveness of continuous subcutaneous insulin infusion in hypoglycaemia-prone type 1 diabetes. Practical Diabetes International 22: Pickup JC. (2006) Long-term use of continuous subcutaneous insulin infusion. Diabetes Research and Clinical Practice 74:S101-S Pickup JC, Kidd J, Burmiston S, and Yemane N. (2006) Determinants of glycaemic control in type 1 diabetes during intensified therapy with multiple daily insulin injections or continuous subcutaneous insulin infusion: Importance of blood glucose variability. Diabetes/Metabolism Research and Reviews 22: Pietzsch M, Theuer S, Haase G, Plath F, Keyser M, and Riethling AK. (2002) Results of systematic screening for serious gastrointestinal bleeding associated with NSAIDs in Rostock hospitals. International Journal of Clinical Pharmacology and Therapeutics 40: Plockinger U and Wiedenmann B. (2005) Management of metastatic endocrine tumours. Best Practice and Research in Clinical Gastroenterology 19: Plotnick LP, Clark LM, Brancati FL, and Erlinger T. (2003) Safety and effectiveness of insulin pump therapy in children and adolescents with type 1 diabetes. Diabetes Care 26: Pohle T and Domschke W. (2003) Gastric function measurements in drug development. British Journal of Clinical Pharmacology 56: Polaka M and Shield J. (2004) Neonatal and very-early-onset diabetes mellitus. Seminars in Neonatology 9: Poulaki V, Qin W, Joussen AM, Hurlbut P, Wiegand SJ, Rudge J, Yancopoulos GD, and Adamis AP. (2002) Acute intensive insulin therapy exacerbates diabetic blood-retinal barrier breakdown via hypoxia-inducible factor- 1(alpha) and VEGF. Journal of Clinical Investigation 109: Pouwels MJJ, Tack CJ, Hermus AR, and Lutterman JA. (2003) Treatment with intravenous insulin followed by continuous subcutaneous insulin infusion improves glycaemic control in severely resistant Type 2 diabetic patients. Diabetic Medicine 20: Pozzilli P, Crino A, Schiaffini R, Manfrini S, Fioriti E, Coppolino G, Pitocco D, Visalli N, Corbi S, Spera S, Suraci C, Cervoni M, Matteoli MC, Patera IP, Ghirlanda G, Valente L, Guglielmi C, Anguissola GB, Costanza F, Montemari AL, Cantagallo A, De Mattia G, Faldetta MRC, Bitti MLM, Marietti G, and Bizzarri C. (2003) A 2-Year Pilot Trial of Continuous Subcutaneous Insulin Infusion Versus Intensive Insulin Therapy in Patients with Newly Diagnosed Type 1 Diabetes (IMDIAB 8). Diabetes Technology and Therapeutics 5: Notes: Abstract/title: Included. Full paper: Exclude. <10 evaluable subjects per treatment arm 530. Prasek M, Bozek T, and Metelko Z. (2003) Continuous subcutaneous insulin infusion (CSII). Diabetologia Croatica 32: Puder JJ, Lachelt S, Endrass J, Muller B, and Keller U. (2005) What are disease perceptions and subjective treatment goals of insulin treated diabetic patients? Swiss Medical Weekly 135: Quatrini M, Castoldi L, Rossi G, Cesana BM, Peracchi M, and Bardella MT. (2005) A follow-up study of patients with Zollinger-Ellison syndrome in the period : Effects of surgical and medical treatments on long-term survival. Journal of Clinical Gastroenterology 39: Radermecker RP and Scheen AJ. (2004) Continuous subcutaneous insulin infusion with short-acting insulin analogues or human regular insulin: Efficacy, safety, quality of life; and cost-effectiveness. Diabetes/Metabolism Research and Reviews 20: Radermecker RP, Pierard GE, and Scheen AJ. (2007) Lipodystrophy reactions to insulin: Effects of continuous insulin infusion and new insulin analogs. American Journal of Clinical Dermatology 8:21-28.

100 Rahman W and Rahman FZ. (2005) Giant cell (temporal) arteritis: An overview and update. Survey of Ophthalmology 50: Raile K, Noelle V, Landgraf R, and Schwarz HP. (2002) Weight in adolescents with type 1 diabetes mellitus during continuous subcutaneous insulin infusion (CSII) therapy. Journal of Pediatric Endocrinology and Metabolism 15: Raine 3rd. CH. (2003) Self-monitored blood glucose: a common pitfall. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 9: Rajeswaran C, Harris N, Bodansky HJ, and Amery CM. (2005) Tuberculous osteomyelitis in the diabetic foot. British Journal of Diabetes and Vascular Disease 5: (case report) 539. Ramchandani N, Ten S, Anhalt H, Sinha S, Ching J, Finkelstein A, and Maclaren NK. (2006) Insulin pump therapy from the time of diagnosis of type 1 diabetes. Diabetes Technology and Therapeutics 8: Raskin P, Bode BW, Marks JB, Hirsch IB, Weinstein RL, McGill JB, Peterson GE, Mudaliar SR, and Reinhardt RR. (2003) Continuous subcutaneous insulin infusion and multiple daily injection therapy are equally effective in type 2 diabetes: A randomized, parallel-group, 24-week study. Diabetes Care 26: Notes: Abstract/title: Included Rasmussen JJ, Fuller W, and Ali MR. (2007) Marginal ulceration after laparoscopic gastric bypass: An analysis of predisposing factors in 260 patients. Surgical Endoscopy 21: Rassias AJ, Givan AL, Marrin CAS, Whalen K, Pahl J, and Yeager MP. (2002) Insulin increases neutrophil count and phagocytic capacity after cardiac surgery. Anesthesia and Analgesia 94: Razeghi S, Schubert V, Knerr I, Plank C, and Zimmermann T. (2002) Night-time only insulin pump therapy in young children with type 1 diabetes mellitus. Practical Diabetes International 19: Reda E, Von Reitzenstein A, and Dunn P. (2007) Metabolic control with insulin pump therapy: The Waikato experience. New Zealand Medical Journal Reed K and Lehmann ED. (2005) Diabetes website review: Diabetes Technology and Therapeutics 7: Reinhart L and Panning CA. (2002) Insulin glargine: A new long-acting insulin product. American Journal of Health-System Pharmacy 59: Ren JG. (2004) A clinical study of insulin pump therapy in 32 patients of diabetes ketoacidosis. Journal of Chinese Clinical Medicine 5: Notes: Abstract/title: Excluded. Not in english 548. Renard E. (2002) Implantable closed-loop glucose-sensing and insulin delivery: the future for insulin pump therapy. Current opinion in pharmacology 2: Renard E. (2004) Implantable insulin delivery pumps. Minimally Invasive Therapy and Allied Technologies 13: Renard E. (2005) Intensive insulin therapy today: 'Basal-bolus' using multiple daily injections or CSII? Diabetes and Metabolism 31:4S40-4S Renard E, Costalat G, Chevassus H, and Bringer J. (2006) Closed loop insulin delivery using implanted insulin pumps and sensors in type 1 diabetic patients. Diabetes Research and Clinical Practice 74:S173-S177. (case report) 552. Renard E, Costalat G, Chevassus H, and Bringer J. (2006) Artificial (beta)-cell: Clinical experience toward an implantable closed-loop insulin delivery system. Diabetes and Metabolism 32: Renard E and Schaepelynck-Belicar P. (2007) Implantable insulin pumps. A position statement about their clinical use. Diabetes and Metabolism 33: Retnakaran R, Hochman J, Devries JH, Hanaire-Broutin H, Heine RJ, Melki V, and Zinman B. (2004) Continuous subcutaneous insulin infusion versus multiple daily injections: The impact of baseline A1c. Diabetes Care 27: Notes: Abstract/title: Included.

101 Reynolds NA and Wagstaff AJ. (2004) Insulin aspart: A review of its use in the management of type 1 or 2 diabetes mellitus. Drugs 64: Richardson T, Kentish J, and Kerr D. (2002) Something old, something new... - Novel treatments for diabetes in the elderly. CME Journal Geriatric Medicine 4: Richardson T and Kerr D. (2003) Skin-Related Complications of Insulin Therapy: Epidemiology and Emerging Management Strategies. American Journal of Clinical Dermatology 4: Richter B and Neises G. (2005) 'Human' insulin versus animal insulin in people with diabetes mellitus. Richter. B, Neises. G. 'Human'. insulin. versus. animal insulin. in people. with. diabetes mellitus. Cochrane Database of Systematic Reviews: Reviews Issue. 1 John. Wiley. & Sons., Ltd. Chichester, UK DOI. : / CD pub2. Notes: Abstract/title: Excluded. Wrong comparator 559. Richter B, Bandeira EE, Bergerhoff K, Clar C, and Ebrahim SH. (2006) Pioglitazone for type 2 diabetes mellitus. Richter. B, Bandeira. Echtler. E, Bergerhoff. K., Clar. C, Ebrahim. SH. Pioglitazone. for type. 2 diabetes mellitus. Cochrane Database of Systematic Reviews: Reviews Issue. 4 John. Wiley. & Sons., Ltd. Chichester, UK DOI. : / CD pub2. Notes: Abstract/title: Excluded. Wrong intervention 560. Richter B, Bandeira EE, Bergerhoff K, and Ebrahim SH. (2007) Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus. Richter. B, Bandeira. Echtler. E, Bergerhoff. K., Ebrahim. SH. Dipeptidyl. peptidase. 4 inhibitors. for type. 2 diabetes mellitus. Cochrane Database of Systematic Reviews: Protocols Issue. 3 John. Wiley. & Sons., Ltd. Chichester, UK DOI. : / CD006. Notes: Abstract/title: Excluded. Wrong intervention 561. Richter B, Bandeira EE, Bergerhoff K, Clar C, and Ebrahim SH. (2007) Rosiglitazone for type 2 diabetes mellitus. Richter. B, Bandeira. Echtler. E, Bergerhoff. K., Clar. C, Ebrahim. SH. Rosiglitazone. for type. 2 diabetes mellitus. Cochrane Database of Systematic Reviews: Reviews Issue. 3 John. Wiley. & Sons., Ltd. Chichester, UK DOI. : / CD pub2. Notes: Abstract/title: Excluded. Wrong intervention 562. Ritholz MD, Smaldone A, Lee J, Castillo A, Wolpert H, and Weinger K. (2007) Perceptions of psychosocial factors and the insulin pump. Diabetes Care 30: Riveline JP, Vantyghem MC, Fermon C, Brunet C, Gautier JF, Renard E, and Charpentier G. (2005) Subcutaneous insulin resistance successfully circumvented on long term by peritoneal insulin delivery from an implantable pump in four diabetic patients. Diabetes and Metabolism 31: (case report) 564. Rivera EV and Woods S. (2003) Prevalence of asymptomatic Clostridium difficile colonization in a nursing home population: A cross-sectional study. Journal of Gender-Specific Medicine 6: Roberts DE, Van Walleghem N, Chang HM, Poluha W, Cheang MST, Moffatt MEK, and Taback SP. (2005) Glargine versus other basal insulins (NPH, Lente, or Ultralente) for the treatment of type 1 diabetes mellitus. Roberts. DE, Van Walleghem. N, Chang HM., Poluha. W., Cheang. MST., Moffatt. MEK., Taback. SP. Glargine. versus. other basal. insulins. for the treatment of type. 1 diabetes mellitus. Cochrane Database of Systematic Reviews: Protocols Issue. 2 John. Wiley. & Sons. Notes: Abstract/title: Excluded. Wrong intervention 566. Rodrigues IAS, Reid HA, Ismail K, and Amiel SA. (2005) Indications and efficacy of continuous subcutaneous insulin infusion (CSII) therapy in Type 1 diabetes mellitus: A clinical audit in a specialist service. Diabetic Medicine 22: Ronsin O, Jannot-Lamotte MF, Vague P, and Lassman-Vague V. (2005) Factors related to CSII compliance. Diabetes and Metabolism 31: Rosenberg VA, Eglinton GS, Rauch ER, and Skupski DW. (2006) Intrapartum maternal glycemic control in women with insulin requiring diabetes: A randomized clinical trial of rotating fluids versus insulin drip. American Journal of Obstetrics and Gynecology 195: Notes: Abstract/title: Excluded. Wrong outcomes 569. Rossi C, Quadri R, and Cavallo Perin P. (2004) Helicobacter pylori infection and diabetic complications. Diabetes, Nutrition and Metabolism - Clinical and Experimental 17: Royle P, Waugh N, McAuley L, McIntyre L, and Thomas S. (2003) Inhaled insulin in diabetes mellitus. Royle. P, Waugh. N, McAuley. L., McIntyre. L., Thomas. S. Inhaled. insulin. in diabetes mellitus. Cochrane Database of Systematic Reviews: Reviews Issue. 4 John. Wiley. & Sons., Ltd. Chichester, UK DOI. : / CD pub2. Notes: Abstract/title: Excluded. Wrong intervention

102 Roze S, Valentine WJ, Zakrzewska KE, and Palmer AJ. (2005) Health-economic comparison of continuous subcutaneous insulin infusion with multiple daily injection for the treatment of Type 1 diabetes in the UK. Diabetic Medicine 22: Roze S, Valentine WJ, Zakrzewska KE, and Palmer AJ. (2005) Health-economic comparison of continuous subcutaneous insulin infusion with multiple daily injection for the treatment of Type 1 diabetes in the UK (Structured abstract). Diabetic Medicine 22: Rubino F and Castagneto M. (2006) Surgery for severe obesity: Indications, techniques, mechanisms of weight loss and diabetes resolution. Immunology, Endocrine and Metabolic Agents in Medicinal Chemistry 6: Rudolph JW and Hirsch IB. (2002) Assessment of therapy with continuous subcutaneous insulin infusion in an academic diabetes clinic. Endocrine Practice 8: Rule AM, Drincic A, and Galt KA. (2007) New technology, new errors: how to prime an upgrade of an insulin infusion pump. Joint Commission journal on quality and patient safety / Joint Commission Resources 33: Rusavy Z, Macdonald IA, Sramek V, Lacigova S, Tesinsky P, and Novak I. (2005) Glycemia influences on glucose metabolism in sepsis during hyperinsulinemic clamp. JPEN. Journal of parenteral and enteral nutrition 29: Ruxer J, Mozdzan M, Czupryniak L, Saryusz WM, and Loba J. (2004) [Effectiveness of selected methods of the short-term intensive insulin therapy in patients with poorly controlled type 2 diabetes mellitus]. Polskie. archiwum. medycyny. wewn. &#553. ;trznej. 112: Notes: Abstract/title: Excluded. Wrong intervention 578. Ryan EA and Shapiro AMJ. (2006) A patient with severe, recurrent hypoglycemia and glycemic lability who underwent islet transplantation. Nature Clinical Practice Endocrinology and Metabolism 2: (case report) 579. Saha MT, Huupponen T, Knip M, Juuti M, and Komulainen J. (2002) Continuous subcutaneous insulin infusion in the treatment of children and adolescents with type 1 diabetes mellitus. Journal of Pediatric Endocrinology and Metabolism 15: Salsali A and Nathan M. (2006) A review of types 1 and 2 diabetes mellitus and their treatment with insulin. American Journal of Therapeutics 13: Samarasinghe YP, Purcell I, Rivas-Toro H, and Feher MD. (2007) Costs of aspirin should include treatment costs for dyspepsia. British Journal of Cardiology 14: Samson D. (2004) Special report: cost-effectiveness of left-ventricular assist devices as destination therapy for end-stage heart failure (Structured abstract). Notes: Abstract/title: Excluded. Wrong patient group 583. Samuelsson U and Ludvigsson J. (2002) When should determination of ketonemia be recommended? Diabetes Technology and Therapeutics 4: Sanchez LM, Chronis AM, and Hunter J. (2006) Improving Compliance With Diabetes Management in Young Adolescents With Attention-Deficit/Hyperactivity Disorder Using Behavior Therapy. Cognitive and Behavioral Practice 13: (case report) 585. Sanfield JA, Hegstad M, and Hanna RS. (2002) Protocol for outpatient screening and initiation of continuous subcutaneous insulin infusion therapy: impact on cost and quality (Structured abstract). Diabetes Educator. 28: Sanfield JA, Hegstad M, and Hanna RS. (2002) Protocol for outpatient screening and initiation of continuous subcutaneous insulin infusion therapy: impact on cost and quality. The Diabetes educator 28: Sano M, Amatniek J, Feely M, Sinyak F, Holton D, Ascher S, and Finkel SI. (2005) Undertreatment of patients with Alzheimer's disease in an elderly United States population. Alzheimer's and Dementia 1: Sarner M. (2003) Treatment of Pancreatic Exocrine Deficiency. World Journal of Surgery 27: Saseen JJ. (2005) ASHP therapeutic position statement on the daily use of aspirin for preventing cardiovascular events. American Journal of Health-System Pharmacy 62:

103 Satapathy SK, Garg S, Chauhan R, Sakhuja P, Malhotra V, Sharma BC, and Sarin SK. (2004) Beneficial effects of tumor necrosis factor-(alpha) inhibition by pentoxifylline on clinical, biochemical, and metabolic parameters of patients with nonalcoholic steatohepatitis. American Journal of Gastroenterology 99: Saudek CD. (2006) Implantable insulin pumps: the Veterans Administration Study, a decade later. Diabetes Research and Clinical Practice 74:S169-S Schaepelynck-Belicar P, Dufaitre-Patouraux L, and Lassmann-Vague V. (2005) What could be the reasons for giving up the implanted pump treatment? Diabetes and Metabolism 31: Schatz D, Cuthbertson D, Atkinson M, Salzler MC, Winter W, Muir A, Silverstein J, Cook R, Maclaren N, She JX, Greenbaum C, and Krischer J. (2004) Preservation of C-peptide secretion in subjects at high risk of developing type 1 diabetes mellitus--a new surrogate measure of non-progression? Pediatric Diabetes 5: Scheiner G and Boyer BA. (2005) Characteristics of basal insulin requirements by age and gender in Type-1 diabetes patients using insulin pump therapy. Diabetes Research and Clinical Practice 69: Scherbaum WA. (2002) Insulin therapy in Europe. Diabetes/Metabolism Research and Reviews 18:S50-S Schiaffini R, Ciampalini P, Spera S, Cappa M, and Crino A. (2005) An observational study comparing continuous subcutaneous insulin infusion (CSII) and insulin glargine in children with type 1 diabetes. Diabetes/Metabolism Research and Reviews 21: Schiel R. (2003) Continuous subcutaneous insulin infusion in patients with diabetes mellitus. Therapeutic Apheresis 7: Schlotthauer G, Gamero LG, Torres ME, and Nicolini GA. (2006) Modeling, identification and nonlinear model predictive control of type I diabetic patient. Medical Engineering and Physics 28: Schmeltz LR, DeSantis AJ, Schmidt K, O'Shea-Mahler E, Rhee C, Brandt S, Peterson S, and Molitch ME. (2006) Conversion of intravenous insulin infusions to subcutaneously administered insulin glargine in patients with hyperglycemia. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 12: Notes: Abstract/title: Excluded. Wrong intervention 600. Schmidt WA. (2006) Current diagnosis and treatment of temporal arteritis. Current Treatment Options in Cardiovascular Medicine 8: Schutt M, Kern W, Krause U, Busch P, Dapp A, Grziwotz R, Mayer I, Rosenbauer J, Wagner C, Zimmermann A, Kerner W, and Holl RW. (2006) Is the frequency of self-monitoring of blood glucose related to long-term metabolic control? Multicenter analysis including patients from 191 centers in Germany and Austria. Experimental and Clinical Endocrinology and Diabetes 114: Scuffham P and Carr L. (2003) The cost-effectiveness of continuous subcutaneous insulin infusion compared with multiple daily injections for the management of diabetes. Diabetic Medicine 20: Scuffham P and Carr L. (2003) The cost-effectiveness of continuous subcutaneous insulin infusion compared with multiple daily injections for the management of diabetes (Structured abstract). Diabetic Medicine 20: Selam JL. (2006) CSII in Europe: where are we, where are we going? An analysis of articles published in Infusystems International. Diabetes Research and Clinical Practice 74:S123-S Service RF. (2002) Can sensors make a home in the body? Science 297: Shah M, Butler M, Bramley T, Curtice TG, and Fine S. (2007) Comparison of health care costs and comorbidities between men diagnosed with benign prostatic hyperplasia and cardiovascular disease (CVD) and men with CVD alone in a US commercial population. Current Medical Research and Opinion 23: Shalitin S and Phillip M. (2006) Closing the loop: Combining insulin pumps and glucose sensors in children with type 1 diabetes mellitus. Pediatric Diabetes 7: Sharkey JR, Browne B, Ory MG, and Wang S. (2005) Patterns of therapeutic prescription medication catergory use among community-dwelling homebound older adults. Pharmacoepidemiology and Drug Safety 14:

104 Shehadeh N, Battelino T, Galatzer A, Naveh T, Hadash A, de Vries L, and Phillip M. (2004) Insulin pump therapy for 1-6 year old children with type 1 diabetes. Israel Medical Association Journal 6: Shim YH, Kweon D, Lee JH, Nam SB, and Kwak YL. (2006) Intravenous glucose-insulin-potassium during offpump coronary artery bypass surgery does not reduce myocardial injury. Acta Anaesthesiologica Scandinavica 50: Notes: Abstract/title: Excluded. Wrong intervention 611. Siebenhofer A, Plank J, Berghold A, Horvath K, Sawicki PT, Beck P, and Pieber TR. (2004) Meta-analysis of short-acting insulin analogues in adult patients with type 1 diabetes: Continuous subcutaneous insulin infusion versus injection therapy. Diabetologia 47: Notes: Abstract/title: Excluded. Wrong comparator 612. Siebenhofer A, Plank J, Berghold A, Narath M, Gfrerer R, and Pieber TR. (2004) Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus. Cochrane database of systematic reviews (Online : Update Software) -:CD Notes: Abstract/title: Excluded. Wrong comparator 613. Siebenhofer A, Plank J, Berghold A, Jeitler K, Horvath K, Narath M, Gfrerer R, and Pieber TR. (2006) Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus. Cochrane database of systematic reviews (Online) -:CD Notes: Abstract/title: Excluded. Wrong comparator 614. Siebenhofer A, Plank J, Berghold A, Jeitler K, Horvath K, Narath M, Gfrerer R, and Pieber TR. (2006) Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus. Siebenhofer. A, Plank. J, Berghold. A, Jeitler. K., Horvath. K., Narath. M., Gfrerer. R, Pieber. TR. Short acting. insulin. analogues. versus. regular. human insulin. in patients. with. diabetes mellitus. Cochrane Database of Systematic Reviews: Reviews Issue. 2 John. Notes: Abstract/title: Excluded. Wrong comparator 615. Siebenhofer A, Plank J, Berghold A, Jeitler K, Horvath K, Narath M, Gfrerer R, and Pieber TR. (2006) Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus. Cochrane Database of Systematic Reviews -. Notes: Abstract/title: Excluded. Wrong comparator 616. Simpson D, McCormack PL, Keating GM, and Lyseng-Williamson KA. (2007) Insulin lispro: A review of its use in the management of diabetes mellitus. Drugs 67: Singh T. (2006) Inhaled insulin: A novel therapeutic option for diabetes mellitus. JMS - Journal of Medical Society 20: Skyler JS, Ponder S, Kruger DF, Matheson D, and Parkin CG. (2007) Is there a place for insulin pump therapy in your practice? Clinical Diabetes 25: Smith A, Grattan A, Harper M, Royston D, and Riedel BJ. (2002) Coronary revascularization: a procedure in transition from on-pump to off-pump? The role of glucose-insulin-potassium revisited in a randomized, placebocontrolled study. Journal of cardiothoracic. and vascular anesthesia 16: Notes: Abstract/title: Excluded. Wrong patient group 620. Soni S, Mentzelopoulos V, and Hatipoglu B. (2004) Complete recovery from prolonged hypoglycemic coma after intentional overdose with an insulin pump. Endocrinologist 14: (case report) 621. Sood A, Midha V, Sood N, Bansal M, Kaur M, Goyal A, and Sharma N. (2007) Coexistence of chronic calcific pancreatitis and celiac disease. Indian Journal of Gastroenterology 26: (case report) 622. Springer D, Dziura J, Tamborlane WV, Steffen AT, Ahern JH, Vincent M, and Weinzimer SA. (2006) Optimal control of type 1 diabetes mellitus in youth receiving intensive treatment. Journal of Pediatrics 149: Stechova K, Snajderova M, Kolouskova S, Sumnik Z, Hladikova M, Sitova R, and Vavrinec J. (2002) Noncompliance of insulin pump users; questionnaire and case reports. Diabetologie Metabolismus Endokrinologie Vyziva 5: (case report) 624. Stechova K, Bartaskova D, Mrstinova M, Cerny M, Snajderova M, Cinek O, Sumnik Z, and Vavrinec J. (2004) Pregnancy in a woman suffering from type 1 diabetes associated with Addison's disease and Hashimoto's thyroiditis (fully developed Autoimmune Polyglandular Syndrome Type 2). Experimental and Clinical Endocrinology and Diabetes 112: (case report) 625. Steel K. (2002) Gastrin and gastrin receptor ligands - A review of recent patent literature. IDrugs 5:

105 Steil GM, Panteleon AE, and Rebrin K. (2004) Closed-loop insulin delivery - The path to physiological glucose control. Advanced Drug Delivery Reviews 56: Steil GM and Rebrin K. (2005) Closed-loop insulin delivery - What lies between where we are and where we are going? Expert Opinion on Drug Delivery 2: Steil GM and Saad MF. (2006) Automated insulin delivery for type 1 diabetes. Current Opinion in Endocrinology and Diabetes 13: Stephens FB, Constantin TD, Laithwaite D, Simpson EJ, and Greenhaff PL. (2007) A threshold exists for the stimulatory effect of insulin on plasma L-carnitine clearance in humans. American journal of physiology. Endocrinology and metabolism 292:E637-E641. Notes: Abstract/title: Excluded. Wrong patient group 630. Stettler C, Jenni S, Allemann S, Steiner R, Hoppeler H, Trepp R, Christ ER, Zwahlen M, and Diem P. (2006) Exercise capacity in subjects with type 1 diabetes mellitus in eu- and hyperglycaemia. Diabetes/Metabolism Research and Reviews 22: Stewart KM, Wilson MF, and Rider JM. (2004) Insulin Delivery Devices. Journal of Pharmacy Practice 17: Stewart SM, Emslie GJ, Klein D, Haus S, and White P. (2005) Self-care and glycemic control in adolescents with type I diabetes. Children's Health Care 34: Stork AD, Erkelens DW, and Veneman TF. (2006) A practical insulin infusion algorithm for the establishment of euglycaemia in both lean and obese patients with type 1 and type 2 diabetes. Diabetes Research and Clinical Practice 72: Strack TR. (2006) Inhaled human insulin. Drugs of Today 42: Streisand R, Swift E, Wickmark T, Chen R, and Holmes CS. (2005) Pediatric parenting stress among parents of children with type 1 diabetes: The role of self-efficacy, responsibility, and fear. Journal of Pediatric Psychology 30: Strippoli GFM, Bonifati C, Craig M, Navaneethan SD, and Craig JC. (2006) Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists for preventing the progression of diabetic kidney disease. Strippoli. GFM., Bonifati. C, Craig. M., Navaneethan. SD, Craig. JC. Angiotensin. converting. enzyme inhibitors. and angiotensin. II receptor antagonists. for preventing. the progression. of diabetic kidney disease. Cochrane Database of Systematic Reviews: Reviews 20. Notes: Abstract/title: Excluded. Wrong intervention 637. Strowig SM and Raskin P. (2005) Combination therapy using metformin or thiazolidinediones and insulin in the treatment of diabetes mellitus. Diabetes, Obesity and Metabolism 7: Sulli N and Shashaj B. (2003) Continuous subcutaneous insulin infusion in children and adolescents with diabetes mellitus: Decreased HbA1c with low risk of hypoglycemia. Journal of Pediatric Endocrinology and Metabolism 16: Sulli N and Shashaj B. (2006) Long-term benefits of continuous subcutaneous insulin infusion in children with Type 1 diabetes: A 4-year follow-up. Diabetic Medicine 23: Sulli N, Bertasi S, Zullo S, and Shashaj B. (2007) Use of continuous subcutaneous insulin infusion in patients with cystic fibrosis related diabetes: Three case reports. Journal of Cystic Fibrosis 6: (case report) 641. Sullivan-Bolyai S, Knafl K, Tamborlane W, and Grey M. (2004) Parents' reflections on managing their children's diabetes with insulin pumps. Journal of nursing scholarship : an official publication of Sigma Theta Tau International Honor Society of Nursing / Sigma Theta Tau 36: Svoren BM, Volkening LK, Butler DA, Moreland EC, Anderson BJ, and Laffel LMB. (2007) Temporal Trends in the Treatment of Pediatric Type 1 Diabetes and Impact on Acute Outcomes. Journal of Pediatrics 150: Sze MN, May JE, and Emmerson AJB. (2005) Continuous insulin infusion in hyperglycaemic extremely-low-birthweight neonates: An evaluation of treatment response. Biology of the Neonate 87: Talbot TR. (2005) Diabetes mellitus and cardiothoracic surgical site infections. American Journal of Infection Control 33:

106 Tamborlane WV, Fredrickson LP, and Ahern JH. (2003) Insulin pump therapy in childhood diabetes mellitus: Guidelines for use. Treatments in Endocrinology 2: Tamborlane WV, Swan K, Sikes KA, Steffen AT, and Weinzimer SA. (2006) The renaissance of insulin pump treatment in childhood type 1 diabetes. Reviews in Endocrine and Metabolic Disorders 7: Tamborlane WV, Sikes KA, Steffen AT, and Weinzimer SA. (2006) Continuous subcutaneous insulin infusion (CSII) in children with type 1 diabetes. Diabetes Research and Clinical Practice 74:S112-S Tamborlane WV. (2006) Diabetes in overweight pediatric patients. Clinical Cornerstone 7:S25-S Tamborlane WV. (2006) Fulfilling the promise of insulin pump therapy in childhood diabetes. Pediatric Diabetes 7: Taylor MJ, Tanna S, and Sahota TS. (2004) Closed-loop delivery of insulin: Progress to date for diabetes mellitus therapy. American Journal of Drug Delivery 2: Thabet F, Bourgeois J, Guy B, and Putet G. (2003) Continuous insulin infusion in hyperglycaemic very-low-birthweight infants receiving parenteral nutrition. Clinical Nutrition 22: Thiebaud P, Patel BV, and Nichol MB. (2006) Impact of rofecoxib withdrawal on cyclooxygenase-2 utilization among patients with and without cardiovascular risk. Value in Health 9: Thisted H, Johnsen SP, and Rungby J. (2006) An update on the long-acting insulin analogue glargine. Basic and Clinical Pharmacology and Toxicology 99: Thomas RM, Aldibbiat A, Griffin W, Cox MAA, Leech NJ, and Shaw JAM. (2007) A randomized pilot study in type 1 diabetes complicated by severe hypoglycaemia, comparing rigorous hypoglycaemia avoidance with insulin analogue therapy, CSII or education alone. Diabetic Medicine 24: Notes: Abstract/title: Excluded. Fewer than 10 patients per study arm 655. Thomson RD, Lestina LS, Bensen SP, Toor A, Maheshwari Y, and Ratcliffe NR. (2002) Lansoprazoleassociated microscopic colitis: A case series. American Journal of Gastroenterology 97: Tibaldi J and Rakel RE. (2007) Why, when and how to initiate insulin therapy in patients with type 2 diabetes. International Journal of Clinical Practice 61: Toth GH. (2005) Continuous subcutaneous insulin infusion in children and adolescents with type 1 diabetes: Do the benefits outweigh the risks? Paediatrics and Child Health 10: Trout KK, Rickels MR, Schutta MH, Petrova M, Freeman EW, Tkacs NC, and Teff KL. (2007) Menstrual cycle effects on insulin sensitivity in women with type 1 diabetes: A pilot study. Diabetes Technology and Therapeutics 9: Tsalikian E, Fox L, Janz KF, Wilson D, Chase HP, Fiallo-Scharer R, Messer L, Tallant B, Tansey MJ, Larson LF, Coffey J, Wysocki T, Mauras N, Fox LA, Bird K, Englert K, Buckingham BA, Wilson DM, Block JM, Clinton P, Weinzimer SA, Tamborlane WV, Doyle EA, Sikes K, Beck RW, Ruedy KJ, Kollman C, Xing D, Stockdale CR, Steffes MW, Bucksa JM, Nowicki ML, Van Hale CA, Makky V, Grave GD, Teff K, Winer KK, Becker DM, Cleary P, Ryan CM, White NH, and White PC. (2006) Prevention of hypoglycemia during exercise in children with type 1 diabetes by suspending basal insulin. Diabetes Care 29: Notes: Abstract/title: Excluded. Wrong intervention 660. Tubiana-Rufi N, Coutant R, Bloch J, Munz-Licha G, Delcroix C, Montaud-Raguideau N, Ducrocq R, Limal JM, and Czernichow P. (2004) Special management of insulin lispro in continuous subcutaneous insulin infusion in young diabetic children: A randomized cross-over study. Hormone Research 62: Notes: Abstract/title: Excluded. Wrong comparator 661. Tubiana RN, Coutant R, Bloch J, Munz LG, Delcroix C, Montaud RN, Ducrocq R, Limal JM, and Czernichow P. (2004) Special management of insulin lispro in continuous subcutaneous insulin infusion in young diabetic children: a randomized cross-over study. Hormone Research 62: Notes: Abstract/title: Excluded. Wrong comparator 662. Tyagi P. (2002) Insulin delivery systems: Present trends and the future direction. Indian Journal of Pharmacology 34: Umpierrez GE, Latif K, Stoever J, Cuervo R, Park L, Freire AX, and Kitabchi A. (2004) Efficacy of subcutaneous insulin lispro versus continuous intravenous regular insulin for the treatment of patients with diabetic ketoacidosis. The

107 93 American journal of medicine 117: Notes: Abstract/title: Excluded. Wrong comparator 664. Umpierrez GE, Latif K, Stoever J, Cuervo R, Park L, Freire A, X, and Kitabchi AE. (2004) Efficacy of subcutaneous insulin lispro versus continuous intravenous regular insulin for the treatment of patients with diabetic ketoacidosis (Brief record). American Journal of Medicine 117: Notes: Abstract/title: Excluded. Wrong comparator 665. Umpierrez GE, Cuervo R, Karabell A, Latif K, Freire AX, and Kitabchi AE. (2004) Treatment of diabetic ketoacidosis with subcutaneous insulin aspart. Diabetes Care 27: Notes: Abstract/title: Excluded. Wrong intervention 666. Uomo G. (2003) Inflammatory pancreatic diseases in older patients: Recognition and management. Drugs and Aging 20: Uslan MM, Burton DM, Chertow BS, and Collins R. (2004) Accessibility of insulin pumps for blind and visually impaired people. Diabetes Technology and Therapeutics 6: Vakil N. (2006) The prevention of gastropathy and upper abdominal symptoms caused by nonsteroidal antiinflammatory drugs. Reviews in Gastroenterological Disorders 6: Valenzuela JM, Patino AM, McCullough J, Ring C, Sanchez J, Eidson M, Nemery R, and Delamater AM. (2006) Insulin pump therapy and health-related quality of life in children and adolescents with type 1 diabetes. Journal of Pediatric Psychology 31: Van Den Berghe G. (2004) Insulin Therapy in Critical Illness. Canadian Journal of Diabetes 28: Vanhaverbeke G, Mertens A, and Mathieu C. (2004) Diabetic management in high risk patients (pregnancy, insulin pumps). Acta Clinica Belgica 59: Vantyghem MC, Perimenis P, Tourvieille S, Touzet L, and Pattou F. (2004) Eligibility of diabetic patients for islet transplantation alone. Transplantation Proceedings 36: Vantyghem MC and Press M. (2006) Management strategies for brittle diabetes. Annales d'endocrinologie 67: Vardi M and Nini A. (2006) Intermediate acting versus long acting insulin for type 1 diabetes mellitus. Vardi. M., Nini. A. Intermediate. acting. versus. long acting. insulin. for type. 1 diabetes mellitus. Cochrane Database of Systematic Reviews: Protocols Issue. 4 John. Wiley. & Sons., Ltd. Chichester, UK DOI. : / CD Notes: Abstract/title: Excluded. Wrong intervention 675. Varvarovska J, Siala K, Pomahacova R, Sykora J, Stozicky F, and Rusavy Z. (2007) Mastering the treatment of diabetes mellitus type 1 in childhood and adolescence. Current Pediatric Reviews 3: Vigersky RA, Hanson E, McDonough E, Rapp T, Pajak J, and Galen RS. (2003) A wireless diabetes management and communication system. Diabetes Technology and Therapeutics 5: Vogelzang M, Zijlstra F, and Nijsten MWN. (2005) Design and implementation of GRIP: A computerized glucose control system at a surgical intensive care unit. BMC Medical Informatics and Decision Making 5:10p Vogelzang M, Zijlstra F, and Nijsten MW. (2005) Design and implementation of GRIP: a computerized glucose control system at a surgical intensive care unit. BMC medical informatics and decision making [electronic resource]. 5: Vonkeman HE, Fernandes RW, Van der Palen J, Van Roon EN, and Van de Laar MAFJ. (2007) Proton-pump inhibitors are associated with a reduced risk for bleeding and perforated gastroduodenal ulcers attributable to nonsteroidal anti-inflammatory drugs: A nested case-control study. Arthritis Research and Therapy Vora AC, Saleem TM, Polomano RC, Eddinger VL, Hollenbeak CS, Girdharry DT, Joshi R, Martin D, and Gabbay RA. (2004) Improved perioperative glycemic control by continuous insulin infusion under supervision of an endocrinologist does not increase costs in patients with diabetes. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 10: Vora AC, Saleem TM, Polomano RC, Eddinger VL, Hollenbeak CS, Girdharry DT, Joshi R, Martin D, and Gabbay RA. (2004) Improved perioperative glycemic control by continuous insulin infusion under supervision of an endocrinologist does not increase costs in patients with diabetes (Structured abstract). Endocrine Practice 10:

108 Wagner JA, Abbott G, and Lett S. (2004) Age related differences in individual quality of life domains in youth with type 1 diabetes. Health and Quality of Life Outcomes 2:9p Wainstein J, Metzger M, Boaz M, Minuchin O, Cohen Y, Yaffe A, Yerushalmy Y, Raz I, and Harman-Boehm I. (2005) Insulin pump therapy vs. multiple daily injections in obese Type 2 diabetic patients. Diabetic Medicine 22: Notes: Abstract/title: Included Wake DJ, Homer NZ, Andrew R, and Walker BR. (2006) Acute in vivo regulation of 11beta-hydroxysteroid dehydrogenase type 1 activity by insulin and intralipid infusions in humans. The Journal of clinical endocrinology and metabolism 91: Notes: Abstract/title: Excluded. Wrong patient group 685. Waldron S, Hanas R, and Palmvig B. (2002) How do we educate young people to balance carbohydrate intake with adjustments of insulin? Hormone Research 57: Wang TY, Chang CT, Chen CC, Chen RH, and Huang WL. (2006) Diabetic ketoacidosis as the first manifestation of new onset juvenile type 2 diabetes. Mid-Taiwan Journal of Medicine 11: (case report) 687. Warren E, Weatherley-Jones E, Chilcott J, and Beverley C. (2004) Systematic review and economic evaluation of a long-acting insulin analogue, insulin glargine. Health Technology Assessment 8:iii-41. Notes: Abstract/title: Excluded. Wrong intervention 688. Wasikowa RB and Basiak A. (2007) Progress in the treatment of diabetes type 1 and 2. Endokrynologia, Diabetologia i Choroby Przemiany Materii Wieku Rozwojowego 13: Wasse H, Gillen DL, Ball AM, Kestenbaum BR, Seliger SL, Sherrard D, and Stehman-Breen CO. (2003) Risk factors for upper gastrointestinal bleeding among end-stage renal disease patients. Kidney International 64: Waters MJ. (2006) Endocrinology: The next 60 years - The Helix and the chip. Journal of Endocrinology 190: Webb KE. (2006) Use of insulin pumps for diabetes management. Medsurg nursing : official journal of the Academy of Medical-Surgical Nurses. 15:61-68, Weintrob N, Benzaquen H, Galatzer A, Shalitin S, Lazar L, Fayman G, Lilos P, Dickerman Z, and Phillip M. (2003) Comparison of continuous subcutaneous insulin infusion and multiple daily injection regimens in children with type 1 diabetes: A randomized open crossover trial. Pediatrics. 112: Notes: Abstract/title: Included 693. Weintrob N, Shalitin S, and Phillip M. (2004) Why pumps? Continuous subcutaneous insulin infusion for children and adolescents with type 1 diabetes. Israel Medical Association Journal 6: Weintrob N, Schechter A, Benzaquen H, Shalitin S, Lilos P, Galatzer A, and Phillip M. (2004) Glycemic patterns detected by continuous subcutaneous glucose sensing in children and adolescents with type 1 diabetes mellitus treated by multiple daily injections vs continuous subcutaneous insulin infusion. Archives of Pediatrics and Adolescent Medicine 158: Notes: Abstract/title: Included Weinzimer SA, Ahern JH, Doyle EA, Vincent MR, Dziura J, Steffen AT, and Tamborlane WV. (2004) Persistence of benefits of continuous subcutaneous insulin infusion in very young children with type 1 diabetes: a follow-up report. Pediatrics. 114: Weinzimer SA, Doyle EA, Steffen AT, Sikes KA, and Tamborlane WV. (2004) Rediscovery of insulin pump treatment of childhood type 1 diabetes. Minerva Medica 95: Weinzimer SA, Tamborlane WV, Chase P, and Garg SK. (2004) Continuous glucose monitoring in type 1 diabetes. Current Diabetes Reports 4: Weinzimer SA, Sikes KA, Steffen AT, and Tamborlane WV. (2005) Insulin pump treatment of childhood type 1 diabetes. Pediatric Clinics of North America 52: Weinzimer SA, Doyle EA, and Tamborlane J. (2005) Disease management in the young diabetic patient: Glucose monitoring, coping skills, and treatment strategies. Clinical Pediatrics 44: Weinzimer SA, Swan KL, Sikes KA, and Ahern JH. (2006) Emerging evidence for the use of insulin pump therapy in infants, toddlers, and preschool-aged children with type 1 diabetes. Pediatric Diabetes 7:15-19.

109 Weissberg-Benchell J, Antisdel-Lomaglio J, and Seshadri R. (2003) Insulin pump therapy: A meta-analysis. Diabetes Care 26: Notes: Abstract/title: Included. Full paper: Exclude. Wrong comparator. Level I evidence. No additonal studies identified. Wrong study types included Weitzman JB. (2003) Electronic medical devices: A primer for pathologists. Archives of Pathology and Laboratory Medicine 127: Wentholt IME, Maran A, Masurel N, Heine RJ, Hoekstra JBL, and Devries JH. (2007) Nocturnal hypoglycaemia in Type 1 diabetic patients, assessed with continuous glucose monitoring: Frequency, duration and associations. Diabetic Medicine 24: White Jr WA, Montalvo H, and Monday JM. (2004) Continuous subcutaneous insulin infusion during general anesthesia: A case report. AANA Journal 72: (case report) 705. Wiederrecht GJ, Hill RG, and Beer MS. (2006) Partnership between small biotech and big pharma. IDrugs 9: Wilinska ME, Bodenlenz M, Chassin LJ, Schaller HC, Schaupp LA, Pieber TR, and Hovorka R. (2004) Interstitial glucose kinetics in subjects with type 1 diabetes under physiologic conditions. Metabolism: Clinical and Experimental 53: Wilinska ME, Chassin LJ, Schaller HC, Schaupp L, Pieber TR, and Hovorka R. (2005) Insulin kinetics in type-i diabetes: continuous and bolus delivery of rapid acting insulin. IEEE transactions on bio medical engineering 52:3-12. Notes: Abstract/title: Excluded. Wrong intervention 708. Wilinska ME, Chassin LJ, Schaller HC, Schaupp L, Pieber TR, and Hovorka R. (2005) Insulin kinetics in type-1 diabetes: Continuous and bolus delivery of rapid acting insulin. IEEE Transactions on Biomedical Engineering 52: Willi SM, Planton J, Egede L, and Schwarz S. (2003) Benefits of continuous subcutaneous insulin infusion in children with type 1 diabetes. Journal of Pediatrics 143: Williams RM, Amin R, Saukkonen T, and Dunger D. (2003) Recent advances in diabetes mellitus. Current Paediatrics 13: Wilson DM. (2002) Progress in the treatment of childhood diabetes mellitus and obesity. Journal of pediatric endocrinology & metabolism : JPEM. 15 Suppl 2: Wilson DM. (2002) Progress in the treatment of childhood diabetes mellitus and obesity. Journal of Pediatric Endocrinology and Metabolism 15: Wilson DM, Buckingham BA, Kunselman EL, Sullivan MM, Paguntalan HU, and Gitelman SE. (2005) A twocenter randomized controlled feasibility trial of insulin pump therapy in young children with diabetes. Diabetes Care 28: Notes: Abstract/title: Included. Full paper: Exclude. <10 evaluable subjects per treatment arm 714. Wintergerst KA, Hargadon S, and Hsiang HY. (2004) Continuous subcutaneous insulin infusion in neonatal diabetes mellitus. Pediatric Diabetes 5: (case report) 715. Wittlin SD. (2006) Treating the spectrum of type 2 diabetes: Emphasis on insulin pump therapy. Diabetes Educator 32:39S-46S. (case report) 716. Wood JR, Moreland EC, Volkening LK, Svoren BM, Butler DA, and Laffel LMB. (2006) Durability of insulin pump use in pediatric patients with type 1 diabetes. Diabetes Care 29: Wood JR and Laffel LMB. (2007) Technology and intensive management in youth with type 1 diabetes: State of the art. Current Diabetes Reports 7: Worthley MI, Holmes AS, Willoughby SR, Kucia AM, Heresztyn T, Stewart S, Chirkov YY, Zeitz CJ, and Horowitz JD. (2007) The deleterious effects of hyperglycemia on platelet function in diabetic patients with acute coronary syndromes mediation by superoxide production, resolution with intensive insulin administration. Journal of the American College of Cardiology 49: Notes: Abstract/title: Excluded. Wrong intervention 719. Wysocki T, Harris MA, Buckloh LM, Wilkinson K, Sadler M, Mauras N, and White NH. (2006) Self-care autonomy and outcomes of intensive therapy or usual care in youth with type 1 diabetes. Journal of Pediatric Psychology 31: Notes: Abstract/title: Excluded. Wrong intervention

110 Yang NL, Xue B, and Lin P. (2006) Basal or bolus dose, which is the key factor in CSII? Journal of Zhejiang University. Science. B. 7: Yano F, Omura N, Tsuboi K, Kashiwagi H, and Yanaga K. (2006) Delayed esophageal perforation after laparoscopic fundoplication in a patient with diabetes mellitus: A case report. Esophagus 3: (case report) 722. Yates K, Milton AH, Dear K, and Ambler G. (2006) Continuous glucose monitoring-guided insulin adjustment in children and adolescents on near-physiological insulin regimens: A randomized controlled trial. Diabetes Care 29: Notes: Abstract/title: Included. Full paper: Exclude. Wrong comparator (compared CGMS vs control in subjects on intensive insulin therapy) 723. Yogev Y and Hod M. (2007) Use of New Technologies for Monitoring and Treating Diabetes in Pregnancy. Obstetrics and Gynecology Clinics of North America 34: Zander M, Christiansen A, Madsbad S, and Holst JJ. (2004) Additive effects of glucagon-like peptide 1 and pioglitazone in patients with type 2 diabetes. Diabetes Care 27: Notes: Abstract/title: Excluded. Wrong intervention 725. Zrebiec J. (2005) A national study of the certified diabetes educator: Report on a job analysis conducted by the National Certification Board for Diabetes Educators. Diabetes Spectrum 18: Zung A, Glaser B, Nimri R, and Zadik Z. (2004) Glibenclamide treatment in permanent neonatal diabetes mellitus due to an activating mutation in Kir6.2. Journal of Clinical Endocrinology and Metabolism 89: (case report)

111 97 Appendix C: Data extraction tables Studies of adults with type 1 diabetes Citation Level of evidence Objective Type of included studies Types of participants Type of intervention Outcomes Data analyses & statistics Retnakaran R, Hochman J, Devries JH, Hanaire-Broutin H, Heine RJ, Melki V et al (2004) Continuous subcutaneous insulin infusion versus multiple daily injections: The impact of baseline A1c. Diabetes Care 27(11): I To perform a pooled analysis of the published randomised controlled trials that have compared CSII and optimised MDI therapy using rapid-acting insulin analogues in adults with type 1 diabetes. Randomised controlled trials. Studies of short duration ( 2 weeks on either therapy) were excluded. Adult patients with type 1 diabetes. Studies of patients with newly diagnosed type 1 diabetes or pregnant patients were excluded. Studies comparing optimised MDI with CSII regimens using rapid-acting insulin analogues. Optimised MDI therapy required at least 3 premeal injections of rapid-acting insulin per day. Change in HbA 1c, incidence of hypoglycaemic events, change in total daily insulin dose, incidence of ketoacidosis Treatment effects were pooled using the standard fixed effects model based on the inverse variance method and the Dersimonian & Laird random effects model. Heterogeneity was assessed by the Q statistic. For assessment of within-patient variation of treatment effect, data were drawn from the crossover phase in each study. Also included in the pooled dataset were data from patients who only participated in a single treatment phase. List of included studies Description of included studies The treatment effect on HbA 1c was analysed using a conservative mixed linear modelling approach with an isotropic exponential special covariance structure. Pooled analysis of the incidence of hypoglycaemia was performed using the number of hypoglycaemic events during the last 2 or 3 weeks of treatment. The pooled data were analysed in a generalised linear model. DeVries et al, 2002 [note that this study was identified in the current review] Tsui et al, 2001 [included in the NICE 2004 Health Technology Assessment] Hanaire-Broutin et al, 2000 [included in the NICE 2004 Health Technology Assessment] DeVries 2002: Crossover RCT (analysed as parallel-design because of significant patient dropout at crossover) of 79 subjects (39 in the CSII arm and 40 in the MDI arm) with persistent poor glycaemic control with 3 insulin injections per day. Treatment duration 4 months. Tsui 2001: Parallel-design RCT of 27 patients (13 in the CSII arm and 14 in the MDI arm) with disease duration > 2 yrs and onset at or before age 40. Treatment duration 9 months. Study quality Hanaire-Broutin 2000: Crossover RCT of 41 patients with HbA 1c <10% and experience with intensive insulin therapy. Treatment duration 2 x 4-month treatment phases. A. Adequate. The clinical question was clearly defined. The authors identified that previous metaanalyses included studies that compared CSII and MDI regimens using regular insulin for premeal boluses. The current study was to compare only those studies in which both regimens use rapid-acting analogues. B. Adequate. Electronic (to 2002) and manual searching was conducted. C. Partial. The inclusion criteria were reported but it is unknown whether eligibility was assessed by more than one reviewer. D. Inadequate. No attempt was made to assess the quality of the included studies. E. Adequate. The characteristics of the included studies were reported. Outcome data for HbA 1c and insulin dose from each included study were available in forest plots. F. Adequate. Data were pooled using both fixed and random effects models. G. Inadequate. Sources of heterogeneity were not explored.

112 98 Results (within scope of systematic review update) Treatment effect on HbA 1c: Treatment effect favouring CSII but due to heterogeneity, no significant overall difference in the reduction in HbA 1c (95% CI 0.13, 0.45) [fixed effect model] 0.34 (95% CI -0.09, 0.77) [random effects model] Using raw patient data from the 3 trials [random effects]: 0.35 (95% CI -0.10, 0.80) CSII vs MDI P= 0.08 The relative benefit of CSII over MDI is directly proportional to baseline HbA 1c ie, baseline HbA 1c is a predictor of treatment effect (P= 0.002). Severe hypoglycaemic events: Rate of total hypoglycaemic events was evaluated but not the rate of severe events. Ketoacidotic episodes: CSII 1 event MDI 1 event Authors conclusions Quality of life: Not assessed. When rapid-acting insulin analogues are used in CSII and MDI regimens in adults with type 1 diabetes, insulin pump therapy is associated with better glycaemic control, particularly in those individuals with higher baseline HbA 1c. Thus, may be uniquely advantageous in the high-risk population of patients with poor glycaemic control. Reviewers notes Given the introduction of insulin analogues with superior pharmacodynamics, advanced in pump technology, and greater experience with intensitfied regimens, it is not clear whether earlier studies reflect current clinical practice. Nevertheless, the relative effects of CSII compared with those of MDI on glycaemic control and total daily insulin dose in the current analysis remain similar to early findings. The trend toward better glycaemic control with CSII is modest and non-significant. Relevance to study question Conflict of interest: None declared Intervention and comparator appropriate (both rapid-acting analogues) One of the 3 included studies was identified in the current review; the other 2 studies were included in the NICE Health Technology Assessment. Abbreviations: CI, confidence interval; CSII, continuous subcutaneous insulin infusion; MDI, multiple daily injections; ns, not significant; RCTs, randomised controlled trials The quality of systematic reviews was assessed using the following questions: (A) Was a clinical question clearly defined?; (B) Was an adequate search strategy used?; (C) Were the inclusion criteria appropriate and applied in an unbiased way?; (D) Was a quality assessment of included studies undertaken?; (E) Were the characteristics and results of the individual studies appropriately summarised?; (F) Were the methods for pooling the data appropriate?; (G) Were sources of heterogeneity explored?

113 99 Citation Level of evidence Country Research question/aims Study type/design DeVries JH, Snoek FJ, Kostense PJ, Masurel N, Heine RJ (2002) A randomized trial of continuous subcutaneous insulin infusion and intensive injection therapy in type 1 diabetes for patients with longstanding poor glycemic control. Diabetes Care 25(11): Level II the Netherlands (11 centres) The primary objective was to compare the efficacy in improving glycaemic control of CSII and insulin injection therapy in diabetic patients in persistent poor control. The secondary objective was to investigate possible different effects of these modes of treatment on health-related quality of life. Multicentre, open, randomised crossover trial. NOTE: due to a high drop-out rate at crossover, the study was analysed as a parallel-group trial for the first phase only. The total study duration was 70 weeks, including 2 x 16-week treatment phases, a 14-week qualification phase to exclude patients not able to comply with the demands of a good practice clinical trial (especially in terms of a minimum frequency of self-monitoring of blood glucose) and to study the phenomenon of a study effect, and a 24-week follow-up phase consisting of three bimonthly routine visits to the outpatient department. Patient group Subjects were randomised after the 14-week qualification phase and were seen at 2, 4, 8, 12, and 16 weeks during each treatment period. No washout period between treatments was reported. Participants: adults with type 1 diabetes in persistent poor control recruited from the outpatient clinic population from participating centres. Inclusion criteria: Type 1 diabetes (defined as diabetes diagnosed at or before age 30 years with a C-peptide level 0.20 nmol/l at a concomitant glucose level 7.0 nmol/l, or diagnosed at or before age 40 with a C-peptide level 0.05 nmol/l at a concomitant glucose level 7.0 nmol/l), age between 18 and 70 years, persistent poor control while on 3 insulin injections per day (defined as a mean of all HbA 1c values measured 8.5% in the last 6 months before the trial). Exclusion criteria: Severe active retinopathy, impaired hepatic function, nephropathy, insulin resistance, cardiac disease, uncontrolled hypertension, insulin allergy, substance abuse, pregnancy or lactation, past or current psychiatric treatment for schizophrenia, organic mental disorder, or bipolar disorder. Subject disposition: Of 89 subjects who entered the qualification phase, 79 subjects were randomised into two arms. In the MDI then CSII arm, 40/40 (100%) completed the first half of the crossover phase and 34/40 (85%) completed the second half. In the CSII then MDI arm, 32/39 (82%) completed the first half of the crossover phase and 21/32 (66%) completed the second half of the crossover phase. CSII (then MDI) arm: N=39, 54% male, mean (± SD) age 36.2 (± 10.3) years, weight 77.3 (± 13.6) kg, duration of diabetes 17.6 (± 9.8) years, HbA 1c 9.27% (± 1.4%), mild hypoglycaemic episodes per week 2.13 (± 2.05), insulin use 0.89 (± 0.33) units/kg/day, retinopathy in 48.7%, neuropathy in 10.2%, microalbuminuria in 28.2%, proteinuria in 10.2%, smoking 46.2%. MDI (then CSII) arm: N=40, 53% male, mean (± SD) age 37.3 (± 10.6) years, weight 79.8 (± 13.5) kg, duration of diabetes 18.0 (± 9.4) years, HbA 1c 9.25% (± 1.4%), mild hypoglycaemic episodes per week 1.97 (± 1.53), insulin use 0.88 (± 0.39) units/kg/day, retinopathy in 42.5%, neuropathy in 15.0%, microalbuminuria in 20.0%, proteinuria in 10.0%, smoking 65.0%.

114 100 Intervention CSII using the wearable Disetronic H-TRONplus insulin pump (Disetronic Medical Systems) with insulin aspart (NovoRapid) as pump insulin. Comparator The starting dose was 90% of the previously used total insulin dose per day or 80% when hypoglycaemia was a problem to the patient. It was advised to start with one basal rate, or two at the most with the night-time rate 0.2 units/hr lower than the daytime rate. Initially, 50% of the total daily dose was given as basal insulin, the rest equally divided, before each meal. Mealtime bolus insulin aspart was adjusted according to the post-prandial measurements and the basal rate was adjusted according to the preprandial measurements, targeting for the same glucose levels as in the injection therapy group. Intensive injection therapy (MDI, 3 injections daily) with insulin aspart and NPH. Previous total daily dose was unchanged. However, 80% of the previously given pre-meal human insulin dose was given as insulin aspart before meals, and the prandial dose decrement was added to the night-time NPH insulin (Insulatard) dose. When the interval between two daytime injections was more than 5hr, additional NPH doses were added. Outcome definitions Target blood glucose range: mmol/l preprandially, mmol/l postprandially, and mmol/l at bedtime. Primary outcome: change in HbA 1c from baseline to 12 and 16 weeks (the mean of these two values was taken). HbA 1c was assessed using ion-exchange HPLC (reference value %). Secondary outcomes: number of hypoglycaemias; mean blood glucose values in the nine-point home blood glucose profiles; SD of all measurements in these profiles; changes in dimensions of the quality of life measures. Mild hypoglycaemia was defined as a value 3.9 mmol/l at self-monitoring of blood glucose in the last 3 weeks of the study confirmed in the meter readouts. Severe hypoglycaemia was defined by the requirement of third-party help. The nine-point self-measured blood glucose profile included the following blood glucose measurements: preprandial, 90 min postprandial, before bedtime, 5 hr after going to bed, and before breakfast the next day. The nine-point profile was collected once in the week before each visit. Data analyses & statistics Health-related quality of life was assessed using the SF-36 instrument. Treatment satisfaction was assessed using the 6-item Diabetes Treatment Satisfaction Questionnaire. Analysis: Because of the high drop-out rate after crossover, the trial was analysed as a parallel clinical trial using the data from the first half of the crossover phase only. Change between groups from baseline to 16 weeks was analysed with the independent samples t test for biomedical variables and the Mann-Whitney U test for quality of life levels. Missing baseline values were carried forward from earlier measurements during the qualification phase, if possible. Missing values at 16 weeks of treatment were carried forward from 12-week measurements, if available, for the SD of nine-point blood glucose profiles, body weight, and insulin use. For the comparison of stability of glycaemic control, the SD of the nine-point blood glucose profiles was taken as an individual endpoint. A minimum of 4 measurements was required to produce such an endpoint. Data presented as mean ± SD with 95% CIs or median (25th, 75th percentile). Sample size calculation: Although the study was originally designed as a crossover trial, it was anticipated that due to high drop-out it would have to be analysed as a parallel randomised clinical trial. It was calculated that 48 subjects would be required per arm to have an 80% chance of detecting a 0.75% difference in HbA 1c at the two-sided 5% level, with an assumed SD of 1.3%. Based on drop-outs from another trial of similar design, the authors thereafter assumed that the trial could be analysed as a crossover trial and stopped inclusion after 79 patients were randomised.

115 101 Study quality Results (within scope of systematic review update) A. Adequate. The randomisation list was generated by computer in permuted blocks of size 6 for each centre. B. Adequate. Numbered scratch labels were sequentially assigned to patients by the coordinating centre after fulfilment of the glycaemic inclusion criterion for the crossover phase. C. Reported. The two treatment arms were comparable with respect to demographic variables, disease characteristics, and quality of life variables measured at baseline. D. Adequate. Inclusion and exclusion criteria were defined. E. Partial. The change from baseline was reported as mean ± SD but the mean outcome at endpoint in each group was not reported. The difference between treatment arms and 95% CIs were reported. F. Inadequate. The main analysis was based on 72 of the 79 randomised subjects. 7 subjects in the CSII then MDI arm did not complete the first phase and were not included in the main analysis. G. Adequate. The number of withdrawals and drop-outs was stated and reasons provided. Of the 40 subjects randomised to the MDI then CSII arm, all completed the first phase. Six subjects did not start the second phase (5 refused to start and 1 had insufficient self-monitoring of blood glucose). Of the 39 subjects randomised to the CSII then MDI arm, 32 completed the first phase, 2 dropped out (1 serious AE and 1 lost to follow-up) and 5 did not start the pump (4 refused to start and 1 was contraindicated). The second phase was completed by 21 subjects, 7 refused to crossover and 4 dropped out (1 AE, 1 lost to follow-up, 1 with increased hypoglycaemia rate after crossover, 1 no reason given). Mean ±SD change from baseline in HbA 1c: CSII arm (n=32) ± 1.28% MDI arm (n=40) ± 0.70% CSII vs MDI P= Difference 0.84% (95% CI -1.31, -0.36) Number of severe hypoglycaemic episodes: CSII arm 3 events MDI arm 6 events CSII vs MDI P= 0.48 Number of ketoacidotic episodes: CSII arm 1 event MDI arm 1 event Authors conclusions Reviewers notes Change in health-related quality of life (SF-36): General health subscale CSII arm +5.9 MDI arm -1.2 CSII vs MDI P= Mental health subscale CSII arm +5.2 MDI arm -0.6 CSII vs MDI P= In patients with a history of long-term poor control, CSII improves glycaemic control and some aspects of health-related quality of life. CSII resulted in a greater reduction of HbA 1c as compared with MDI, probably explained by superior basal insulin supplementation resulting in a lower and more stable glucose profile. Improved stability was reflected by a significantly lower SD in 24 hr glucose profiles in the CSII arm. The publication does not report a washout period between treatments. However, no data were reported for the second half of the crossover phase. Overall, 17 of 79 randomised patients (22%) discontinued therapy after at or after crossover. In total, after randomisation or crossover, 9 subjects (11.4%) refused to start CSII therapy. Conflict of interest: The study was reported on behalf of the Dutch Insulin Pump Study Group and was supported by a grant from Novo Nordisk Farma B.V., the Netherlands. Additional support was received from Disetronic Medical Systems B.V., the Netherlands.

116 102 Relevance to study question At study entry, participants had poorly controlled diabetes while on 3 insulin injections per day (note: mean HbA 1c 9.27% and 9.25% in the 2 treatment arms) Intervention and comparator appropriate (both rapid-acting analogues) Abbreviations: AE, adverse event; CI, confidence interval; CSII, continuous subcutaneous insulin infusion; HPLC, highperformance liquid chromatography; MDI, multiple daily injections; NPH, neutral protamine hagedorn; SD, standard deviation; SF-36, 36-item Short Form Health Survey The quality of the RCTs was assessed using the following questions: (A) Was the assignment to the treatment groups really random?; (B) Was the treatment allocation concealed?; (C) Were the groups similar at baseline in terms of prognostic factors?; (D) Were the eligibility criteria specified?; (E) Were the point estimates and measure of variability presented for the primary outcome measure?; (F) Did the analysis include an intention-to-treat analysis?; (G) Were withdrawals and dropouts completely described?

117 103 Citation Level of evidence Country Research question/aims Study type/design Hoogma RPLM, Hammond PJ, Gomis R, Kerr D, Bruttomesso D, Bouter KP et al (2006) Comparison of the effects of continuous subcutaneous insulin infusion (CSII) and NPH-based multiple daily insulin injections (MDI) on glycaemic control and quality of life: Results of the 5-nations trial. Diabetic Med 23(2): Level II Europe (11 centres in the Netherlands, UK, Spain, Italy, and Germany) The aim of the study was to compare CSII with MDI with respect to metabolic parameters in an adequately powered RCT with a crossover design. Multicentre, open, randomised crossover trial. Patient group The total study duration was 16 months, including 2 x 6-month treatment phases, each started with a 2-month run-in period, during which patients received education to optimise intensive insulin therapy. Study visits took place at baseline and every two months thereafter. Participants: adults with type 1 diabetes on MDI for at least 6 months. Inclusion criteria: Type 1 diabetes and absent C-peptide secretion, aged years, on MDI for 6 months, able to manage intensive insulin therapy and the technical aspects of insulin pump usage. Exclusion criteria: Hypoglycaemia unawareness, progressive retinopathy, renal insufficiency, acute coronary syndrome or cerebrovascular accident within the last 6 months, uncontrolled hypertension, autonomic neuropathy, planned or existing pregnancy, or other clinically significant concomitant disorders. Subject disposition: 272 subjects were enrolled and randomised into two arms. 223 subjects (82%) completed the study. 31 subjects withdrew during the first treatment phase, 12 subjects completed the first phase but did not cross over into the second treatment phase, and 6 subjects withdrew during the second treatment phase. CSII then MDI arm: N=127, 48% male, mean (± SD) age 35.3 (± 9.8) years, BMI 24.9 (± 3.3) kg/m2, duration of diabetes 14.4 (± 8.9) years, duration of MDI 7.6 (± 4.3) years, HbA 1c 8.2% (± 1.4%), total daily insulin usage 53.4 (± 21.4) IU. Intervention Comparator MDI then CSII arm: N=129, 47% male, mean (± SD) age 37 (± 10.6) years, BMI 24.8 (± 3.4) kg/m2, duration of diabetes 15.4 (± 10.1) years, duration of MDI 8.1 (± 6.2) years, HbA 1c 8.3% (± 1.1%), total daily insulin usage 50.8 (± 18.5) IU. CSII using a H-TRON V100 or H-TRONplus V100 insulin pump (Disetronic Medical Systems) with insulin lispro (Eli Lilly Inc.). MDI with 3 injections of insulin lispro before meals and 1 injection of insulin NPH to achieve optimal control. Outcome definitions The glycaemic targets for both treatments were identical. Target blood glucose range: mmol/l preprandially, mmol/l postprandially, and mmol/l at bedtime. Patients were advised to decrease or increase the dose of NPH insulin if fasting glucose was repeatedly < 4.0 or > 7.0 mmol/l and to decrease or increase the dose of rapid-acting insulin at meals if the 1hr postprandial blood glucose was repeatedly <8.0 or > 10.0 mmol/l. Primary outcomes: (1) mean HbA 1c values at the end of each treatment period (determined by HPLC with normal range %), (2) daily blood glucose fluctuation defined as the average SD of the mean daily blood glucose, using measurements taken during the 14 days prior to the final visit in each treatment period. Secondary outcomes: mean daily blood glucose values (determined from standardised 24 hr blood glucose profiles), the frequency and severity of hypoglycaemic episodes, quality of life (using the 46-item DQoL questionnaire, the SF-12, and an additional 4-item questionnaire related to lifestyle and therapy manageability), signs of discomfort at the injection or infusion site, serious AEs (especially severe hypoglycaemia graded according to DCCT criteria, and ketoacidosis). Blood glucose levels were checked at least 4 times per day (before meals and at bedtime).

118 104 Standardised eight-point blood glucose profiles were performed the day before each study visit, with measurements before and 1 hr after meals, at bedtime, and between 2 and 3 am. Data analyses & statistics Hypoglycaemic episodes were subject defined as mild (self-treated) or severe (requiring thirdparty help). As a result of the absence of a carry-over effect, the study was analysed as a crossover study. Run-in periods were excluded from the statistical analysis. The primary endpoint HbA 1c was initially analysed for non-inferiority of CSII with respect to MDI. Non-inferiority was shown if the upper limit of the one-sided 97.5% CI was 0.7% in favour of MDI. The test of inferiority was based on the per-protocol crossover cohort of 212 subjects. In case of non-inferiority, the superiority of CSII and MDI was to be analysed using a one-sided student s t test with a significance level of 2.5%, based on the ITT crossover cohort of 229 subjects. The second primary endpoint and the main secondary endpoints were analysed using a twosided student s t test with a significance level of 5%, based on the ITT cohort. Missing data was substituted using a last observation carried forward analysis. Study quality Results (within scope of systematic review update) The safety cohort comprised 256 subjects. A. Unknown. Details of the randomisation procedure were not provided. B. Unknown. No details of the concealment of randomisation were provided. C. Reported. The two treatment arms were comparable with respect to patients characteristics. The publication states that there were no significant differences with respect to concomitant diseases or medications but data were not shown. D. Adequate. Inclusion and exclusion criteria were defined. E. Adequate. Mean EOT HbA 1c was reported and the SEM was shown graphically. The difference between treatment arms and 95% CIs were reported. F. Adequate. Analyses were based on the ITT crossover cohort. Although 272 subjects were randomised, 43 subjects dropped out during or after the first treatment phase and were not included in the analyses. G. Partial. The number of withdrawals was stated along with the main reason for withdrawal (refusal to start CSII for the MDI then CSII arm and refusal to leave CSII for the CSII then MDI arm). During the first treatment phase 16 subjects in the CSII-MDI arm and 15 subjects in the MDI-CSII arm withdrew from the study. After the first treatment phase, 10 subjects in the CSII- MDI arm and 2 subjects in the MDI-CSII arm did not crossover into the second treatment phase. Three subjects in each treatment arm withdrew during the second treatment phase. The publication states that there was no carry-over effect. Data were not shown. Mean ± SEM HbA 1c at 8 months: CSII 7.45 ± ~0.065% (note: SEM estimated from figure) MDI 7.67 ± ~0.075% (note: SEM estimated from figure) CSII vs MDI P< Difference 0.23% (upper 97.5% CI 0.104%) Mean ± SEM HbA 1c at 6 months: CSII ~7.51 ± ~0.065% (note: mean and SEM estimated from figure) MDI ~7.64 ± ~0.075% (note: mean and SEM estimated from figure) CSII vs MDI P< 0.05 Mean ± SEM HbA 1c at 4 months: CSII ~7.47 ± ~0.065% (note: mean and SEM estimated from figure) MDI ~7.57 ± ~0.075% (note: mean and SEM estimated from figure) Number of severe hypoglycaemic episodes: CSII 0.2 events per patient per year MDI 0.5 events per patient per year CSII vs MDI P< Ratio 2.60 (95% CI 2.08, 3.25)

119 105 Number of ketoacidotic episodes: 4 episodes in total, 2 during the first CSII treatment phase and 2 during the run-in phase, resulting in a total frequency of 0.03 events per patient year. No episodes occurred during MDI therapy. Quality of life (DQoL): CSII arm EOT score 75 MDI arm EOT score 71 CSII vs MDI P< Whereas all scores deteriorated during MDI, an improvement in all categories was observed with CSII. There were significant improvements in treatment satisfaction (P< 0.001), treatment impact (P< 0.001) and a significant reduction in diabetes-related worry (P< 0.01) when using CSII compared with MDI. Quality of life (SF-12): Physical health subscale No difference when using CSII compared with MDI (no data provided) Mental health subscale Significant improvement in perception of mental health when using CSII compared with MDI (P=0.05) Authors conclusions Reviewers notes Quality of life (Lifestyle and manageability): Patients perceived significantly more flexibility with regard to eating habits (P< 0.001) and significant improvement in lifestyle flexibility and sleep patterns (P< 0.001) when using CSII compared with MDI. The study demonstrated the superiority of CSII over an NPH-based MDI regimen with respect to HbA 1c, reduced mean blood glucose levels, and blood glucose fluctuations, and a reduction in the incidence of severe as well as minor episodes of hypoglycaemia. In addition, CSII conferred significant advantages in terms of quality of life with improvements in treatment satisfaction, treatment impact, perception of mental health, flexibility of eating habits and lifestyle, and reduction in diabetes-related worry. There was no significant difference in treatment modalities with respect to incidence of diabetic ketoacidosis. However, CSII was uniquely associated with a small number of infusion-site problems, notably skin reactions and local pain. Despite this, once patients had experienced CSII they were much more likely to recommend it than an NPH-based MDI regimen. The second treatment phase was preceded by a 2-month run-in/washout period. The authors state that as a result of the absence of a carry-over effect, the study was analysed as a crossover trial. Relevance to study question Conflict of interest: The study was reported on behalf of the 5-Nation Study Group with grant support from Disetronic Medical Systems AG. One author was reimbursed by Disetronic/Roche for attending a conference, and received fees for speaking and membership of an advisory board. Another received honoraria from Roche/Disetronic for participating in advisory boards. A third author received fees for speaking to a symposium by Disetronic Medical Systems, Italy. One author was reimbursed by Disetronics for attending a conference. A fifth author has been employed by Disetronic Medical Systems. At study entry, participants were receiving 3 insulin injections per day (note: mean HbA 1c 8.3% and 8.2% in the 2 treatment arms) Intervention and comparator appropriate (both rapid-acting analogues) Abbreviations: AE, adverse event; BMI, body mass index; CI, confidence interval; CSII, continuous subcutaneous insulin infusion; DQoL, Diabetes Quality of Life; EOT, end of treatment; HPLC, high-performance liquid chromatography; ITT, intention to treat; MDI, multiple daily injections; NPH, neutral protamine hagedorn; SD, standard deviation; SF-12, 12-item Short Form Health Survey The quality of the RCTs was assessed using the following questions: (A) Was the assignment to the treatment groups really random?; (B) Was the treatment allocation concealed?; (C) Were the groups similar at baseline in terms of prognostic factors?; (D) Were the eligibility criteria specified?; (E) Were the point estimates and measure of variability presented for the primary outcome measure?; (F) Did the analysis include an intention-to-treat analysis?; (G) Were withdrawals and dropouts completely described?

120 106 Studies of children and/or adolescents with type 1 diabetes Citation Level of evidence Country Research question/aims Study type/design Cohen D, Weintrob N, Benzaquen H, Galatzer A, Fayman G, Phillip M (2003) Continuous subcutaneous insulin infusion versus multiple daily injections in adolescents with type I diabetes mellitus: a randomized open crossover trial. Journal of pediatric endocrinology & metabolism : JPEM 16: Level II Israel (no. of centres unknown) To compare the CSII with MDI for glycaemic control, dose requirements, weight change, incidence of AEs, quality of life, and satisfaction in adolescents. Open, randomised, crossover trial. Patient group Patients were randomly assigned to either CSII or MDI for a 6-month period and thereafter switched to the other treatment for another 6-month period. Study assessments were conducted at study start, at 3 months, and at 6 months. Participants: adolescents with type 1 diabetes. Inclusion criteria: type 1 diabetes of 2 yrs duration, C-peptide secretion < 0.6 ng/ml, and no other chronic disease that could interfere with treatment for diabetes. Exclusion criteria: evidence of microvascular complications or other significant disorders, patients unable to detect hypoglycaemia Subject disposition: Of 16 randomised subjects, 12 completed the study: three were satisfied with pump therapy and did not wish to switch to MDI, and one patient who started with MDI refused to connect to the pump. Participants: N=16, 37.5% male, age years (median 14.2), all treated with MDI (3-4 times/day) at study entry. A comparison of demographics and baseline disease characteristics in the two treatment arms was not provided. However, when starting CSII, mean (±SD) BMI SDS 0.30 (± 0.38), HbA 1c 8.58% (± 0.82%), fructose amine 401 (± 42) nmol/l, insulin dose 0.99 (±0.24) U/kg/day Intervention Comparator Outcome definitions Data analyses & statistics Study quality When starting MDI, mean (±SD) BMI SDS 0.20 (± 0.39), HbA 1c 8.48% (± 1.4%), fructose amine 408 (± 78) nmol/l, insulin dose 0.98 (±0.30) U/kg/day CSII using a Tayco programmable external pump (Disetronic) with lispro (Humalog, Eli Lilly). MDI (four injections daily) with the insulin used before study entry. The MDI schedule consisted of a combination of NPH and regular insulin before breakfast, regular insulin only before lunch and dinner, and NPH only at bedtime. Patient satisfaction (using the DTSQ), and quality of life (using the DQOLY). Analyses: Data presented as mean ± SD. No details of the statistical analyses were provided. Sample size calculation: Not reported. A. Unknown. No details of random sequence generation were provided. B. Unknown. No details were provided to determine whether treatment allocation was concealed. C. Unknown. Demographics and baseline disease characteristics were not reported for the two treatment arms. D. Adequate. Inclusion and exclusion criteria were defined. E. Adequate. Mean (±SD) HbA 1c at study start, middle and end was reported. F. Adequate. Efficacy analyses were based on the total number of patients who entered each treatment period with a particular treatment. G. Adequate. The number of withdrawals and reason for withdrawal were stated. 4 subjects withdrew, all after the first treatment phase. 3 subjects in the CSII then MDI arm did not wish to switch to MDI. 1 subject from the MDI then CSII arm refused to connect to the pump.

121 107 Results (within scope of systematic review update) Mean ± SD HbA 1c at start of treatment: CSII 8.58 ± 0.82% (n=15) MDI 8.48 ± 1.4% (n=13) Mean ± SD HbA 1c at 3 months: CSII 8.19 ± 0.96% MDI 8.31 ± 1.04% Mean ± SD HbA 1c at EOT (6 months): CSII 8.15 ± 1.3% MDI 8.57 ± 0.44% CSII vs MDI ns Mean change in HbA 1c from start to EOT: CSII -0.43% MDI +0.09% CSII vs MDI ns Number of severe hypoglycaemic episodes: CSII 1 event MDI 4 events Number of diabetic ketoacidotic episodes: CSII 1 event MDI no events Authors conclusions Reviewers notes EOT quality of life (DQOLY): Satisfaction subscale CSII 82.7 ± 13 MDI 76.4 ± 14.3 CSII vs MDI P< 0.05 Impact scale and Worry scale CSII and MDI similar The study showed a trend of improvement in diabetic control with CSII compared with MDI, although the difference did not reach statistical significance, perhaps due to small sample size. CSII is feasible, safe and well received in adolescents, improving their coping with the disease and quality of life. The study suggests that CSII can serve as a good alternative to MDI in adolescents with type 1 diabetes. At enrolment, all patients were treated with MDI (3-4 times/day). Results are not reported by treatment phase and arm and the authors did not report any investigation of a carry-over effect. The publication does not report a washout period between treatments. It is not known whether the method of randomisation was adequate because the baseline characteristics of subjects in each treatment arm were not reported. CSII was not significantly different to MDI in reducing HbA 1c in adolescents with type 1 diabetes. Although the number of severe hypoglycaemic events was higher in patients treated with MDI, no firm conclusions can be drawn due to rarity of events. Likewise, no firm conclusions can be drawn regarding diabetic ketoacidosis. Conflict of interest: The study was supported by Tayco Diagnostica Ltd.

122 108 Relevance to study question At study entry, participants were all treated with MDI (3-4 times/day). Participants ranged in age from years Intervention and comparator inappropriate (CSII with rapid-acting analogue and MDI with shortacting insulin) Abbreviations: BMI SDS, body mass index standard deviation score; CSII, continuous subcutaneous insulin infusion; DQOLY, Diabetes Quality of Life Questionnaire; DTSQ, Diabetes Treatment Satisfaction Questionnaire; EOT, end of treatment; MDI, multiple daily injections; NPH, neutral protamine hagedorn; ns, not significant; SD, standard deviation The quality of the RCTs was assessed using the following questions: (A) Was the assignment to the treatment groups really random?; (B) Was the treatment allocation concealed?; (C) Were the groups similar at baseline in terms of prognostic factors?; (D) Were the eligibility criteria specified?; (E) Were the point estimates and measure of variability presented for the primary outcome measure?; (F) Did the analysis include an intention-to-treat analysis?; (G) Were withdrawals and dropouts completely described?

123 109 Citation Doyle EA (Boland), Weinzimer SA, Steffen AT, Ahern JAH, Vincent M, Tamborlane WV (2004) A randomized, prospective trial comparing the efficacy of continuous subcutaneous insulin infusion with multiple daily injections using insulin glargine. Diabetes Care 27(7): Level of evidence Country Research question/aims Study type/design Level II US (1 centre) The principal aim was to compare the efficacy of CSII and MDIs with glargine in lowering HbA 1c levels in youth with type 1 diabetes. Single centre, open, randomised, parallel group trial. Total treatment duration was 16 weeks. 1-2 weeks prior to randomisation subjects received instruction on CSII and MDI therapy. Patient group Treatment goals were the same for both groups and included an HbA 1c < 7%. Blood glucose targets were mg/dl before meals and mg/dl at bedtime. Participants: children and adolescents with type 1 diabetes. Inclusion criteria: aged 8-21 yrs, type 1 diabetes with screening HbA 1c %, otherwise healthy except for treated thyroid or celiac disease, treated with insulin for 6 months, naïve to CSII and glargine, and willing to perform at least 4 blood glucose tests per day. Exclusion criteria: No further exclusion criteria provided. Subject disposition: The first 32 subjects who met all eligibility criteria were invited to enrol in the study and were randomised equally into two arms. The study was completed by all 16 subjects in the CSII arm and 15/16 subjects in the MDI arm. CSII arm: N=16, 38% male, age 12.5 (±3.2) years, 69% white, duration of diabetes 6.8 (±3.8) years, HbA 1c 8.1 (±1.2%), insulin dose 1.4 (±0.5) units/kg, 75% received twice daily injections and 25% received MDI. Intervention MDI arm: N=16, 50% male, age 13 (±2.8) years, 81% white, duration of diabetes 5.6 (±4.0) years, HbA 1c 8.2 (±1.1%), insulin dose 1.1 (±0.3) units/kg, 87.5% received twice daily injections and 12.5% received MDI. CSII using MiniMed 508 (Medtronic) or Paradigm 511 pumps with insulin aspart. Comparator The initial basal CSII dose was ~50% of the total daily insulin dose. MDI ( 3 injections/day) with glargine and premeal insulin aspart. Outcome definitions Data analyses & statistics The initial dose of glargine was calculated as 80% of their total daily insulin dose of NPH or lente, according to usual practice guidelines with glargine. Glargine was given in the morning or at bedtime. Mean HbA 1c at study end, HbA 1c over time, mean blood glucose levels, total daily insulin dose, basal and bolus insulin doses, hypoglycaemic events, change in BMI, hospitalisations, preference of poststudy treatment modality, quality of life using the Diabetes Quality of Life Youth (DQOL- Y) scale. Analyses: Comparisons were conducted using ITT analysis with the last observation carried forward for missing data. Paired t tests were used for within-group comparisons of HbA 1c and insulin doses. ANOVA test were used for between-group comparisons of HbA 1c levels and insulin doses at study end. Data are presented as means ± SD. Sample size calculation: Not reported.

124 110 Study quality Results (within scope of systematic review update) A. Adequate. Subjects were stratified according to gender and age (<18 and 18years). Within each stratum, a randomisation scheme was generated using a random number table with a block size of 4. B. Adequate. The randomisation process was completed by the centre s Investigational Pharmacy, using a block size of 4. C. Reported. Both groups were similar with respect to baseline clinical characteristics. D. Adequate. Eligibility criteria were defined. E. Adequate. Mean (±SD) HbA 1c at study end was reported. F. Adequate. Efficacy analyses were conducted on an ITT basis. G. Adequate. During the study only one subject withdrew. The subject discontinues after 8 weeks on MDI due to two episodes of dehydration and ketosis. Mean ± SD HbA 1c at EOT (16 weeks): CSII arm 7.2 ± 1.0%, P< 0.02 MDI arm 8.1 ± 1.2%, ns CSII vs MDI P< 0.05 Severe hypoglycaemic episodes: CSII arm no episodes MDI arm 5 episodes in 4 subjects (one event occurred prior to randomisation) Number of ketoacidotic episodes: CSII arm one hospitalisation for diabetic ketoacidosis. MDI arm one subject had 2 hospitalisations for dehydration and ketosis. Authors conclusions Quality of life (DQOL-Y): Completed in 8/16 (50%) of subjects in each study arm. There were no differences between arms at baseline or 16 weeks (data not shown). In the context of a short-term randomised clinical trial, a considerably greater improvement in HbA 1c levels was seen with CSII than with MDI & glargine. However, no single approach to treatment is ideal for every patient and the availability of multiple therapeutic options will allow clinicians who care for children with type 1 diabetes to choose the best treatment for an individual patient at a particular time. Reviewers notes The DQOL-Y questionnaire was successfully completed by only half the participants in each study arm. Although there was no difference between the groups at baseline and 16 weeks, the poor completion rate does not permit any conclusions to be drawn about diabetes-related quality of life in the current study. Insufficient data were available to compare the relative safety of CSII with MDI & glargine due to the small number of patients studied over a short duration. Long-acting analogue insulin glargine was used as basal insulin in the MDI arm. Relevance to study question Conflict of interest: The study was supported by grants from Medtronic MiniMed. Equipment and supplies were provided by Aventis Pharmaceuticals, Novo Nordisk Pharmaceuticals, and LifeScan. At study entry, participants were required to be 8-21 yrs old (ie, some adults may have been included) and have HbA 1c between 6.5% and 11%. Intervention and comparator appropriate (both rapid-acting analogues) MDI therapy used glargine as basal insulin Abbreviations: AE, adverse event; BMI, body mass index; CI, confidence interval; CSII, continuous subcutaneous insulin infusion; DQOL-Y, Diabetes Quality of Life - Youth; EOT, end of treatment; ITT, intention to treat; MDI, multiple daily injections; ns, not significant; SD, standard deviation The quality of the RCTs was assessed using the following questions: (A) Was the assignment to the treatment groups really random?; (B) Was the treatment allocation concealed?; (C) Were the groups similar at baseline in terms of prognostic factors?; (D) Were the eligibility criteria specified?; (E) Were the point estimates and measure of variability presented for the primary outcome measure?; (F) Did the analysis include an intention-to-treat analysis?; (G) Were withdrawals and dropouts completely described?

125 111 Citation a Level of evidence Country Research question/aims Study type/design Weintrob N, Benzaquen H, Galatzer A, Shalitin S, Lazar L, Fayman G et al (2003) Comparison of continuous subcutaneous insulin infusion and multiple daily injection regimens in children with type 1 diabetes: A randomized open crossover trial. Pediatrics 112(3 I): Level II Israel (1 centre) To compare the efficacy and feasibility of CSII with MDI in children with type 1 diabetes. Single centre, open, randomised, crossover trial. Patients were randomly assigned to either CSII or MDI for a 3.5-month period and thereafter switched to the other treatment for another 3.5-month period. The first treatment phase was preceded by a 2-week run-in period. The second treatment phase was preceded by a 2-week washout period. Subjects and their families attended an educational session 3 months before study onset. Visits were scheduled at 2 weeks, 2 days (CSII arm only), 1 and 3 weeks, and then twice every 5-6 weeks. Patient group Blood glucose targets: mmol/l before meals and at midnight; mmol/l 2 hr after meals. Participants: children and young adolescents with type 1 diabetes. Inclusion criteria: type 1 diabetes treated with insulin for 2 yrs, aged 8-14 yrs, deficient C- peptide secretion (fasting level < 200 pmol/l), ability to cope with treatment procedures. Exclusion criteria: No further exclusion criteria provided. Subject disposition: The first 24 subjects who expressed a desire to participate were enrolled. One subject was excluded because of endogenous insulin secretion. All 23 subjects who started the study completed the 2 study arms. At enrolment, all subjects were being treated with MDI ( 3/day) with Insulatard and Actrapid (Novo Nordisk) or Humulin N and R (Eli Lilly). All subjects were CSII-naïve and had no clinical evidence of microvascular complications, hypoglycaemia unawareness, concomitant disorders, mental retardation, or a psychiatric disorder. CSII then MDI arm: N=11, 36% male, age 11.9 (±1.4) years, BMI SDS 0.3 (±1.0), duration of diabetes 5.3 (±1.9) years, HbA 1c at randomisation 7.9 (±1.3%), HbA 1c 3 months before randomisation 8.6 (±0.8%), insulin dose 0.93 (±0.22) units/kg/day. Intervention MDI then CSII arm: N=12, 50% male, age 11.6 (±1.5) years, BMI SDS 0.3 (±0.4), duration of diabetes 6.3 (±2.6) years, HbA 1c at randomisation 8.6 (±0.8%), HbA 1c 3 months before randomisation 9.2 (±1.0%), insulin dose 0.97 (±0.22) units/kg/day. CSII using MiniMed 508 (Medtronic) with insulin lispro (Humalog, Eli Lilly) immediately before meals. Comparator The insulin dosage was determined by decreasing the average total insulin dosage per day over the preceding 2 weeks by 20%; 50% was given as a basal rate and 50% as premeal boluses. Blood glucose levels > 8.3 mmol/l were corrected with additional insulin given before meals and snacks, using 1 U for every mmol/l above 8.3 mmol/l. MDI ( 3 injections/day) with combined NPH and regular insulin min before breakfast, regular insulin min before lunch and supper, and NPH at bedtime. Insulin dosage was determined as for the CSII arm.

126 112 Outcome definitions Change in mean HbA 1c, HbA 1c over time, mean blood glucose levels, daily insulin dose, hypoglycaemic events, hyperglycaemia events, change in BMI SDS, ketonuria, diabetic ketoacidosis, treatment satisfaction (using DTSQ), quality of life (using the DQOLY). Data analyses & statistics Hypoglycaemia was defined as symptoms relieved by ingestion of glucose or food and/or a capillary blood glucose level of < 3.8 mmol/l. Severe hypoglycaemia was defined as any hypoglycaemic event requiring assistance from another person or resulting in seizure or coma. Diabetic ketoacidosis was defined as a ketotic event requiring hospital admission with venous blood ph of < Analyses: Data are presented as means ± SD or median (range) as appropriate. ANOVA was used to compare baseline variables between the 2 randomised arms and ANOVA with repeated measures was applied to compare the changes in variables over time between the 2 study arms. Study quality Results (within scope of systematic review update) Sample size calculation: Not reported. A. Unknown. No details of the randomisation scheme were provided. B. Unknown. No details of the randomisation process were provided. C. Reported. No significant differences between the study arms were noted for any of the variables. D. Adequate. Eligibility criteria were defined. E. Adequate. Change in mean (±SD) HbA 1c and the increment were reported. F. Adequate. All randomised subjects completed the study. Efficacy analyses were conducted on an ITT basis of all randomised subjects. G. Adequate. No subjects withdrew following randomisation. Mean ± SD HbA 1c at EOT: CSII 8.0 ± 0.7% MDI 8.1 ± 0.8% CSII vs MDI repeated measures, secondary to the differences at the start of the treatment P= 0.03 Change from baseline in mean ± SD HbA 1c: CSII (8.0 ± 1.1% at randomization) ± 1.0% MDI (8.3 ± 0.7% at randomisation) ± 1.0% CSII vs MDI ns Rate per patient-year of severe hypoglycaemic events: CSII 1 event; 0.13 (95% CI 0.0, 0.4) MDI 3 events ; 0.39 (95% CI 0.0, 0.84) CSII vs MDI ns Number of ketoacidotic episodes: No events in either treatment arm. EOT quality of life (DQOLY): There was no significant difference between treatments for any of the DQOLY subscales. Satisfaction scale CSII 74.8 ± 13.5 MDI 73.5 ± 14.0 Impact scale CSII 73.2 ± 9.6 MDI 73.5 ± 9.7 Worry scale CSII 79.8 ± 12.8 MDI 81.6 ± 12.4

127 113 Authors conclusions Intensive insulin therapy with either CSII or MDI is feasible, safe, and well accepted by children with type 1 diabetes and their families. Patients treated intensively with CSII and MDI achieve a similar metabolic control and have the same rate of AEs. The use of CSII led to lower insulin requirement and higher satisfaction rate, with no change in BMI. The lower HbA 1c values during CSII on repeated measures were accounted for solely by the lower HbA 1c value at the start of the treatment arm but there was no significant difference between modes of therapy in the change over time. Reviewers notes The main improvement in metabolic control (a significant reduction in HbA 1c of ~0.6%) was achieved in the period before the study, simply by intensifying patient education without a change in the diabetes treatment regimen. The results, therefore, suggest that both modes be made available to the diabetic team and the patients to better tailor therapy, and that enrolling patients into a research study is an effective tool to improve diabetic control. The second treatment phase was preceded by a 2-week run-in/washout period. A carry-over effect was not investigated. Relevance to study question Conflict of interest: The study was supported by Minimed/Agentek Ltd. At study entry, participants were required to be 8-14 yrs old and treated with 3 insulin injections/day (note: mean HbA 1c 7.9% and 8.6% in the 2 treatment arms) Intervention and comparator inappropriate (CSII with rapid-acting analogue and MDI with shortacting) Abbreviations: AE, adverse event; BMI SDS, body mass index standard deviation score; CI, confidence interval; CSII, continuous subcutaneous insulin infusion; DQOLY, Diabetes Quality of Life for Youth; DTSQ, Diabetes Quality of Life Questionnaire for Youth; EOT, end of treatment; ITT, intention to treat; MDI, multiple daily injections; ns, not significant; SD, standard deviation The quality of the RCTs was assessed using the following questions: (A) Was the assignment to the treatment groups really random?; (B) Was the treatment allocation concealed?; (C) Were the groups similar at baseline in terms of prognostic factors?; (D) Were the eligibility criteria specified?; (E) Were the point estimates and measure of variability presented for the primary outcome measure?; (F) Did the analysis include an intention-to-treat analysis?; (G) Were withdrawals and dropouts completely described? a A related publication comparing glycaemic patterns using a Continuous Glucose Monitoring System (CGMS) is also available (Weintrob et al (2004) Arch Pediatr Adolesc Med 158(7): ). However, no additional study details or relevant outcomes were reported.

128 114 Studies of adults with type 2 diabetes Citation Level of evidence Country Research question/aims Study type/design Berthe E, Lireux B, Coffin C, Goulet-Salmon B, Houlbert D, Boutreux S et al (2007) Effectiveness of intensive insulin therapy by multiple daily injections and continuous subcutaneous infusion: A comparison study in type 2 diabetes with conventional insulin regimen failure. Horm Metab Res 39(3): Level II France (2 centres) To compare the efficacy, safety, and patient satisfaction of two procedures of intensified insulin therapy ie, MDI and CSII, in patients with type 2 diabetes poorly controlled by conventional insulin therapy (CIT), with the assessment of daily blood glucose profile with a Continuous Glucose Monitoring System (CGMS). Two-centre, open, randomised, crossover trial. Patients were randomly assigned to either CSII or MDI for a 12-week period and thereafter switched to the other treatment for another 12-week period. Patients were enrolled in a 6-week run-in period with CIT (premixed human insulin 30% regular/70% NPH twice daily, except 1 subject who received two daily NPH injections). Participants received counselling at the beginning of each treatment phase and were hospitalised for hr at the beginning of MDI treatment and for 5 days at the beginning of CSII treatment. All patients were taught to titrate the insulin dose in order to reach a total dose not exceeding the conventional insulin dose at randomisation. The insulin starting dose was based on the insulin requirement during the run-in period, ranging from UI/kg/day. Patient group Glycaemic targets were defined as mmol/l before meals and < 8.8 mmol/l 2 hr after meals. Participants: adults with type 2 diabetes not optimally controlled with CIT. Inclusion criteria: received insulin for > 6 months, aged years, BMI kg/m2, HbA 1c level 6.5% on 2 determinations, willing to use an insulin pump device. Exclusion criteria: renal failure, proliferative retinopathy, triglyceride level > 5.7 mmol/l, use of an oral antidiabetic medication or oral corticosteroid, insulin dose requirements > 1.5 U/kg/day, patients refusing the pump device. Subject disposition: 17 subjects were randomised into two treatment arms. All patients completed the study. CSII then MDI arm: N=7, 14% male, mean (± SD) age 50.6 (± 6.4) years, BMI 34.6 (± 4.0) kg/m2, duration of diabetes 17.3 (± 4.3) years, HbA 1c 8.6% (± 0.4%), duration of insulin treatment 7.6 (± 7.5) years, insulin daily dose 1.0 (± 0.3) U/kg MDI then CSII arm: N=10, 50% male, mean (± SD) age 58.4 (± 4.6) years, BMI 33.0 (± 4.9) kg/m2, duration of diabetes 16.5 (± 7.1) years, HbA 1c 9.3% (± 2.1%), duration of insulin treatment 5.0 (± 5.5) years, insulin daily dose 1.0 (± 0.3) U/kg Intervention CSII using a Medtronic 508 insulin pump with insulin lispro (Humalog; Eli Lilly), starting with 70% daily dose as basal and 30% as prandial bolus. Comparator MDI with 3 daily injections of premixed lispro-nph insulin (Humalog Mix 50; Eli Lilly) started at equal dose before each meal. Outcome definitions Clinical parameters (BMI, systolic and diastolic blood pressure), HbA 1c values (measured by HPLC), 6-point capillary blood glucose profiles, CGMS profile patterns, insulin dose, hypoglycaemic events, lipid profile, treatment satisfaction, and choice for after-study insulin regimen (CSII or MDI). Hypoglycaemia was defined as capillary blood glucose or sensor reading of 3.3 mmol/l.

129 115 Data analyses & statistics Analyses: Results are presented as mean ± SD. Categorical variables at baseline were compared using Fisher s exact test and continuous variables were compared by the Mann- Whitney U test. Between-treatment comparisons for all end-points except CGMS patterns were performed using a non-parametric test for multiple related samples (Friedman test). A carry-over effect was investigated by comparing the 2 arms defined by the treatment order using a Wilcoxon rank-sum test. Study quality Results (within scope of systematic review update) Sample size calculation: Not reported. A. Unknown. No details of random sequence generation were provided. B. Unknown. No details of concealment of randomisation were provided. C. Reported. The two treatment arms were comparable with respect to demographics and baseline disease characteristics. However, mean age was significantly higher in the MDI-CSII arm compared with the CSII-MDI arm (58.4 vs 50.6 yrs, P< 0.01). D. Adequate. Inclusion and exclusion criteria were defined. E. Adequate. Mean (±SD) HbA 1c at end of treatment was reported. F. Adequate. All subjects completed the study. G. Adequate. No subjects withdrew from the study. No carry-over effect was observed for HbA 1c. CSII-MDI arm 8.57 ± 0.45% on CIT, 7.78 ± 0.65% on CSII, 7.97 ± 0.84% on MDI MDI-CSII arm 9.3 ± 2.05% on CIT, 7.72 ± 0.94% on CSII, 8.97 ± 1.9% on MDI Mean ± SD HbA 1c at EOT (12 weeks): CIT 9.0 ± 1.6% CSII 7.7 ± 0.8% (CSII vs CIT P< 0.01) MDI 8.6 ± 1.6% (MDI vs CIT P< 0.02) CSII vs MDI P< 0.03 Rate of severe hypoglycaemic episodes: No self-reported hypoglycaemia was observed. However, the rate of mild but not severe hypoglycaemic episodes was recorded by CGMS. Rate of ketoacidotic episodes: Not reported. However, no AEs occurred with MDI or CSII. Authors conclusions Reviewers notes Lipid levels: No difference between CSII and MDI (data not shown). The study demonstrates that an intensified insulin regimen using CSII allows a better glycaemic control than CIT or MDI using a combination of lispro plus NPH three times daily, providing a better 6-point blood glucose profile, 24 hr CGMS glucose AUC, and finally lowering HbA 1c levels substantially. An external pump seems convenient and safe for patients with type 2 diabetes who fail to respond to a CIT regimen. The publication does not report a washout period between treatments. However, no carry-over effect was observed for HbA 1c. Relevance to study question Conflict of interest: study supported by Eli Lilly At study entry, participants were not optimally controlled (HbA 1c 6.5%) on insulin injections. Participants were aged yrs Intervention and comparator appropriate (both rapid-acting analogues) Abbreviations: AE, adverse event; AUC, area under the curve; BMI, body mass index; CIT, conventional insulin therapy; CGMS, Continuous Glucose Monitoring System; CSII, continuous subcutaneous insulin infusion; EOT, end of treatment; HPLC, high-performance liquid chromatography; MDI, multiple daily injections; NPH, neutral protamine hagedorn; SD, standard deviation The quality of the RCTs was assessed using the following questions: (A) Was the assignment to the treatment groups really random?; (B) Was the treatment allocation concealed?; (C) Were the groups similar at baseline in terms of prognostic factors?; (D) Were the eligibility criteria specified?; (E) Were the point estimates and measure of variability presented for the primary outcome measure?; (F) Did the analysis include an intention-to-treat analysis?; (G) Were withdrawals and dropouts completely described?

130 116 Citation Level of evidence Country Research question/aims Study type/design Herman WH, Ilag LL, Johnson SL, Martin CL, Sinding J, Al Harthi A et al (2005) A clinical trial of continuous subcutaneous insulin infusion versus multiple daily injections in older adults with type 2 diabetes. Diabetes Care; 28(7): Level II US (2 centres) The purpose of the study was to compare the efficacy and safety of CSII and MDI in older adults with insulin-treated type 2 diabetes. Two-centre, open, randomised, parallel-group trial. Patient group The total treatment duration was 12 months. Subjects were screened 4 weeks before randomisation to allow for discontinuation of oral antidiabetic medications and study instruction. There was an additional 1 week between randomisation and treatment initiation where subjects monitored their diet, physical activity and blood glucose levels in order to estimate the initial total daily insulin dose. Study visits took place at baseline, weeks 1, 2, and 4, at 2 months, and every two months thereafter. Participants: older adults aged at least 60 years with insulin-treated type 2 diabetes. Inclusion criteria: age 60 years, clinical diagnosis of type 2 diabetes for 1 yr, taking 1 insulin injection per day for the past month (with or without oral antidiabetic medications), and had an HbA 1c 7.0%. Exclusion criteria: BMI > 45 kg/m2; severe impairment of cardiac, hepatic, or renal function; presence of any physical, psychological, or cognitive impairments that would interfere with adherence to an intensive insulin therapy program; 2 episodes of severe hypoglycaemia in the past year or a history of hypoglycaemia unawareness. Subject disposition: Of 144 screened subjects, 107 were randomised into two treatment arms. The study was completed by 48/53 subjects (91%) in the CSII arm and 50/54 subjects (93%) in the MDI arm. CSII arm: N=53, 72% male, mean (± SD) age 66.6 (± 5.9) years, BMI 32.5 (± 5.8) kg/m2, Caucasian 81%, duration of diabetes 16.9 (± 9.0) years, HbA 1c 8.4% (± 1.1%), retinopathy 42%, nephropathy 17%, neuropathy 72%, prior insulin only 57%, prior insulin & oral agent(s) 43%, duration of insulin treatment 8.1 (± 8.3) years. Intervention MDI arm: N=54, 44% male, mean (± SD) age 66.2 (± 4.5) years, BMI 31.8 (± 5.8) kg/m2, Caucasian 91%, duration of diabetes 15.4 (± 8.9) years, HbA 1c 8.1% (± 1.2%), retinopathy 36%, nephropathy 13%, neuropathy 59%, prior insulin only 61%, prior insulin & oral agent(s) 39%, duration of insulin treatment 8.2 (± 7.7) years. CSII using a MiniMed 508 insulin infusion pump (Medtronic MiniMed) with insulin lispro (Humalog; Eli Lilly). Comparator The initial basal rate (units/hr) was calculated as 50% of the total daily insulin dose divided by 24 hr. The remaining 50% was administered as preprandial lispro boluses. Participants were instructed to adjust their premeal boluses based on their premeal capillary glucose readings and anticipated carbohydrate consumption. MDI ( 3 injections/day) with preprandial insulin lispro and once daily insulin glargine (Lantus, Aventis). Outcome definitions Basal insulin was calculated as 50% of the total daily insulin dose and administered as glargine before bedtime. The remaining 50% was administered as for the CSII arm. Mean HbA 1c at study end, mean HbA 1c over time, weight, infusion and injection site problems, hypoglycaemic episodes, quality of life (using DQOLCTQ and SF-36). Minor hypoglycaemia was defined as capillary glucose < 65 mg/dl that was self-treatable or, if glucose was not measured, symptoms of hypoglycaemia that resolved with oral carbohydrate. Severe hypoglycaemia was defined as a capillary glucose < 50 mg/dl associated with confusion, loss of consciousness, or seizures, or, in the absence of a glucose determination, confusion, loss of consciousness, or seizures that resolved with the administration or oral carbohydrate, glucagon, or intravenous glucose by another person. Catastrophic hypoglycaemia was defined as severe hypoglycaemia that resulted in life-threatening injury to the patient or another person,

131 117 Data analyses & statistics hospitalisation, and/or death. Analyses: Results are presented as mean ± SD. An ITT analysis employing repeated-measures ANOVA, adjusted for gender and baseline HbA 1c, was used to test the change in mean HbA 1c over time. Differences in proportions were compared using Fisher s exact test (two-tailed), and number of events, adjusted for exposure time, were compared using Poisson regression. Results are presented as mean ± SD. The pre-randomisation DQOLCTQ scores were subtracted from those at the subsequent visits to create change scores. Repeated measures ANOVA was used to assess differences. Safety was assessed in 105/107 subjects. Study quality Results (within scope of systematic review update) Sample size calculation: Based on 180 subjects (90 in each arm), the study had 90% power to detect a difference in HbA 1c of 0.5% between groups using a two-tailed Students t test, at 0.05% significance. Recruitment was halted early due to a recommendation from the data safety monitoring board due to an observed difference of 0.2% between treatment groups that was unlikely to become significant even if the study was continued. A. Unknown. However, randomisation was provided by a data-coordinating centre. B. Adequate. A block randomisation scheme was used at each site. Upon verification of eligibility, the study coordinator or investigator contacted the data-coordinating centre for the randomisation assignment. C. Reported. The two treatment arms were generally comparable with respect to demographics and baseline disease characteristics. However, more men were randomised to the CSII arm compared with the MDI arm (72% vs 44%) and HbA 1c levels at baseline tended to be higher in the CSII arm than the MDI arm (8.4% vs 8.1%). D. Adequate. Inclusion and exclusion criteria were defined. E. Adequate. Mean (±SD) HbA 1c at study end was reported together with the mean (±SD) change from baseline to study end. F. Adequate. Efficacy analyses were conducted on an ITT basis. G. Partial. The number of withdrawals was stated but not the reason for withdrawal. 8 subjects, 4 from each arm withdrew from the study and one CSII subject died at 8 months due to cancer. 2 subjects in the CSII arm withdrew before initiation of therapy, 1 withdrew after 2 weeks, and the other after 4 months. In the MDI arm, 2 subjects withdrew after 2 months, 1 after 8 months, and 1 after 10 months. Mean ± SD HbA 1c at study end: CSII 6.6 ± 0.8% MDI 6.4 ± 0.8% CSII vs MDI P= 0.19 Mean ± SD change in HbA 1c from baseline to study end: CSII -1.7 ± 1.0% MDI -1.6 ± 1.2% Change in mean HbA 1c over time: In both treatment arms, HbA 1c improved significantly over time (P< ). The mean difference between treatment groups was not significant (P= 0.19). There was no interaction between treatment group and time. Gender, BMI, and study site were not significantly associated with HbA 1c values. Achievement of HbA 1c < 7.0% at study end: CSII 75% MDI 84% CSII vs MDI P= 0.30 Incidence of severe hypoglycaemic episodes: CSII 4 episodes in 3 subjects MDI 12 episodes in 6 subjects, including one episode classified as catastrophic CSII vs MDI P= events per person-year 0.23 events per person-year CSII vs MDI P= 0.61 Number of ketoacidotic episodes:

132 118 Not reported. Quality of life (DQOLCTQ): Diabetes impact score increased by 2 points over time in both arms, P< 0.01 CSII vs MDI P= 0.19 Worry scores improved by 3 points over time in both arms, P< 0.02 CSII vs MDI P= 0.62 Diabetes worry, social worry, treatment flexibility, and social stigma did not change over the course of the study and there were no differences between arms. Quality of life (SF-36): Physical health subscale CSII 40.5 at baseline to 41.1 at study end, ns MDI 40.6 at baseline to 41.0 at study end, ns CSII vs MDI ns Authors conclusions Mental health subscale CSII 51.0 at baseline to 50.0 at study end, ns MDI 53.0 at baseline to 50.5 at study end, ns CSII vs MDI ns This study suggests that for highly functioning insulin-treated type 2 diabetics 60 years of age, intensive treatment with either MDI or CSII is feasible and safe. Both treatment groups had significant decreases in mean HbA 1c to levels < 7.0% and were able to maintain HbA 1c levels <7.0% with good safety and high treatment satisfaction. There was no difference in efficacy between CSII and MDI and no difference in efficacy by baseline HbA 1c, gender, BMI, or study site. Although there was a trend toward a higher number of severe hypoglycaemic events in the MDI arm, this was largely related to one subject who experienced four events. Reviewers notes Because MDI achieved results comparable to CSII and because MDI is less expensive than CSII, MDI may be preferred as an initial regimen for older patients with type 2 diabetes requiring intensive insulin therapy. Long-acting analogue insulin glargine was used as basal insulin in the MDI arm. Relevance to study question Conflict of interest: Insulin, syringes, monitoring equipment and supplies, and insulin infusion pumps and continuous blood glucose monitoring devices were donated by Eli Lilly, Aventis, Becton Dickinson, Roche Diagnostics, and Medtronic MiniMed. At study entry, participants were not optimally controlled (HbA 1c 7.0%) on insulin injections. Participants were aged 60 yrs Participants with 2 episodes of severe hypoglycaemia in the previous year were excluded Intervention and comparator appropriate (both rapid-acting analogues) MDI therapy used glargine as basal insulin Abbreviations: AE, adverse event; ANOVA, analysis of variance; BMI, body mass index; CI, confidence interval; CSII, continuous subcutaneous insulin infusion; DQOLCTQ, Diabetes Quality of Life Clinical Trial Questionnaire; EOT, end of treatment; HPLC, high-performance liquid chromatography; ITT, intention to treat; MDI, multiple daily injections; ns, not significant; SD, standard deviation; SF-36, 36-item Short Form Health Survey The quality of the RCTs was assessed using the following questions: (A) Was the assignment to the treatment groups really random?; (B) Was the treatment allocation concealed?; (C) Were the groups similar at baseline in terms of prognostic factors?; (D) Were the eligibility criteria specified?; (E) Were the point estimates and measure of variability presented for the primary outcome measure?; (F) Did the analysis include an intention-to-treat analysis?; (G) Were withdrawals and dropouts completely described?

133 119 Citation Level of evidence Country Research question/aims Study type/design Raskin P, Bode BW, Marks JB, Hirsch IB, Weinstein RL, McGill JB et al (2003) Continuous subcutaneous insulin infusion and multiple daily injection therapy are equally effective in type 2 diabetes: A randomized, parallel-group, 24-week study. Diabetes Care 26(9): Level II US (14 sites) The objective was to show that pump-naïve type 2 diabetic patients could be trained as outpatients to use CSII and then to compare the efficacy, safety, and patient satisfaction of CSII with that of MDI therapy. Multicentre, open, randomised, parallel-group trial. The total treatment duration was 24 weeks, including a 8-week dose adjustment period and 16- week maintenance period. Subjects received instruction on intensive insulin therapy during the first 2 weeks after randomisation. Intensive insulin therapy was defined as mealtime administration of a fast-acting insulin at each meal with basal insulin coverage by a long-acting insulin administered once or twice daily. Oral antidiabetics were discontinued upon receiving study medication. Subjects were assessed at randomisation and at weeks 8, 16, 20, and 24. Patient group The target fasting (pre-breakfast) blood glucose level was mmol/l, without unacceptable hypoglycaemia. Participants: CSII-naïve subjects with type 2 diabetes. Inclusion criteria: type 2 diabetes for 2 yrs and treatment for 6 months with at least 1 insulin dose per day, with or without oral antidiabetic medication, age 35 yrs, fasting C-peptide level at baseline >0.2 nmol/l, BMI 43 kg/m2, HbA 1c 6% and 12%. Exclusion criteria: Impaired hepatic, renal, or cardiac function or recurrent major hypoglycaemia, pregnancy or lactation, women of childbearing age not practicing contraception. Subject disposition: Of 205 screened subjects, 132 were randomised into two treatment arms (69 to CSII and 63 to MDI). 5 subjects (3 in the CSII arm and 2 in the MDI arm withdrew from the study during the 2-week training period, prior to receipt of study medication. 115 subjects completed the study (60 in the CSII arm and 55 in the MDI arm). CSII arm: N=66 (who received study medication), 64% male, mean (± SD) age 55.1 (± 10.2) years, BMI 32.2 (± 4.2) kg/m2, Caucasian 80%, duration of diabetes 13.8 (± 7.9) years, HbA 1c 8.2% (± 1.4%), retinopathy 21%, nephropathy 6%, neuropathy 35%, prior insulin treatment only 59%, prior insulin & oral agent(s) 41%, duration of insulin treatment 5.9 (± 5.0) years, insulin at enrolment 0.75 (± 0.46) units/kg. Intervention Comparator Outcome definitions MDI arm: N=61 (who received study medication), 57% male, mean (± SD) age 56.0 (± 8.18) years, BMI 32.2 (± 5.1) kg/m2, Caucasian 82%, duration of diabetes 11.9 (± 6.4) years, HbA 1c 8.0% (± 1.1%), retinopathy 21%, nephropathy 2%, neuropathy 39%, prior insulin treatment only 64%, prior insulin & oral agent(s) 36%, duration of insulin treatment 4.6 (± 5.1) years, insulin at enrolment 0.69 (± 0.39) units/kg. CSII using a MiniMed 507C insulin infusion pump (Medtronic MiniMed) with insulin aspart (NovoLog), administered as bolus just before meals. MDI with insulin aspart before meals and NPH administered as basal insulin. Change from baseline to study end in mean HbA 1c, mean HbA 1c over time, blood glucose over time, safety (AEs, physical examination findings, clinical laboratory evaluations), incidence of clogs or blockages (CSII arm only), patient satisfaction and quality of life. Patient satisfaction was assessed using a questionnaire that used components of the PHASE V Technologies Outcomes Information System and includes a diabetes treatment satisfaction module and a quality of life summary scale. Subjects in the CSII arm answered an additional module specific to insulin pump therapy. Eight-point (preprandial, 90-min postprandial, bedtime, and at 2 am) blood glucose profiles were recorded before each study visit. Hypoglycaemia was defined as blood glucose > 19.4 mmol/l. Hypoglycaemia was defined as minor if the subject had symptoms of hypoglycaemia confirmed by blood glucose < 2.8 mmol/l

134 120 Data analyses & statistics and was able to deal with the episode without assistance. A major hypoglycaemic event was defined as blood glucose < 2.8 mmol/l that was associated with severe CNS dysfunction that required the assistance of another person or required administration of parenteral glucose or glucagon. Analyses: Efficacy and safety analyses were based only on subjects who received treatment (66/69 randomised subjects in the CSII arm and 61/63 randomised subjects in the MDI arm). Between-treatment comparisons for efficacy endpoints, except daily insulin dose, were made using an ANCOVA model with treatment and centre as fixed effects and corresponding baseline measurement as the covariate. The last observation carried forward approach was used. Results were reported as mean ± SD. Study quality Results (within scope of systematic review update) Sample size calculation: A total of 51 subjects per arm were required to ensure 80% of power to claim an HbA 1c difference of 0.4%. A. Unknown. No details of random sequence generation were provided. B. Unknown. However, subjects were randomised to the lowest available randomisation number within each centre. No criterion were used to stratify subject randomisation. C. Reported. The two treatment arms were generally comparable with respect to demographics and baseline disease characteristics. D. Adequate. Inclusion and exclusion criteria were defined. E. Adequate. Mean (±SD) HbA 1c at study end was reported together with the mean (±SD) change from baseline to study end. F. Inadequate. Efficacy and safety analyses were based on the number of subjects who received treatment rather than an ITT basis. G. Adequate. The number of withdrawals and reason for withdrawal were stated. 5 subjects (3 in the CSII arm and 2 in the MDI arm withdrew from the study during the 2-week training period, prior to receipt of study medication. 12 subjects withdrew during treatment (6 from each arm). In the CSII arm, 5 subjects withdrew consent and 1 subject was noncompliant. In the MDI arm, 1 subject withdrew consent, 2 were noncompliant, 1 withdrew due to ineffective therapy, and 2 withdrew because of AEs. Mean ± SD HbA 1c at study end: CSII 7.6 ± 1.22%, P< 0.05 MDI 7.5 ± 1.17%, P< 0.05 Mean ± SD change in HbA 1c from baseline to study end: CSII ± 1.11% MDI ± 0.89% CSII vs MDI ns Incidence of severe hypoglycaemic episodes: CSII no episodes MDI no episodes Number of ketoacidotic episodes: Not reported. Authors conclusions Reviewers notes Quality of life: All reported results referred to treatment satisfaction and treatment preference only. Insulin aspart was a highly effective and compatible insulin for CSII using an external pump and was as safe and effective as MDI therapy for patients with type 2 diabetes initiating intensive insulin therapy. The study showed that patients can be trained to use pumps on an outpatient basis and prefer CSII to insulin injections. Subjects with recurrent major hypoglycaemia were excluded from participation in the study. Conflict of interest: Financial support for the project was provided by Novo Nordisk Pharmaceuticals.

135 121 Relevance to study question At study entry, participants were receiving insulin and had HbA 1c 6.0% and 12%. Participants were aged 35 yrs Participants with recurrent major hypoglycaemia were excluded Intervention and comparator appropriate (both rapid-acting analogues) Abbreviations: AE, adverse event; ANCOVA, analysis of covariance; BMI, body mass index; CI, confidence interval; CNS, central nervous system; CSII, continuous subcutaneous insulin infusion; EOT, end of treatment; ITT, intention to treat; MDI, multiple daily injections; NPH, neutral protamine hagedorn; ns, not significant; SD, standard deviation The quality of the RCTs was assessed using the following questions: (A) Was the assignment to the treatment groups really random?; (B) Was the treatment allocation concealed?; (C) Were the groups similar at baseline in terms of prognostic factors?; (D) Were the eligibility criteria specified?; (E) Were the point estimates and measure of variability presented for the primary outcome measure?; (F) Did the analysis include an intention-to-treat analysis?; (G) Were withdrawals and dropouts completely described?

136 122 Citation Level of evidence Country Research question/aims Study type/design Wainstein J, Metzger M, Boaz M, Minuchin O, Cohen Y, Yaffe A et al (2005) Insulin pump therapy vs. multiple daily injections in obese Type 2 diabetic patients. Diabetic Med 22(8): Level II Israel (7 centres) To compare the efficacy of insulin pump treatment with MDI in the treatment of poorly controlled obese type 2 diabetic patients already receiving two or more daily injections of insulin plus metformin. Multicentre, open, randomised, crossover trial. After a 2-week single run-in period during which subjects were treated with insulin therapy plus metformin, patients were randomised and then treated in two 18-week treatment periods separated by a 12-week washout period during which they were treated with MDI plus metformin. Evaluations were conducted at weeks 0, 18, 30, and 48, after randomisation. Patient group Changes in insulin dose were made according to similar rules and treatment guidelines. There was no specific protocol treatment; each investigator made recommendations based on clinical judgement. The treatment target was to achieve HbA 1c < 7%. There was no upper limit for insulin dose. Participants: obese, uncontrolled, insulin-treated type 2 diabetic subjects. Inclusion criteria: obese (BMI kg/m2) men or women, aged years, suffering from uncontrolled type 2 diabetes (HbA 1c > 8.5%), treated for 3 months with diet, metformin (850 mg 2-3 times daily) and high doses of insulin (> 1 unit/kg/day), divided into 2 or 3 daily injections. Exclusion criteria: New-onset diabetes (< 6 months), type 1 diabetes, or diabetes secondary to pancreatitis or other disease, history of ischaemic heart disease or CVA within the last 6 months, pre-proliferative or proliferative diabetic retinopathy, advanced nephropathy, liver enzymes twice above the upper limit of the normal range, HbA 1c > 15% at screening. Subject disposition: Of 58 screened subjects, 40 were randomised equally into two treatment arms and 29 subjects (14 in the CSII-MDI arm and 15 subjects in the MDI-CSII arm) completed the study per protocol. During the first treatment period, 3 subjects randomised to the CSII-MDI arm and 5 subjects randomised to the MDI-CSII arm dropped out. One subject from each arm discontinued during the washout period. In the second treatment period, 1 subject in the MDI- CSII arm discontinued. CSII then MDI arm: N=20, weight 91.8 (±17.4) kg, HbA 1c 10.2% (± 1.4%), insulin dose 99.3 (±24.5) units/day. MDI then CSII arm: N=20, weight (±12.4) kg, HbA 1c 10.3% (± 1.2%), insulin dose (±28.04) units/day. Intervention Comparator Outcome definitions Gender, age, and ethnicity were not reported for subjects in the two treatment arms. However, compared with subjects who completed the study protocol, subjects who dropped out of the study were similar in terms of age (both 56.8 years, P= 0.9) and gender (73% vs 60% female, P= 0.4). HbA 1c was marginally significantly lower in subjects who completed the study protocol (8.9 ± 2.1% vs 9.5 ± 1.5%, P= 0.05). CSII using MiniMed with insulin lispro. MDI (four injections daily) with regular insulin (Actrapid, Novo Nordisk; or Humulin R, Eli Lilly) and NPH (Insulatard-HM, Novo Nordisk; or Humulin N, Eli Lilly). Mean HbA 1c at study end, insulin dose, weight, blood glucose (mean meal-test AUC), lipid profile, hypoglycaemic events. Patients performed 4-point daily self blood glucose monitoring on a regular basis and 7-point monitoring prior to study visits. A minor hypoglycaemic event was defined as a blood glucose < 3.3 mmol/l that the subject handles without assistance from others. A major hypoglycaemic event was defined as one in which the patient was unable to self treat and either had a blood glucose < 2.8 mmol/l, symptoms remitted after intake of intravenous glucose, intramuscular glucagon or food intake.

137 123 Data analyses & statistics Analyses: Descriptive data were reported as mean ± SD. Distributions of continuous variables were tested using the Kolmogorov-Smirnov test. For distributions that varied significantly from normal, the Mann-Whitney U-test was used. Categorical variables were compared using the Chisquare test with 99% Monte Carlo CIs. Change from baseline was compared by treatment assignment using the t-test for independent samples or the Mann-Whitney U-test, as appropriate. Carry-over effects were determined by summing subjects values obtained at the end of each treatment period and comparing them by treatment arm using the t-test for independent samples. Period effect was estimated by subtracting second-period values from the first-period values and comparing by group using the t-test for independent samples. Direct treatment effects were estimated as the difference between the subject values at the end of each treatment period and compared by arm. In the ITT analysis of all enrolled subjects, the LOCF method was used to account for missing data. A completers analysis was also conducted. Study quality Results (within scope of systematic review update) Sample size calculation: The present study was designed to have 80% power to detect a true bytreatment group difference of 0.85% in HbA 1c, assuming a two-sided alpha of 0.05, and a SD of the difference of 1.3%. Based on these assumptions, a sample size of 39 was required. Taking into consideration dropouts or assumption errors, a total of 58 subjects was recruited. A. Unknown. No details of random sequence generation were provided. B. Unknown. No details were provided to determine whether treatment allocation was concealed. C. Unknown. Gender, age, and ethnicity were not reported for the two treatment arms. However, HbA 1c was similar between arms (10.2% in the CSII-MDI arm vs 10.3% MDI-CSII arm). D. Adequate. Inclusion and exclusion criteria were defined. E. Adequate. Mean (±SD) HbA 1c at study end was reported together with the mean (±SD) change from baseline to study end. F. Adequate. Efficacy analyses were conducted on an ITT basis, in addition to a completers analysis. G. Adequate. The number of withdrawals and reason for withdrawal were stated. During the first treatment phase, 3 subjects randomised to CSII then MDI dropped out (1 unable to use the pump, 1 with severe hypoglycaemia, and 1 with hyperglycaemia), and 5 subjects randomised to MDI then CSII dropped out (2 due to non-compliance, 2 for protocol violations, and 1 with diagnosis of carcinoma of the lung). During washout, 2 subjects withdrew, 1 in the CSII-MDI arm because of non-compliance and 1 in the MDI-CSII arm due to protocol violation. In the second treatment period, 1 subject in the CSII-MDI arm discontinued because of severe hypoglycaemia. To test for a carry-over effect, the sum of the subject values obtained at the end of each treatment period was compared by treatment group. Inadequate evidence exists to reject that the carry-over effect in group 1 is equal to the carry-over effect in group 2. Equal carry-over effects can thus be assumed. Mean ± SD HbA 1c at end of first treatment period (18 weeks) [ITT cohort]: CSII-MDI arm 7.9 ± 1.0% MDI-CSII arm 8.4 ± 1.3% CSII vs MDI P< 0.05 Mean ± SD HbA 1c at end of second treatment period (18 weeks) [ITT cohort]: CSII-MDI arm 8.8 ± 1.4% MDI-CSII arm 8.8 ± 1.5% Mean ± SD change in HbA 1c from baseline to study end [ITT cohort]: CSII -0.8 ± 1.5% MDI 0.4 ± 1.3% CSII vs MDI P= Mean ± SD change in HbA 1c from baseline to study end [completers cohort]: CSII -0.8 ± 1.6% MDI -0.2 ± 1.2% CSII vs MDI P= 0.4 Incidence of major hypoglycaemic episodes: CSII 3 subjects

138 124 MDI 2 subjects Number of ketoacidotic episodes: Not reported. Change from baseline in lipid profile (mmol/l): Total cholesterol CSII 0.1 ± 0.7 MDI -0.1 ± 1.1 CSII vs MDI P= 0.5 Triglycerides CSII 0.01 ± 0.7 MDI 0.5 ± 2.9 CSII vs MDI P= 0.5 HDL CSII ± 0.2 MDI 0.01 ± 0.2 CSII vs MDI P= 0.4 Authors conclusions Reviewers notes LDL CSII 0.1 ± 0.4 MDI -0.1 ± 0.6 CSII vs MDI P= 0.1 In the ITT analysis, CSII appeared to be superior to MDI in reducing HbA 1c and glucose AUC values without significant change in weight or insulin dose in obese, uncontrolled, insulin-treated type 2 diabetic subjects. The number of major hypoglycaemic events were few and similar in both groups. However, the study was not powered to detect a difference in the frequency of major hypoglycaemic events by treatment groups. The second treatment phase was preceded by a 12-week washout period in which patients were treated with MDI plus metformin. The authors attempted to investigate evidence of a carry-over effect and found no evidence. Relevance to study question Conflict of interest: None declared. At study entry, participants were uncontrolled on insulin (note: mean HbA 1c 10.2% and 10.3% in the 2 treatment arms). Participants were required to be obese and aged yrs Participants with HbA 1c >15% were excluded Intervention and comparator inappropriate (CSII with rapid-acting analogue and MDI with shortacting insulin) Abbreviations: AE, adverse event; AUC, area under the curve; BMI, body mass index; CI, confidence interval; CSII, continuous subcutaneous insulin infusion; ITT, intention to treat; MDI, multiple daily injections; NPH, neutral protamine hagedorn; ns, not significant; SD, standard deviation The quality of the RCTs was assessed using the following questions: (A) Was the assignment to the treatment groups really random?; (B) Was the treatment allocation concealed?; (C) Were the groups similar at baseline in terms of prognostic factors?; (D) Were the eligibility criteria specified?; (E) Were the point estimates and measure of variability presented for the primary outcome measure?; (F) Did the analysis include an intention-to-treat analysis?; (G) Were withdrawals and dropouts completely described?

139 125 Studies of pregnant women with pre-existing diabetes Citation Level of evidence Objective Type of included studies Types of participants Type of intervention Outcomes Data analyses & statistics List of included studies Description of included studies Farrar D, Tuffnell DJ, West J (2007) Continuous subcutaneous insulin infusion versus multiple daily injections of insulin for pregnant women with diabetes. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD DOI: / CD pub2. I To conduct a systematic review of RCTs comparing CSII with MDI of insulin in diabetic pregnancy. Published and unpublished randomised trials comparing CSII with MDI of insulin for pregnant women with diabetes. Quasi-randomised trials were excluded. Pregnant women with pre-existing or gestational diabetes Any comparisons of CSII with MDI of insulin Main outcomes: perinatal mortality; fetal anomaly; hypoglycaemic/hyperglycaemic episodes requiring intervention; admission and length of stay on special care baby unit due to hypoglycaemia. Additional outcomes for the mother: diabetic metabolic control (HbA 1c and blood glucose); rate of antenatal clinic visits and admission for treatment relating to diabetic control; rate of antenatal assessment of fetal wellbeing; rate of induction of labour; rate of operative delivery; rate of severe perineal trauma; rate of pre-eclampsia, postpartum haemorrhage, abruption, postpartum infection, and postnatal depression; woman s preference/satisfaction with treatment, quality of life. Additional outcomes for the baby: perinatal morbidity; macrosomia; gestation at delivery; birthweight centile; birth trauma; hypoglycaemia; measures of growth and neurodevelopment at childhood follow-up. Statistical analyses were conducted using the Review Manager software. Fixed-effect metaanalysis was used for combining data in the absence of significant heterogeneity. Dichotomous data are presented as summary RR (95% CI). Continuous data are presented as weighted mean difference. Heterogeneity was tested using the I 2 statistic. Carta et al, 1986 Nosari et al, 1993 Carta 1986 was a single-centre Italian RCT of 15 women with type 1 diabetes (13 on conventional insulin therapy and 2 on CSII) and 14 women with type 2 diabetes (4 on oral hypoglycaemic drugs and 10 diet-controlled), recruited during the first semester. Subjects randomised to CSII used a Microjet MC 20 portable syringe pump with porcine insulin (Actrapid MC). Subjects randomised to MDI were given Acrapid MC split into 4 boluses. Study quality Nosari 1993 was a single-centre Italian RCT of 31 women with type 1 diabetes, 28 of whom were recruited during the first semester and 4 in the pre-conception period. Subjects randomised to CSII used Microjet MC 20 and Daedi B.V. portable syringe pumps. Subjects randomised to MDI received 4 injections/day (regular insulin at each meal and intermediate-acting insulin at night). A. Adequate. The objective of the study was clearly defined. B. Adequate. Electronic (to Nov 2006) and manual searching was conducted including a handsearch of 30 journals and the proceedings of major conferences and a weekly current awareness search of a further 37 journals. C. Adequate. Trials were identified and coded using the methods of the Cochrane Pregnancy and Childbirth Group D. Adequate. The validity of each study was assessed using criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (2005). E. Adequate. Included studies were summarised and outcome data were available in forest plots. F. Adequate. There was no heterogeneity between the two studies and therefore data were pooled using the fixed effects model. G. Adequate. There was no heterogeneity between the two studies.

140 126 Results (within scope of systematic review update) HbA 1c: N=32 (1 study) First trimester favours CSII : WMD (95% CI -2.13, 1.73), P= 0.8. Second trimester favours MDI: WMD 0.70 (95% CI -2.29, 3.69), P= 0.6. Third trimester favours MDI: WMD 0.10 (95% CI -2.38, 2.58), P= 0.9. Hypoglycaemic events: Note that it is not clear whether data refers to severe events requiring intervention only. N=61 (2 studies) RR 3.00 (95% CI 0.35, 25.87), ns. Ketoacidotic episodes: Not assessed in included studies. Authors conclusions Reviewers notes Relevance to study question Quality of life: Not assessed in included studies. At present there are insufficient data to draw conclusions in relation to best practice. Both methods of administration appear to have advantages and disadvantages. Decisions regarding diabetes management in the context of pregnancy should be made according to individual needs. This review is included because the included studies are of women with pre-existing diabetes rather than gestational diabetes. All participants were pregnant. One of the two included studies included both type 1 and type 2 diabetic patients. Intervention and comparator appropriate (both short-acting insulin) Abbreviations: CI, confidence interval; CSII, continuous subcutaneous insulin infusion; MDI, multiple daily injections; ns, not significant; RCTs, randomised controlled trials; RR, relative risk; WMD, weighted mean difference The quality of systematic reviews was assessed using the following questions: (A) Was a clinical question clearly defined?; (B) Was an adequate search strategy used?; (C) Were the inclusion criteria appropriate and applied in an unbiased way?; (D) Was a quality assessment of included studies undertaken?; (E) Were the characteristics and results of the individual studies appropriately summarised?; (F) Were the methods for pooling the data appropriate?; (G) Were sources of heterogeneity explored?

141 127 Appendix D: Forest plots Figure 4: Meta-analysis of the effect of CSII vs MDI on glycosylated haemoglobin in adults with type 1 diabetes: Base case unadjusted data - WMD (random effects model) Review: Comparison: Outcome: CSII for diabetes 01 Efficacy: unadjusted for baseline 01 Mean HbA1c at endpoint: Adults with type 1 diabetes Study CSII MDI WMD (random) Weight WMD (random) or sub-category N Mean (SD) N Mean (SD) 95% CI % 95% CI 01 At 3-4 months DeVries (1.40) (1.40) [-1.47, -0.17] Hoogma (1.00) (1.10) [-0.30, 0.10] Subtotal (95% CI) [-1.08, 0.30] Test for heterogeneity: Chi² = 4.31, df = 1 (P = 0.04), I² = 76.8% Test for overall effect: Z = 1.11 (P = 0.27) 02 At 6 months Hoogma (1.00) (1.10) [-0.33, 0.07] Subtotal (95% CI) [-0.33, 0.07] Test for heterogeneity: not applicable Test for overall effect: Z = 1.31 (P = 0.19) 03 At 8 months Hoogma (1.00) (1.10) [-0.42, -0.02] Subtotal (95% CI) [-0.42, -0.02] Test for heterogeneity: not applicable Test for overall effect: Z = 2.21 (P = 0.03) Favours CSII Favours MDI Abbreviations: CI, confidence interval; CSII, continuous subcutaneous insulin infusion; HbA 1c, glycolylated haemoglobin; MDI, multiple daily injections; WMD, weighted mean difference Figure 5: Meta-analysis of the effect of CSII vs MDI on glycosylated haemoglobin in children and adolescents with type 1 diabetes: Base case unadjusted data - WMD (random effects model) Review: Comparison: Outcome: CSII for diabetes 01 Efficacy: unadjusted for baseline 02 Mean HbA1c at endpoint: Children and adolescents with type 1 diabetes Study CSII MDI WMD (random) Weight WMD (random) or sub-category N Mean (SD) N Mean (SD) 95% CI % 95% CI 01 At 3-4 months Doyle (1.00) (1.20) [-1.68, -0.12] Subtotal (95% CI) [-1.68, -0.12] Test for heterogeneity: not applicable Test for overall effect: Z = 2.26 (P = 0.02) 02 At 6 months Subtotal (95% CI) 0 0 Not estimable Test for heterogeneity: not applicable Test for overall effect: not applicable Favours CSII Favours MDI Abbreviations: CI, confidence interval; CSII, continuous subcutaneous insulin infusion; HbA 1c, glycolylated haemoglobin; MDI, multiple daily injections; WMD, weighted mean difference

142 128 Figure 6: Meta-analysis of the effect of CSII vs MDI on glycosylated haemoglobin in adults with type 2 diabetes: Base case unadjusted data - WMD (random effects model) Review: Comparison: Outcome: CSII for diabetes 01 Efficacy: unadjusted for baseline 03 Mean HbA1c at endpoint: Adults with type 2 diabetes Study CSII MDI WMD (random) Weight WMD (random) or sub-category N Mean (SD) N Mean (SD) 95% CI % 95% CI 01 At 2-4 months Herman (0.80) (0.80) [-0.12, 0.52] Berthe (0.80) (1.60) [-1.75, -0.05] Subtotal (95% CI) [-1.34, 0.79] Test for heterogeneity: Chi² = 5.64, df = 1 (P = 0.02), I² = 82.3% Test for overall effect: Z = 0.51 (P = 0.61) 02 At 5-6 months Raskin (1.22) (1.17) [-0.35, 0.55] Subtotal (95% CI) [-0.35, 0.55] Test for heterogeneity: not applicable Test for overall effect: Z = 0.44 (P = 0.66) 03 Any timepoint Raskin (1.22) (1.17) [-0.34, 0.54] Herman (0.80) (0.80) [-0.12, 0.52] Berthe (0.80) (1.60) [-1.75, -0.05] Subtotal (95% CI) [-0.53, 0.42] Test for heterogeneity: Chi² = 5.66, df = 2 (P = 0.06), I² = 64.7% Test for overall effect: Z = 0.22 (P = 0.83) Favours CSII Favours MDI Abbreviations: CI, confidence interval; CSII, continuous subcutaneous insulin infusion; HbA 1c, glycolylated haemoglobin; MDI, multiple daily injections; WMD, weighted mean difference Figure 7: Meta-analysis of the effect of CSII vs MDI on glycosylated haemoglobin in children and adolescents with type 1 diabetes: All studies, unadjusted data - WMD (random effects model) Review: Comparison: Outcome: CSII for diabetes 01 Efficacy: unadjusted for baseline 02 Mean HbA1c at endpoint: Children and adolescents with type 1 diabetes Study CSII MDI WMD (random) Weight WMD (random) or sub-category N Mean (SD) N Mean (SD) 95% CI % 95% CI 01 At 3-4 months Cohen (0.96) (1.04) [-0.92, 0.68] Weintrob (0.70) (0.80) [-0.53, 0.33] Doyle (1.00) (1.20) [-1.68, -0.12] Subtotal (95% CI) [-0.79, 0.16] Test for heterogeneity: Chi² = 3.22, df = 2 (P = 0.20), I² = 37.9% Test for overall effect: Z = 1.28 (P = 0.20) 02 At 6 months Cohen (1.30) (0.44) [-1.20, 0.36] Subtotal (95% CI) [-1.20, 0.36] Test for heterogeneity: not applicable Test for overall effect: Z = 1.06 (P = 0.29) Favours CSII Favours MDI Abbreviations: CI, confidence interval; CSII, continuous subcutaneous insulin infusion; HbA 1c, glycolylated haemoglobin; MDI, multiple daily injections; WMD, weighted mean difference

143 129 Figure 8: Meta-analysis of the effect of CSII vs MDI on glycosylated haemoglobin in adults with type 2 diabetes: All studies, unadjusted data - WMD (random effects model) Review: Comparison: Outcome: CSII for diabetes 01 Efficacy: unadjusted for baseline 03 Mean HbA1c at endpoint: Adults with type 2 diabetes Study CSII MDI WMD (random) Weight WMD (random) or sub-category N Mean (SD) N Mean (SD) 95% CI % 95% CI 01 At 2-4 months Herman (0.80) (0.80) [-0.12, 0.52] Wainstein (1.50) (1.50) [-1.37, 0.17] Berthe (0.80) (1.60) [-1.75, -0.05] Subtotal (95% CI) [-1.09, 0.39] Test for heterogeneity: Chi² = 8.13, df = 2 (P = 0.02), I² = 75.4% Test for overall effect: Z = 0.93 (P = 0.35) 02 At 5-6 months Raskin (1.22) (1.17) [-0.35, 0.55] Subtotal (95% CI) [-0.35, 0.55] Test for heterogeneity: not applicable Test for overall effect: Z = 0.44 (P = 0.66) 03 Any timepoint Raskin (1.22) (1.17) [-0.34, 0.54] Herman (0.80) (0.80) [-0.12, 0.52] Wainstein (1.50) (1.50) [-1.37, 0.17] Berthe (0.80) (1.60) [-1.75, -0.05] Subtotal (95% CI) [-0.61, 0.29] Test for heterogeneity: Chi² = 8.34, df = 3 (P = 0.04), I² = 64.0% Test for overall effect: Z = 0.71 (P = 0.48) Favours CSII Favours MDI Abbreviations: CI, confidence interval; CSII, continuous subcutaneous insulin infusion; HbA 1c, glycolylated haemoglobin; MDI, multiple daily injections; WMD, weighted mean difference Figure 9: Meta-analysis of the effect of CSII vs MDI on glycosylated haemoglobin in adults with type 1 diabetes: Base case adjusted data - WMD (random effects model) Review: Comparison: Outcome: CSII for diabetes 02 Efficacy: adjusted for baseline 01 Mean HbA1c at endpoint: Adults with type 1 diabetes Study CSII MDI WMD (random) Weight WMD (random) or sub-category N Mean (SD) N Mean (SD) 95% CI % 95% CI 01 At 3-4 months DeVries (1.40) (1.40) [-1.49, -0.19] Hoogma (1.00) (1.10) [-0.42, -0.02] Subtotal (95% CI) [-1.04, 0.14] Test for heterogeneity: Chi² = 3.20, df = 1 (P = 0.07), I² = 68.7% Test for overall effect: Z = 1.50 (P = 0.13) 02 At 6 months Hoogma (1.00) (1.10) [-0.45, -0.05] Subtotal (95% CI) [-0.45, -0.05] Test for heterogeneity: not applicable Test for overall effect: Z = 2.51 (P = 0.01) 03 At 8 months Hoogma (1.00) (1.10) [-0.54, -0.14] Subtotal (95% CI) [-0.54, -0.14] Test for heterogeneity: not applicable Test for overall effect: Z = 3.42 (P = ) Favours CSII Favours MDI Abbreviations: CI, confidence interval; CSII, continuous subcutaneous insulin infusion; HbA 1c, glycolylated haemoglobin; MDI, multiple daily injections; WMD, weighted mean difference

144 130 Figure 10: Meta-analysis of the effect of CSII vs MDI on glycosylated haemoglobin in children and adolescents with type 1 diabetes: Base case adjusted data - WMD (random effects model) Review: Comparison: Outcome: CSII for diabetes 02 Efficacy: adjusted for baseline 02 Mean HbA1c at endpoint: Children and adolescents with type 1 diabetes Study CSII MDI WMD (random) Weight WMD (random) or sub-category N Mean (SD) N Mean (SD) 95% CI % 95% CI 01 At 3-4 months Doyle (1.00) (1.20) [-1.58, -0.02] Subtotal (95% CI) [-1.58, -0.02] Test for heterogeneity: not applicable Test for overall effect: Z = 2.01 (P = 0.04) 02 At 6 months Subtotal (95% CI) 0 0 Not estimable Test for heterogeneity: not applicable Test for overall effect: not applicable Favours CSII Favours MDI Abbreviations: CI, confidence interval; CSII, continuous subcutaneous insulin infusion; HbA 1c, glycolylated haemoglobin; MDI, multiple daily injections; WMD, weighted mean difference Figure 11: Meta-analysis of the effect of CSII vs MDI on glycosylated haemoglobin in adults with type 2 diabetes: Base case adjusted data - WMD (random effects model) Review: Comparison: Outcome: CSII for diabetes 02 Efficacy: adjusted for baseline 03 Mean HbA1c at endpoint: Adults with type 2 diabetes Study CSII MDI WMD (random) Weight WMD (random) or sub-category N Mean (SD) N Mean (SD) 95% CI % 95% CI 01 At 2-4 months Herman (0.80) (0.80) [-0.42, 0.22] Berthe (0.80) (1.60) [-1.75, -0.05] Subtotal (95% CI) [-1.16, 0.36] Test for heterogeneity: Chi² = 2.99, df = 1 (P = 0.08), I² = 66.5% Test for overall effect: Z = 1.03 (P = 0.30) 02 At 5-6 months Raskin (1.22) (1.17) [-0.54, 0.34] Subtotal (95% CI) [-0.54, 0.34] Test for heterogeneity: not applicable Test for overall effect: Z = 0.45 (P = 0.65) 03 Any timepoint Raskin (1.22) (1.17) [-0.54, 0.34] Herman (0.80) (0.80) [-0.42, 0.22] Berthe (0.80) (1.60) [-1.75, -0.05] Subtotal (95% CI) [-0.55, 0.13] Test for heterogeneity: Chi² = 3.12, df = 2 (P = 0.21), I² = 35.8% Test for overall effect: Z = 1.20 (P = 0.23) Favours CSII Favours MDI Abbreviations: CI, confidence interval; CSII, continuous subcutaneous insulin infusion; HbA 1c, glycolylated haemoglobin; MDI, multiple daily injections; WMD, weighted mean difference

145 131 Figure 12: Meta-analysis of the effect of CSII vs MDI on glycosylated haemoglobin in children and adolescents with type 1 diabetes: All studies, adjusted data - WMD (random effects model) Review: Comparison: Outcome: CSII for diabetes 02 Efficacy: adjusted for baseline 02 Mean HbA1c at endpoint: Children and adolescents with type 1 diabetes Study CSII MDI WMD (random) Weight WMD (random) or sub-category N Mean (SD) N Mean (SD) 95% CI % 95% CI 01 At 3-4 months Cohen (0.96) (1.04) [-1.02, 0.58] Weintrob (0.70) (0.80) [-0.23, 0.63] Doyle (1.00) (1.20) [-1.58, -0.02] Subtotal (95% CI) [-0.81, 0.40] Test for heterogeneity: Chi² = 4.98, df = 2 (P = 0.08), I² = 59.8% Test for overall effect: Z = 0.67 (P = 0.50) 02 At 6 months Cohen (1.30) (0.44) [-1.20, 0.36] Subtotal (95% CI) [-1.20, 0.36] Test for heterogeneity: not applicable Test for overall effect: Z = 1.06 (P = 0.29) Favours CSII Favours MDI Abbreviations: CI, confidence interval; CSII, continuous subcutaneous insulin infusion; HbA 1c, glycolylated haemoglobin; MDI, multiple daily injections; WMD, weighted mean difference Figure 13: Meta-analysis of the effect of CSII vs MDI on glycosylated haemoglobin in adults with type 2 diabetes: All studies, adjusted data - WMD (random effects model) Review: Comparison: Outcome: CSII for diabetes 02 Efficacy: adjusted for baseline 03 Mean HbA1c at endpoint: Adults with type 2 diabetes Study CSII MDI WMD (random) Weight WMD (random) or sub-category N Mean (SD) N Mean (SD) 95% CI % 95% CI 01 At 2-4 months Herman (0.80) (0.80) [-0.42, 0.22] Wainstein (1.50) (1.50) [-1.37, 0.17] Berthe (0.80) (1.60) [-1.75, -0.05] Subtotal (95% CI) [-0.91, 0.09] Test for heterogeneity: Chi² = 3.89, df = 2 (P = 0.14), I² = 48.7% Test for overall effect: Z = 1.61 (P = 0.11) 02 At 5-6 months Raskin (1.22) (1.17) [-0.54, 0.34] Subtotal (95% CI) [-0.54, 0.34] Test for heterogeneity: not applicable Test for overall effect: Z = 0.45 (P = 0.65) 03 Any timepoint Raskin (1.22) (1.17) [-0.54, 0.34] Herman (0.80) (0.80) [-0.42, 0.22] Wainstein (1.50) (1.50) [-1.37, 0.17] Berthe (0.80) (1.60) [-1.75, -0.05] Subtotal (95% CI) [-0.56, 0.05] Test for heterogeneity: Chi² = 4.22, df = 3 (P = 0.24), I² = 28.8% Test for overall effect: Z = 1.64 (P = 0.10) Favours CSII Favours MDI Abbreviations: CI, confidence interval; CSII, continuous subcutaneous insulin infusion; HbA 1c, glycolylated haemoglobin; MDI, multiple daily injections; WMD, weighted mean difference