Evaluation of: The Local Enhanced Service provision of for Managing Diabetes Injectable Therapies

Transcription

1 Evaluation of: The Local Enhanced Service provision of for Managing Diabetes Injectable Therapies Two CCGs have asked the WSYBCSU to evaluate the current Local Enhanced Service (LES) provision in this area to give assurance that these services are being commissioned in an appropriate way. The evaluation process/method that has been adopted to carry out this work comprised of four major strands: 1. A review of the current literature Appendix 1 2. An analysis of the costs associated with the LES Appendix 2 3. Expert clinical opinion(s) on the LES Appendix 3 4. A survey of similar LES provision in alternative areas Appendix 4 Based upon the evidence found in these areas advice has then been given to the CCGs for their consideration. This review has been produced for two anonymised CCGs by NHS West and South Yorkshire and Bassetlaw Commissioning Support Unit. Full details of the review are available from Paul Carder, paul.carder@wsybcsu.nhs.uk The contents of the review are believed to be valid at the time of publication on 31 May It is important to note that new research which could influence the content of the review may become available at any time after this date. The cost analysis is limited to local data provided by the CCGs. Copyright NHS West and South Yorkshire and Bassetlaw Commissioning Support Unit 2013

2 Local Enhanced Service for Managing Diabetes Injectable Therapies The LES is directed at practices who manage patients with diabetes on insulin/glp 1 therapy in primary care. This service is available to all providers delivering diabetes services at Level 3 or 4 who have been appropriately trained and accredited. All Providers are expected to provide essential diabetes care and the additional services which they are contracted for to all their patients. The specification of this service is designed to cover the enhanced aspects of clinical care of the patient, all of which are beyond the scope of essential services. No part of the specification by commission, omission or implication defines or redefines essential or additional services. As part of the service redesign for diabetes, this local enhanced service (LES) for diabetes care is to provide the framework and resources for providing local comprehensive diabetes management within the practice for appropriate patients with diabetes on insulin or GLP 1 therapy, to support self management and to prevent diabetes complications. This will include the appropriate use of the specialist team working as an integrated team as per the diabetes guidelines and agreed specialist care referral criteria. Service Aims To ensure that specialist diabetes services are available in a timely manner and closer to patients homes and; To provide an educational resource and support to clinicians, in the sharing of knowledge and skills and to improve patient care and outcomes through collaborative working practices. Following accreditation, patients who do not meet the referral criteria who are receiving routine diabetes care from specialist care providers, will be advised that their future diabetes care can be provided within the practice, and will be subsequently discharged, if agreeable. Literature Review In the last decade, the National Institute for Health and Care Excellence (NICE) has published extensive guidance on the management of diabetes and prevention of disease related complications. In addition to providing considerable information related to the content of insulin regimens, initiating therapeutic adjustments, and systems of delivery (NICE Clinical Guidelines 15 and 87; NICE Technology Appraisal Guidance 53, 151, 203, and 248), various recommendations

3 about injectable therapies more generally and about patient education are made. This guidance is summarised below. Where relevant, recommendations relevant to diabetes types 1 and 2 have been combined. Insulin regimens and delivery Type 1 Adults with type 1 diabetes should have access to the preparations and species of insulin that they find allow them optimal wellbeing, and cultural preferences should be discussed and respected when agreeing the insulin regimen required. Those patients whose dietary and activity patterns vary considerably from day to day may require careful, detailed review of their self monitoring and insulin injection regimen. This should include all appropriate preparations, along with consideration of unusual patterns and combinations. For adults who have periods of fasting or sleeping after eating (e.g. during religious feasts or after night shift work), a rapid acting insulin analogue before eating (provided the meal is not over long) should be considered. Patients should be given clear guidelines and protocols ( sick day rules ) to assist them in adjusting insulin doses appropriately during intercurrent illness. Insulin regimens and delivery Type 2 The benefits and risks of insulin therapy should be discussed with patients with type 2 diabetes when blood glucose control becomes or remains inadequate with other measures (HbA1c 7.5% (58mmol/mol) or other agreed higher level). Insulin therapy should then be started if the person agrees. In addition, it should be considered (in preference to adding other drugs to control blood glucose) for those on dual therapy who are markedly hyperglycaemic, unless there is strong justification to the contrary (e.g. employment, social or recreational issues related to putative hypoglycaemia, injection anxieties, other personal issues, obesity). When insulin therapy is initiated a structured programme that employs active insulin dose titration should be used. This should include structured education, continuing telephone support, frequent self monitoring, dose titration to target, dietary understanding, management of hypoglycaemia, management of acute changes in glucose control, and support from an appropriately trained and experienced healthcare professional. Insulin therapy should be initiated from a choice of a number of insulin types and regimens. Use of a GLP 1 mimetic (prolonged release exenatide or liraglutide 1.2mg daily) in triple therapy regimens (in combination with metformin and a sulfonylurea, or metformin and a thiazolidinedione) should be considered when blood glucose control becomes or remains inadequate (HbA1c 7.5% (58mmol/mol) or other agreed higher level) and the person has: body mass index (BMI) 35.0 kg/m 2 in those of European descent (with appropriate adjustment for other ethnic groups) and specific psychological or medical problems associated with high body weight, BMI <35.0 kg/m 2 and insulin therapy would have significant occupational implications, or weight loss would benefit other significant obesity related comorbidities.

4 Use of a GLP 1 mimetic in dual therapy regimens (in combination with metformin or a sulfonylurea) is only recommended if the person is intolerant of either metformin or a sulfonylurea or if treatment with metformin or a sulfonylurea is contraindicated, and the person is intolerant of thiazolidinediones and dipeptidyl peptidase 4 (DPP 4) inhibitors, or treatment with thiazolidinediones and DPP 4 inhibitors is contraindicated. GLP 1 therapy should only be continued if the person has had a beneficial metabolic response (i.e. a reduction of at least 1 percentage point in HbA1c (11mmol/mol), and a weight loss of at least 3% of initial body weight at 6 months). Liraglutide 1.8mg daily is not recommended for treatment of type 2 diabetes as there is no evidence that it works more effectively that liraglutide 1.2mg daily. Insulin regimens and delivery general Patients who inject insulin should have access to the delivery device that they find allows them optimal well being and that is easy to use (for some patients this may involve using one or more types of insulin injection pen). Those with special visual, physical or psychological needs should be provided with injection devices or adaptations that they can use successfully. Injection site condition should be checked annually, and if new problems with blood glucose control occur (taken from guidance for type 1 diabetes). Patients should be provided with containers for the collection of used needles, and local arrangements should be in place for suitable disposal of these. Blood glucose monitoring Self monitoring of blood glucose levels should be offered to patients, and used as an integral part of self management and education, to help patient choice and the achievement of optimal diabetes outcomes. It should be available to those on insulin treatment to provide information on hypoglycaemia, to assess changes in glucose control (from medications and lifestyle changes), to monitor changes during illness, and to ensure safety during activities (including driving). Assessment of the equipment used, self monitoring skills, the quality and appropriate frequency of testing, use made of the results obtained (and for type 2 diabetics impact on quality of life and continued benefit) should be carried out as part of the patient s annual review (or more frequently according to need). Clinical monitoring of blood glucose levels (by DCCT*aligned methods of haemoglobin A1c (HbA1c) should be carried out every 2 6 months (depending on level and stability of blood glucose control and change in insulin dose or regimen). Adults with type 1 diabetes should be advised that maintaining an HbA1c below 7.5% (58mmol/mol) is likely to minimise their risk of developing diabetic complications in the longer term. Adults with type 2 diabetes should be involved in decision making about their individual HbA1c target level, which may be above the level of 6.5% (48mmol/mol) set for people with type 2 diabetes in general. They should also be informed that any reduction towards the agreed target will reduce their risk of complications, and that pursuing a level lower than 6.5% (48mmol/mol)

5 should be avoided. Dietary management Individualised and on going dietary advice should be offered. This should be sensitive to personal needs and culture, and can be integrated with a personalised diabetes management plan that includes other lifestyle factors such as physical activity and weight. Healthcare professionals providing advice on the management diabetes should be aware of appropriate nutritional advice in relation to likely areas of interest and concerns to patients, and should be willing to seek advice from specialist colleagues where necessary. Suggested topics include the glycaemic index of particular foods, body weight, energy balance and obesity management, cultural and religious diets, feasts and fasts, foods that are labelled as diabetic, sweeteners, matching carbohydrate, insulin and physical activity, and the use of peer support groups (taken from guidance for type 1 diabetes). Physical activity Adults who choose to integrate increased physical activity into their lifestyle should be offered advice on appropriate intensity and frequency of activity, the role of self monitoring of changed insulin and/or nutritional needs, the effect of activity on blood glucose levels (likely fall), when insulin levels are adequate, the effect of exercise on blood glucose levels, when hyperglycaemic and hypoinsulinaemic (risk of worsening of hyperglycaemia and ketonaemia), appropriate adjustments of insulin dosage and/or nutritional intake for exercise and post exercise periods and the next 24 hours, interactions between exercise and alcohol, and further sources of information (taken from guidance for type 1 diabetes). Hypoglycaemia Adults with type 1 diabetes should be informed that some hypoglycaemic episodes are an inevitable consequence of insulin therapy, and advised that they should use a regimen that avoids or reduces the frequency of hypoglycaemic episodes while maintaining as optimal a level of blood glucose control as is feasible. Advice to assist in obtaining the best balance from any insulin regimen should be available. When hypoglycaemia becomes a particular problem or increases in frequency, possible contributory causes should be reviewed. These include inappropriate insulin regimens (incorrect dose distributions and insulin types), meal and activity patterns, including alcohol, injection technique and skills, injection site problems, previous physical activity, lack of knowledge and skills for self management. Specific education on the detection and management of hypoglycaemia in adults with problems of hypoglycaemia awareness should be offered. Foot care

6 Foot examination should be carried out at one year intervals, and should include educational assessment and education input relative to the risk identified. Examination of feet and lower legs should include inspection of footwear, inspection of foot shape and deformity, skin condition, foot sensation and palpation of foot pulses (NICE Clinical Guidelines 10 and 15). Patient education It is recommended that structured patient education is made available to all those with diabetes, both at the time of diagnosis and on an on going basis as required, based on regular assessment of need (Nice Technology Appraisal Guidance 60). Multidisciplinary teams providing education should include, as a minimum, a dietician, and a practice nurse with experience in diabetes who has knowledge of the principles of patient education. Input from other disciples such as podiatry is also potentially valuable. The Dose Adjustment for Normal Eating (DAFNE) programme is considered to be a potentially suitable option for individuals with type 1 diabetes as it enables self management. Cost Analysis Remuneration under the LES for both year one and year two of the service is reviewed below. Based on current figures then: Remunerating practices on time costs for three appointments totalling 1hr 10mins rather than paying per patient may be more cost effective than the current LES in both year one and year two for both CCGs. If the practice was remunerated for three appointments totalling 1hr 10mins at the rate of a nurse, provided they were a competent clinician, then this would be the most cost effective solution for year one and year two for both CCGs. If the practice were remunerated for three appointments totalling 1hr 10mins at the rate of a GP, this would be less cost effective than the current approach in year one and year two for both CCGs. If the service was provided by consultant endocrinologists at local NHS Trust level, this would approximately quadruple the cost of the service compared to the current LES in both CCGs for year one and year two. Expert Opinions Responses have been received from three anonymised doctors; Dr. A, Dr. B and Dr. C. The local experts identified that General practice was the appropriate setting for this scheme and importantly made a valuable contribution in a high priority area.

7 Furthermore the following points were highlighted if the current LES were to continue: Provision of Managing Injectable Course and mentorship Provision of Diabetes Footcare Course and mentorship Provision of LES Masterclass for year 2 Provision of Care Planning training and practice support An alternative practice diabetes service assessment tool Co ordination of Self Management questionnaires/practice feedback Process to check all LES requirements with access to a clinician experienced in diabetes care for any ambiguous issues So if the current scheme is to continue there areas that would need to be strengthened/enhanced in order to meet patient need and secure outcomes. It is also apparent that a diabetes group has been formed that wishes to examine the current patient journey and treatment pathway Survey of Local provision There are similar enhanced schemes across the area, some via the GPWSI rote as diabetes is seen as a high priority disease area and scheme such as the one here have been therefore been adopted. The clinical requirements are broadly the same, ie requiring a GP and Nurse to acquire the qualification from the practice, the equipment needed for a consultation is uniform along with the standard time frame. The variation across the area is mostly around the tariff. In other areas practice are being rewarded at nearly double the rate highlighted in this LES. Summary Diabetes is seen a priority area both across the region and nationally. In the last decade, the National Institute for Health and Care Excellence (NICE) has published extensive guidance on the management of diabetes and prevention of disease related complications. In addition to providing considerable information related to the content of insulin regimens, initiating therapeutic adjustments, and systems of delivery (NICE Clinical Guidelines 15 and 87; NICE Technology Appraisal Guidance 53, 151, 203, and 248). This scheme complies with the NICE guidance and offers a method for meeting this priority long term condition area. Additionally the local expert highlighted that primary care was the best setting for this type of patient management.

8 When considering the costs, it became apparent that running similar clinics in secondary would nearly quadruple the price so moving this provision into secondary care would have severe budgetary consequences, therefore maintaining provision in primary care is optimal. The service for the most (monitoring and consulting with the patient) can be a nurse managed service but there are often prescribing decisions to be made so a nurse would have to have this ability. However it is the case that co morbidities can also be a factor with this patient group including the link between long terms and conditions and mental health which makes the position unsure that a nurse could carry overall responsibility for oversight of a case without GP input. Interestingly, across the area there are schemes such as this but the remuneration rate is higher than the one for this scheme The current LES does meet the patient need, maintains clinical care closer to the patient home, is more considerably more cost effective than in secondary care and given the co morbidities and complexity of some cases requires oversight/case management from a GP.

9 Appendix 1 Current Literature National Institute for Health and Care Excellence National Institute for Health and Care Excellence (2002). Guidance on the use of long acting insulin analogues for the treatment of diabetes. Technology Appraisal Guidance National Institute for Health and Care Excellence (2003). Guidance on the use of patient education models for diabetes. Technology Appraisal Guidance National Institute for Health and Care Excellence (2004). Type 2 diabetes: prevention and management of foot problems. Clinical Guideline National Institute for Health and Care Excellence (2004). Type 1 diabetes: diagnosis and management of type 1 diabetes in children, young people and adults. Clinical Guideline National Institute for Health and Care Excellence (2009). Type 2 diabetes: the management of type 2 diabetes. Clinical Guideline National Institute for Health and Care Excellence (2009). Type 2 diabetes: newer agents for blood glucose control in type 2 diabetes. Short Clinical Guideline National Institute for Health and Care Excellence (2010). Liraglutide for the treatment of type 2 diabetes mellitus. Technology Appraisal Guidance National Institute for Health and Care Excellence (2011). Continuous subcutaneous insulin infusion for the treatment of diabetes mellitus. Technology Appraisal Guidance National Institute for Health and Care Excellence (2012). Exenatide prolonged release suspension for injection in combination with oral antidiabetic therapy for the treatment of type 2 diabetes. Technology Appraisal Guidance

10 Additional evidence NICE has provided a wealth of evidence related to management of diabetes. additional literature search was conducted but limited to the Cochrane Library. Given that, an A search of Cochrane using the terms Diabetes, Insulin and Management identified 74 Cochrane Reviews. After excluding duplicates, review of the abstracts of the remaining 14 articles identified evidence related to the use of specific insulin regimens, either generally or for specific patient groups (such as pregnant women). Three of the reviews focused on continuous glucose monitoring or intensive glucose control, while the final article considered the benefits and harms of education programmes for people with diabetic kidney disease. Insulin regimens 1. Abdelghaffar S, Attia Abdelhamid M. Metformin added to insulin therapy for type 1 diabetes mellitus in adolescents. Cochrane Database of Systematic Reviews 2009 (available at: BACKGROUND: In adolescents with type 1 diabetes, insulin resistance likely plays a role in the deterioration of metabolic control. In type 1 diabetes, addition of metformin to insulin therapy, to improve insulin sensitivity, has been assessed in a few trials involving few patients or in uncontrolled studies of short duration. No systematic reviews are available up to date to summarize the evidence about metformin addition to insulin therapy in adolescents with type 1 diabetes. Objectives: To assess the effects of metformin added to insulin therapy for type 1 diabetes mellitus in adolescents. Search methods: We searched The Cochrane Library, MEDLINE and EMBASE. We also searched databases of ongoing trials, reference lists of relevant reviews, and we contacted experts, authors and manufacturers. Selection criteria: Any randomised controlled trial (RCT) of at least three months duration of treatment comparing metformin added to insulin therapy versus insulin therapy alone in adolescents with type 1 diabetes was included. Cross over and quasi randomised controlled trials were excluded. Data collection and analysis: Two reviewers read all abstracts, assessed quality and extracted data independently. Authors were contacted for missing data. Main results: Only two trials (60 participants) investigating the effect of metformin added to insulin therapy for three months in adolescents with poorly controlled type 1 diabetes could be included. Meta analysis was not possible due to the clinical and methodological heterogeneity of data. Both studies suggested that metformin treatment lowered glycosylated haemoglobin A1c (HbA1c) in adolescents with type 1 diabetes and poor metabolic control. Improvements in insulin sensitivity, body composition or serum lipids were not documented in either study, however, one study showed a decrease in insulin dosage by 10%. Adverse effects were mainly gastrointestinal in both studies and hypoglycaemia in one study. No data on health related quality of life, all cause mortality or morbidity are currently available. Authors' conclusions: There is some evidence suggesting improvement of metabolic control in poorly controlled adolescents

11 with type 1 diabetes, on addition of metformin to insulin therapy. Stronger evidence is required from larger studies, carried out over longer time periods to document the long term effects on metabolic control, health related quality of life as well as morbidity and mortality in those patients. 2. 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 2007 (available at: BACKGROUND: Diabetes results in a rise in blood glucose above normal physiological levels; if untreated this may cause damage to many systems including the cardiovascular and renal systems. Pregnancy leads to a physiological resistance to insulin action; for those women who have pregestational diabetes, this results in an increasing insulin requirement. There are several methods of administering insulin. Conventionally, insulin has been administered subcutaneously, formally referred to as intensive conventional treatment, but now more usually referred to as multiple daily injections (MDI). An alternative method of insulin administration is the continuous subcutaneous insulin infusion pump (CSII). Objectives: To compare CSII with MDI of insulin for pregnant women with diabetes. Search methods: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 July 2011). Selection criteria: Randomised trials comparing CSII with MDI for pregnant women with diabetes. Data collection and analysis: Three review authors independently assessed studies and two review authors extracted data. Disagreements were resolved through discussion with the third author. Main results: We included five trials with 153 women and 154 pregnancies. There was no significant difference in either of the primary outcomes; macrosomia (birthweight greater than 4000 g) (risk ratio (RR) 3.20, 95% confidence interval (CI) 0.14 to 72.62; two trials, 61 pregnancies) and operative birth, caesarean birth being the only outcome reported (RR 1.09, 95% CI 0.66 to 1.77; three trials, 71 pregnancies).there was an increase in mean birthweight associated with CSII compared with MDI of borderline significance (mean difference (MD) g, 95% CI 2.09 g to g; two trials, 61 pregnancies, P = 0.05). However, the large CI and the lack of a significant difference in macrosomia rate, suggests uncertainty of effect and a clinically insignificant difference. No significant differences were found in any other outcomes measured, which may reflect the small number of trials suitable for meta analysis and the small number of participants included. No significant differences were found in perinatal mortality (RR 2.33, 95% CI, 0.38 to 14.32; three trials, 71 pregnancies), fetal anomaly (RR 1.07, 95% CI, 0.07 to 15.54; two trials 61 pregnancies), maternal hypoglycaemia (RR 3.00, 95% CI 0.35 to 25.87; two trials, 61 pregnancies) or maternal hyperglycaemia (RR 7.00, 95% CI, 0.39 to ; two trials, 61 pregnancies) or small forgestational age (average RR 1.40, 95% CI 0.10 to 18.71; two trials, 61 pregnancies, random effects analysis T2 = 1.10, I2 = 31%). Authors' conclusions: There is little evidence to support the use of one particular form of insulin administration over another for pregnant women with diabetes. The data are few, there are only a small number of trials appropriate for meta analysis, a small number of women included and questionable generalisability of the trial population. Conclusions cannot be

12 made from the available data. Well designed randomised trials are needed. These trials should be adequately powered to assess the effect of CSII versus MDI on important outcomes for women with diabetes and their infants. 3. Goudswaard AN, Furlong NJ, Valk GD et al. Insulin monotherapy versus combinations of insulin with oral hypoglycaemic agents in patients with type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2004 (available at: BACKGROUND: It is unclear whether patients with type 2 diabetes who have poor glycaemic control despite maximal oral hypoglycaemic agents (OHAs) should be commenced on insulin as monotherapy, or insulin combined with oral hypoglycaemic agents (insulin OHA combination therapy). Objectives: To assess the effects of insulin monotherapy versus insulin OHA combinations therapy. Search methods: Eligible studies were identified by searching MEDLINE, EMBASE, and The Cochrane Library. Selection criteria: Randomised controlled trials (RCTs) with 2 months minimum follow up duration comparing insulin monotherapy (all schemes) with insulin OHA combination therapy. Data collection and analysis: Data extraction and assessment of study quality were undertaken by three reviewers in pairs. Main results: Twenty RCTs (mean trial duration 10 months) including 1,811 participants, with mean age 59.8 years and mean known duration of diabetes 9.6 years. Overall, study methodological quality was low. Twenty eight comparisons in 20 RCTs were ordered according to clinical considerations. No studies assessed diabetes related morbidity, mortality or total mortality. From 13 studies (21 comparisons), sufficient data were extracted to calculate pooled effects on glycaemic control. Insulin OHA combination therapy had statistically significant benefits on glycaemic control over insulin monotherapy only when the latter was applied as a once daily injection of NPH insulin. Conversely, twice daily insulin monotherapy (NPH or mixed insulin) provided superior glycaemic control to insulin OHA combination therapy regimens where insulin was administered as a single morning injection. In more conventional comparisons, regimens utilising OHAs with bedtime NPH insulin provided comparable glycaemic control to insulin monotherapy (administered as twice daily, or multiple daily injections). Overall, insulin OHA combination therapy was associated with a 43% relative reduction in total daily insulin requirement compared to insulin monotherapy. Of the 14 studies (22 comparisons) reporting hypoglycaemia, 13 demonstrated no significant difference in the frequency of symptomatic or biochemical hypoglycaemia between insulin and combination therapy regimens. No significant differences in quality of life related issues were detected. Combination therapy with bedtime NPH insulin resulted in statistically significantly less weight gain compared to insulin monotherapy, provided metformin was used ± sulphonylurea. In all other comparisons no significant differences with respect to weight gain were detected. Authors' conclusions: Bedtime NPH insulin combined with oral hypoglycaemic agents provides comparable glycaemic control to insulin monotherapy and is associated with less weight gain if metformin is used.

13 4. Horvath K, Jeitler K, Berghold A et al. Long acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2007 (available at: BACKGROUND: Despite indications from epidemiological trials that higher blood glucose concentrations are associated with a higher risk for developing micro and macrovascular complications, evidence for a beneficial effect of antihyperglycaemic therapy in patients with type 2 diabetes mellitus is conflicting. Two large studies, the United Kingdom Prospective Diabetes Study (UKPDS) and the University Group Diabetes Program (UGDP), did not find a reduction of cardiovascular endpoints through improvement of metabolic control. The theoretical benefits of newer insulin analogues might result in fewer macrovascular and microvascular events. Objectives: To assess the effects of long term treatment with long acting insulin analogues (insulin glargine and insulin detemir) compared to NPH insulin in patients with type 2 diabetes mellitus. Search methods: Studies were obtained from computerised searches of MEDLINE, EMBASE, The Cochrane Library and communication with experts in the field as well as insulin producing companies. Selection criteria: Studies were included if they were randomised controlled trials in adults with diabetes mellitus type 2 and had a trial duration of at least 24 weeks. Data collection and analysis: Two authors independently assessed trial quality and extracted data. Pooling of studies by means of random effects meta analyses was performed. Main results: Six studies comparing insulin glargine to NPH (Neutral Protamine Hagedorn) insulin and two studies comparing insulin detemir to NPH insulin were identified. In these trials, 1715 patients were randomised to insulin glargine and 578 patients to insulin detemir. Duration of the included trials ranged from 24 to 52 weeks. Metabolic control, measured by glycosylated haemoglobin A1c (HbA1c) as a surrogate endpoint, and adverse effects did not differ in a clinical relevant way between treatment groups. While no statistically significant difference for severe hypoglycaemia rates was shown in any of the trials, the rate of symptomatic, overall and nocturnal hypoglycaemia was statistically significantly lower in patients treated with either insulin glargine or detemir. No evidence for a beneficial effect of long acting analogues on patient oriented outcomes like mortality, morbidity, quality of life or costs could be obtained. Authors' conclusions: Our analysis suggests, if at all only a minor clinical benefit of treatment with long acting insulin analogues for patients with diabetes mellitus type 2 treated with "basal" insulin regarding symptomatic nocturnal hypoglycaemic events. Until long term efficacy and safety data are available, we suggest a cautious approach to therapy with insulin glargine or detemir. 5. Misso ML, Egberts KJ, Page M et al. Continuous subcutaneous insulin infusion (CSII) versus multiple insulin injections for type 1 diabetes mellitus. Cochrane Database of Systematic Reviews 2010 (available at:

14 BACKGROUND: Type 1 diabetes is a metabolic disorder resulting from a defect in insulin secretion. Onset of type 1 diabetes mellitus may occur at any age and it is one of the most common chronic diseases of childhood and adolescence. Since there are no interventions known to prevent onset, it is vital that effective treatment regimes are available. Glycaemic control is maintained by replacement of insulin and may be in the form of 'conventional' insulin therapy (multiple injections per day) or continuous subcutaneous insulin infusion (CSII). Objectives: To assess the effects of CSII compared to multiple insulin injections (MI) in people with type 1 diabetes mellitus. Search methods: Studies were obtained from electronic searches of The Cochrane Library, MEDLINE, EMBASE and CINAHL. Selection criteria: Studies were included if they were randomised controlled trials comparing CSII with three or more insulin injections per day (MI) in people with type 1 diabetes mellitus. Data collection and analysis: Two authors independently assessed risk of bias and extracted characteristics of included studies. Authors contacted study investigators to obtain missing information. Generic inverse variance meta analyses using a random effects model were performed. Main results: Twenty three studies randomised 976 participants with type 1 diabetes to either intervention. There was a statistically significant difference in glycosylated haemoglobin A1c (HbA1c) favouring CSII (weighted mean difference 0.3% (95% confidence interval 0.1 to 0.4). There were no obvious differences between the interventions for non severe hypoglycaemia, but severe hypoglycaemia appeared to be reduced in those using CSII. Quality of life measures suggest that CSII is preferred over MI. No significant difference was found for weight. Adverse events were not well reported, no information is available on mortality, morbidity and costs. Authors' conclusions: There is some evidence to suggest that CSII may be better than MI for glycaemic control in people with type 1 diabetes. Non severe hypoglycaemic events do not appear to be reduced with CSII. There is insufficient evidence regarding adverse events, mortality, morbidity and costs. 6. Richter B, Neises G. 'Human' insulin versus animal insulin in people with diabetes mellitus. Cochrane Database of Systematic Reviews 2005 (available at: BACKGROUND: Human insulin was introduced for the routine treatment of diabetes mellitus in the early 1980s without adequate comparison of efficacy to animal insulin preparations. First reports of altered hypoglycaemia awareness after transfer to human insulin made physicians and especially patients uncertain about potential adverse effects of human insulin. Objectives: To assess the effects of different insulin species by evaluating their efficacy (in particular glycaemic control) and adverse effects profile (mainly hypoglycaemia). Search methods: A highly sensitive search for randomised controlled trials combined with key terms for identifying studies on human versus animal insulin was performed using The Cochrane Library, MEDLINE and EMBASE. We also searched reference lists and databases of ongoing trials. Selection criteria: We included randomised

15 controlled clinical trials with diabetic patients of all ages that compared human to animal (for the most part purified porcine) insulin. Trial duration had to be at least one month in order to achieve reliable results on the main outcome parameter glycated haemoglobin. Data collection and analysis: Trial selection as well as evaluation of study quality was performed by two independent reviewers. The quality of reporting of each trial was assessed according to a modification of the quality criteria as specified by Schulz and by Jadad. Main results: Altogether 2156 participants took part in the 45 randomised controlled studies that were discovered through extensive search efforts. Though many studies had a randomised, double blind design, most studies were of poor methodological quality. Purified porcine and semi synthetic insulin were most often investigated. No significant differences in metabolic control or hypoglycaemic episodes between various insulin species could be elucidated. Insulin dose and insulin antibodies did not show relevant dissimilarities. Authors' conclusions: A comparison of the effects of human and animal insulin as well as of the adverse reaction profile did not show clinically relevant differences. Many patientoriented outcomes like health related quality of life or diabetes complications and mortality were never investigated in high quality randomised clinical trials. The story of the introduction of human insulin might be repeated by contemporary launching campaigns to introduce pharmaceutical and technological innovations that are not backed up by sufficient proof of their advantages and safety. 7. Shyangdan DS, Royle P, Clar C et al. Glucagon like peptide analogues for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2011, available at: BACKGROUND: Glucagon like peptide analogues are a new class of drugs used in the treatment of type 2 diabetes that mimic the endogenous hormone glucagon like peptide 1 (GLP 1). GLP 1 is an incretin, a gastrointestinal hormone that is released into the circulation in response to ingested nutrients. GLP 1 regulates glucose levels by stimulating glucose dependent insulin secretion and biosynthesis, and by suppressing glucagon secretion, delayed gastric emptying and promoting satiety. Objectives: To assess the effects of glucagon like peptide analogues in patients with type 2 diabetes mellitus. Search methods: Studies were obtained from electronic searches of The Cochrane Library (last search issue 1, 2011), MEDLINE (last search March 2011), EMBASE (last search March 2011), Web of Science (last search March 2011) and databases of ongoing trials. Selection criteria: Studies were included if they were randomised controlled trials of a minimum duration of eight weeks comparing a GLP 1 analogue with placebo, insulin, an oral anti diabetic agent, or another GLP 1 analogue in people with type 2 diabetes. Data collection and analysis: Data extraction and quality assessment of studies were done by one reviewer and checked by a second. Data were analysed by type of GLP 1 agonist and comparison treatment. Where appropriate, data were summarised in a meta analysis (mean differences and risk ratios summarised using a randomeffects model). Main results: Seventeen randomised controlled trials including relevant analyses for 6899 participants were included in the analysis. Studies were mostly of short duration, usually 26 weeks. In comparison with placebo, all GLP 1 agonists reduced glycosylated haemoglobin A1c

16 (HbA1c) levels by about 1%. Exenatide 2 mg once weekly and liraglutide 1.8 mg reduced it by 0.20% and 0.24% respectively more than insulin glargine. Exenatide 2 mg once weekly reduced HbA1c more than exenatide 10?g twice daily, sitagliptin and pioglitazone. Liraglutide 1.8 mg reduced HbA1c by 0.33% more than exenatide 10?g twice daily. Liraglutide led to similar improvements in HbA1c compared to sulphonylureas but reduced it more than sitagliptin and rosiglitazone. Both exenatide and liraglutide led to greater weight loss than most active comparators, including in participants not experiencing nausea. Hypoglycaemia occurred more frequently in participants taking concomitant sulphonylurea. GLP 1 agonists caused gastrointestinal adverse effects, mainly nausea. These adverse events were strongest at the beginning and then subsided. Beta cell function was improved with GLP 1 agonists but the effect did not persist after cessation of treatment. None of the studies was long enough to assess long term positive or negative effects. Authors' conclusions: GLP 1 agonists are effective in improving glycaemic control. 8. Siebenhofer A, Plank J, Berghold A et al. Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus. Cochrane Database of Systematic Reviews 2006, available at: BACKGROUND: Short acting insulin analogue use for diabetic patients is still controversial, as reflected in many scientific debates. Objectives: To assess the effects of short acting insulin analogues versus regular human insulin. Search methods: The Cochrane Library, MEDLINE and EMBASE were searched. Selection criteria: Randomised controlled trials with an intervention duration of at least four weeks. Data collection and analysis: Trial selection and evaluation of study quality was done independently by two reviewers. Main results: Altogether 8274 participants took part in 49 randomised controlled studies. Most studies were of poor methodological quality. In patients with type 1 diabetes, the weighted mean difference (WMD) of HbA1c was 0.1% (95% CI: 0.2 to 0.1) in favour of insulin analogue, whereas in patients with type 2 diabetes the WMD was 0.0% (95% CI: 0.1 to 0.0). In subgroup analyses of different types of interventions in type 1 diabetic patients, the WMD in HbA1c was 0.2% (95% CI: 0.3 to 0.1) in favour of insulin analogue in studies using continuous subcutaneous insulin injections (CSII), whereas for conventional intensified insulin therapy (IIT) studies the WMD in HbA1c was 0.1% (95% CI: 0.1 to 0.0). The WMD of the overall mean hypoglycaemic episodes per patient per month was 0.2 (95% CI: 1.1 to 0.7) and 0.2 (95% CI: 0.5 to 0.1) for analogues in comparison to regular insulin in patients with type 1 diabetes and type 2 diabetes, respectively. For studies in type 1 diabetes patients the incidence of severe hypoglycaemia ranged from 0 to (median 21.8) episodes per 100 person years for insulin analogues and from 0 to 544 (median 46.1) for regular insulin, in type 2 the incidence ranged from 0 to 30.3 (median 0.3) episodes per 100 person years for insulin analogues and from 0 to 50.4 (median 1.4) for regular insulin. No study was designed to investigate possible long term effects (e.g. mortality, diabetic complications), in particular in patients with diabetes related complications. Authors' conclusions: Our analysis suggests only a minor benefit of short acting insulin analogues in the majority of diabetic patients treated with insulin. Until long term efficacy and safety data are

17 available we suggest a cautious response to the vigorous promotion of insulin analogues. For safety purposes, we need a long term follow up of large numbers of patients and well designed studies in pregnant women to determine the safety profile for both the mother and the unborn child. 9. Swinnen SG, Simon ACR, Holleman F et al. Insulin detemir versus insulin glargine for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2011, available at: BACKGROUND: Chronically elevated blood glucose levels are associated with significant morbidity and mortality. Many diabetes patients will eventually require insulin treatment to maintain good glycaemic control. There are still uncertainties about the optimal insulin treatment regimens for type 2 diabetes, but the long acting insulin analogues seem beneficial. Several reviews have compared either insulin detemir or insulin glargine to NPH insulin, but research directly comparing both insulin analogues is limited. Objectives: To assess the effects of insulin detemir and insulin glargine compared with each other in the treatment of type 2 diabetes mellitus. Search methods: We searched MEDLINE, EMBASE, The Cochrane Library, online registries of ongoing trials and abstract books. Date of last search was January Selection criteria: All randomised controlled trials comparing insulin detemir with insulin glargine with a duration of 12 weeks or longer were included. Data collection and analysis: Two authors independently selected the studies and extracted the data. Pooling of studies by means of random effects meta analysis was performed. Main results: This review examined four trials lasting 24 to 52 weeks involving 2250 people randomised to either insulin detemir or glargine. Overall, risk of bias of the evaluated studies was high. Insulin glargine was dosed once daily in the evening. Insulin detemir was initiated once daily in the evening with the option of an additional dose in the morning in three studies and initiated twice daily in one study. Of randomised patients 13.6% to 57.2% were injecting insulin detemir twice daily at the end of trial. Glycaemic control, measured by glycosylated haemoglobin A1c (HbA1c) and HbA1c equal to or less than 7% with or without hypoglycaemia, did not differ statistically significantly between treatment groups. The results showed no significant differences in overall, nocturnal and severe hypoglycaemia between treatment groups. Insulin detemir was associated with less weight gain. Treatment with insulin glargine resulted in a lower daily basal insulin dose and a lower number of injection site reactions. There was no significant difference in the variability of FPG or glucose values in 24 hour profiles between treatment groups. It was not possible to draw conclusions on quality of life, costs or mortality. Only one trial reported results on health related quality of life and showed no significant differences between treatment groups. Authors' conclusions: Our analyses suggest that there is no clinically relevant difference in efficacy or safety between insulin detemir and insulin glargine for targeting hyperglycaemia. However, to achieve the same glycaemic control insulin detemir was often injected twice daily in a higher dose but with less weight gain, while insulin glargine was injected once daily, with somewhat fewer injection site reactions.

18 10. Vardi M, Jacobson E, Nini A et al. Intermediate acting versus long acting insulin for type 1 diabetes mellitus. Cochrane Database of Systematic Reviews 2008, available at: BACKGROUND: Diabetes mellitus type 1 is a chronic disease with short and long term complications. Its goals of therapy are to eliminate the symptoms of hyperglycaemia, reduce the long term microvascular and macrovascular complications and allow the patients to achieve a normal life style. Basal insulin replacement for insulin dependent patients can be achieved with either intermediate or long acting insulin preparations. Objectives: To assess the effects of intermediate acting versus long acting insulin preparations for basal insulin replacement in type 1 diabetic patients. Search methods: We searched MEDLINE, EMBASE and The Cochrane Library, as well as reference lists, databases of ongoing trials, and requests from authors of included trials. Selection criteria: Randomised controlled trials, assessing long acting insulin preparations compared to intermediate acting insulin preparations, in type 1 diabetic patients. Data collection and analysis: Two reviewers independently scanned the titles. Data were extracted and analysed accordingly. Main results: Twenty three randomised controlled trials were identified. A total of 3872 and 2915 participants in the intervention and in the control group, respectively, were analysed. The weighted mean difference (WMD) for the level of glycosylated haemoglobin was 0.08 (95% confidence interval (CI) 0.12 to 0.04) in favour of the long acting insulin arm. The WMD between the groups in fasting plasma and blood glucose levels was 0.63 (95% CI 0.86 to 0.40) and 0.86 (95% CI 1.00 to 0.72) in favour of the long acting insulins. The odds ratio for a patient on long acting insulin to develop any type of hypoglycaemia was 0.93 (95% CI 0.8 to 1.08) compared to that of a patient on intermediate acting insulins. The OR for severe hypoglycaemic episodes was 0.73 (95% CI 0.61 to 0.87), and 0.70 (95% CI of 0.63 to 0.79) for nocturnal episodes. The WMD between the long and intermediate insulin groups for hypoglycaemic events per 100 patient follow up days was 0.77 (95% CI 0.89 to 0.65), 0.0 (95% CI 0.02 to 0.02) and 0.40 (95% CI 0.45 to 0.34) for overall, severe, and nocturnal hypoglycaemic episodes. Weight gain was more prominent in the control group. No difference was noted in the quantity or quality of severe adverse events or deaths. Authors' conclusions: Long acting insulin preparations seem to exert a beneficial effect on nocturnal glucose levels. Their effect on the overall diabetes control is clinically unremarkable. Their use as a basal insulin regimen for type 1 diabetes mellitus warrants further substantiation. Glucose control / monitoring 1. Callaghan BC, Little AA, Feldman EL et al. Enhanced glucose control for preventing and treating diabetic neuropathy. Cochrane Database of Systematic Reviews 2012, available at: BACKGROUND: There are two types of diabetes. Type 1 diabetes affects younger people and needs treatment with insulin injections. Type 2 diabetes affects older people and can usually be treated by diet and oral drugs. Diabetic neuropathy affects 10% of patients with diabetes mellitus at diagnosis

19 and 40% to 50% after 10 years. Enhanced glucose control is the best studied intervention for the prevention of this disabling condition but there have been no systematic reviews of the evidence. Objectives: To examine the evidence for enhanced glucose control in the prevention of distal symmetric polyneuropathy in people with type 1 and type 2 diabetes. Search methods: We searched the Cochrane Neuromuscular Disease Group Specialized Register (30 January 2012), CENTRAL (2012, Issue 1), MEDLINE (1966 to January 2012) and EMBASE (1980 to January 2012) for randomized controlled trials of enhanced glucose control in diabetes mellitus. Selection criteria: We included all randomized, controlled studies investigating enhanced glycemic control that reported neuropathy outcomes after at least one year of intervention. Our primary outcome measure was annual development of clinical neuropathy defined by a clinical scale. Secondary outcomes included motor nerve conduction velocity and quantitative vibration testing. Data collection and analysis: Two authors independently reviewed all titles and abstracts identified by the database searches for inclusion. Two authors abstracted data from all included studies with a standardized form. A third author mediated conflicts. We analyzed the presence of clinical neuropathy with annualized risk differences (RDs), and conduction velocity and quantitative velocity measurements with mean differences per year. Main results: This review identified 17 randomized studies that addressed whether enhanced glucose control prevents the development of neuropathy. Seven of these studies were conducted in people with type 1 diabetes, eight in type 2 diabetes, and two in both types. A meta analysis of the two studies that reported the primary outcome (incidence of clinical neuropathy) with a total of 1228 participants with type 1 diabetes revealed a significantly reduced risk of developing clinical neuropathy in those with enhanced glucose control, an annualized RD of 1.84% (95% confidence interval (CI) 1.11 to 2.56). In a similar analysis of four studies that reported the primary outcome, involving 6669 participants with type 2 diabetes, the annualized RD of developing clinical neuropathy was 0.58% (95% CI 0.01 to 1.17). Most secondary outcomes were significantly in favor of intensive treatment in both populations. However, both types of diabetic participants also had a significant increase in severe adverse events including hypoglycemic events. Authors' conclusions: According to high quality evidence, enhanced glucose control significantly prevents the development of clinical neuropathy and reduces nerve conduction and vibration threshold abnormalities in type 1 diabetes mellitus. In type 2 diabetes mellitus, enhanced glucose control reduces the incidence of clinical neuropathy, although this was not formally statistically significant (P = 0.06). However, enhanced glucose control does significantly reduce nerve conduction and vibration threshold abnormalities. Importantly, enhanced glucose control significantly increases the risk of severe hypoglycemic episodes, which needs to be taken into account when evaluating its risk/benefit ratio. 2. Hemmingsen B, Lund Søren S, Gluud C et al. Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2001, available at:

20 BACKGROUND: Patients with type 2 diabetes mellitus (T2D) exhibit an increased risk of cardiovascular disease and mortality compared to the background population. Observational studies report a relationship between reduced blood glucose and reduced risk of both micro and macrovascular complications in patients with T2D. Objectives: To assess the effects of targeting intensive versus conventional glycaemic control in T2D patients. Search methods: Trials were obtained from searches of CENTRAL (The Cochrane Library), MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, and CINAHL (until December 2010). Selection criteria: We included randomised clinical trials that prespecified different targets of glycaemic control in adults with T2D. Data collection and analysis: Two authors independently assessed the risk of bias and extracted data. Dichotomous outcomes were assessed by risk ratios (RR) and 95% confidence intervals (CI). Main results: Twenty trials randomised 16,106 T2D participants to intensive control and 13,880 T2D participants to conventional glycaemic control. The mean age of the participants was 62.1 years. The duration of the intervention ranged from three days to 12.5 years. The number of participants in the included trials ranged from 20 to 11,140. There was no significant difference between targeting intensive and conventional glycaemic control for all cause mortality (RR 1.01, 95% CI 0.90 to 1.13; 29,731 participants, 18 trials) or cardiovascular mortality (RR 1.06, 95% CI 0.90 to 1.26; 29,731 participants, 18 trials). Trial sequential analysis (TSA) showed that a 10% RR reduction could be refuted for all cause mortality. Targeting intensive glycaemic control did not show a significant effect on the risk of non fatal myocardial infarction in the random effects model but decreased the risk in the fixed effect model (RR 0.86, 95% CI 0.78 to 0.96; P = 0.006; 29,174 participants, 12 trials). Targeting intensive glycaemic control reduced the risk of amputation (RR 0.64, 95% CI 0.43 to 0.95; P = 0.03; 6960 participants, 8 trials), the composite risk of microvascular disease (RR 0.89, 95% CI 0.83 to 0.95; P = ; 25,760 participants, 4 trials), retinopathy (RR 0.79, 95% CI 0.68 to 0.92; P = 0.002; 10,230 participants, 8 trials), retinal photocoagulation (RR 0.77, 95% CI 0.61 to 0.97; P = 0.03; 11,142 participants, 7 trials), and nephropathy (RR 0.78, 95% CI 0.61 to 0.99; P = 0.04; 27,929 participants, 9 trials). The risks of both mild and severe hypoglycaemia were increased with targeting intensive glycaemic control but substantial heterogeneity was present. The definition of severe hypoglycaemia varied among the included trials; severe hypoglycaemia was reported in 12 trials that included 28,127 participants. TSA showed that firm evidence was reached for a 30% RR increase in severe hypoglycaemic when targeting intensive glycaemic control. Subgroup analysis of trials exclusively dealing with glycaemic control in usual care settings showed a significant effect in favour of targeting intensive glycaemic control for non fatal myocardial infarction. However, TSA showed more trials are needed before firm evidence is established. Authors' conclusions: The included trials did not show significant differences for all cause mortality and cardiovascular mortality when targeting intensive glycaemic control compared with conventional glycaemic control. Targeting intensive glycaemic control reduced the risk of microvascular complications while increasing the risk of hypoglycaemia. Furthermore, intensive glycaemic control might reduce the risk of non fatal myocardial infarction in trials exclusively dealing with glycaemic control in usual care settings.