Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus NICE has developed the Cochrane Quality and Productivity (QP) topics to help the NHS identify practices which could be significantly reduced or stopped completely, releasing cash and/or resources without negatively affecting the quality of NHS care. Each topic has been derived from a Cochrane systematic review that has concluded that the evidence shows that the practice is harmful or ineffective and should not be used, or that there is insufficient evidence to support widespread use of the practice Summary NICE summary of review conclusions Our analysis of the currently available long-term trials comparing long acting insulin analogues with NPH (human isophane) insulin showed that insulin glargine and insulin detemir were almost identically effective compared with NPH insulin in long-term metabolic control (as measured by glycated haemoglobin). Fewer people experienced symptomatic or nocturnal hypoglycaemic episodes with either of the two analogues. No conclusive information on late complications or on possible differences in the number of fatalities exists. One study found a higher rate of progression of diabetic retinopathy in patients treated with insulin glargine, while in another investigation the opposite result was found. It was thus not possible to conclude for certain whether insulin glargine treatment is safe or not. From the retrieved trials it was also not possible to draw firm conclusions on the effects of these new insulins on quality of life or their cost effectiveness. Until long-term data on benefit and risk are available, we suggest a cautious approach to treatment with insulin glargine or insulin detemir. In the absence of evidence to suggest the superiority of insulin analogues glargine and detemir over NPH insulin in terms of improved safety, glycaemic control or reduction of longterm diabetic complications, a cautious approach to prescription of these two insulins is advised. There are clear productivity savings to be generated by reducing prescription of these insulins. Practitioners should consider the individual features of the patient and the NICE recommendations before prescribing these insulins. The Implications for practice section of the Cochrane review stated: Our analysis suggests, if at all, only a minor clinical benefit of treatment with long-acting insulin analogues for patients with type 2 diabetes mellitus 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. Details of Cochrane review Cochrane review title Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus Page 1 of 5
Citation 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 (human isophane insulin) for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2007, Issue 2. Art. No.: CD005613. DOI: 10.1002/14651858.CD005613.pub3 When the review content was assessed as up to date 10 December 2006 QIPP category Medicines use and procurement Relevant codes OPCS ICD10 HRG Not relevant relates to prescribing Not relevant relates to prescribing Not relevant relates to prescribing Programme budget Endocrine, nutritional and metabolic Evidence Relevance to the NHS This systematic review and meta-analysis included eight studies comparing the effects of long-acting insulin analogues to NPH insulin in patients with type 2 diabetes mellitus. Six studies investigated insulin glargine and two looked at insulin detemir. No superiority in metabolic control (as measured by HbA1c, a test measuring average blood glucose levels) was observed for insulin glargine. For insulin detemir the meta-analysis yielded a statistically significant but probably clinically unimportant superiority of NPH insulin. Symptomatic and nocturnal hypoglycaemic events were lower in patients treated with insulin glargine than in patients with NPH insulin. Also, for insulin detemir the two included studies found a lower number of patients experiencing overall or nocturnal hypoglycaemic episodes in the insulin detemir treatment groups. The methodological quality of the included studies allowed only a cautious interpretation of the results. No study was designed to investigate possible long-term effects. It therefore, remains unclear to what extent the treatment with long-acting insulin analogues will affect the development and progression of microvascular and macrovascular events, compared with NPH insulin. Since the differences in overall effects on metabolic control were only small for insulin glargine and NPH and even disadvantageous for insulin detemir, no important improvements in the development of microvascular late complications would be expected from treatment with long-acting insulin analogues. The advantages found in the rate of severe hypoglycaemic events should also be interpreted with caution. No statistically significant advantage was found for therapy with insulin glargine or detemir. Interpretation of the results with regard to the frequency of severe hypoglycaemia is difficult due to bias-prone definitions used in the trials to identify episodes of hypoglycaemia. In all studies, the frequency of severe hypoglycaemia was very low, so Page 2 of 5
seeing an important clinical effect for the different treatments was difficult. Even though the meta-analysis found a consistent reduction in symptomatic or overall hypoglycaemic effects for therapy with long-acting insulin analogues, no safe inferences can be drawn from these results because defining hypoglycaemia by symptoms (as was done in the trials) only makes the results prone to bias. This is particularly so in open trials with no blinded outcome assessment. The advantage of insulin glargine and detemir could be a lowering of nocturnal hypoglycaemic events in patients with type 2 diabetes taking basal insulin, but again bias cannot be ruled out, thus interpretation of results is difficult. Owing to the maximum observation period of 12 months, this review cannot provide any further guidance on potential adverse properties, such as progression of microvascular complications under treatment with long-acting insulin analogues. One study found a higher rate of progression of diabetic retinopathy in patients treated with insulin glargine, while in another investigation the opposite result was found. The mean age of patients in the included studies ranged from 55 to 62 years, preventing any conclusions from being drawn on possible differences of the effects of the different insulins in old or young patients. Relevant NICE guidance Type 2 diabetes: newer agents (partial update of CG66) NICE clinical guideline 87 (Published May 2009) 1.7.2.4 Initiate insulin therapy from a choice of a number of insulin types and regimens. Begin with human NPH insulin injected at bed-time or twice daily according to need. Consider, as an alternative, using a long-acting insulin analogue (insulin detemir, insulin glargine) if: the person needs assistance from a carer or healthcare professional to inject insulin, and use of a long-acting insulin analogue (insulin detemir, insulin glargine) would reduce the frequency of injections from twice to once daily, or the person s lifestyle is restricted by recurrent symptomatic hypoglycaemic episodes, or the person would otherwise need twice-daily NPH insulin injections in combination with oral glucose-lowering drugs, or the person cannot use the device to inject NPH insulin. 1.7.2.5 Consider switching to a long-acting insulin analogue (insulin detemir, insulin glargine) from NPH insulin in people: who do not reach their target HbA1c because of significant hypoglycaemia, or who experience significant hypoglycaemia on NPH insulin irrespective of the level of HbA1c reached, or who cannot use the device needed to inject NPH insulin but who could administer their own insulin safely and accurately if a switch to a long-acting insulin analogue were made, or who need help from a carer or healthcare professional to administer insulin injections and for whom switching to a long-acting insulin analogue would reduce the number of daily injections. Page 3 of 5
Other accredited guidance Management of diabetes SIGN clinical guideline 116 (Published: March 2010) 2.4 Pharmacological management of glycaemic control in people with type 2 diabetes Once daily bedtime NPH insulin should be used when adding insulin to metformin and/or sulphonylurea therapy. Basal insulin analogues should be considered if there are concerns regarding hypoglycaemia risk. Potential productivity savings Estimate of current NHS use About 59,000 people currently take long acting insulin, of which just over 4000 are prescribed it due to repeated and unpleasant hypoglycaemia. Level of productivity savings anticipated The average annual price of long-acting insulin (glargine or detemir) is 399.86 and the average annual price of NPH insulin is 239.54 based on October 2010 BNF prices excluding VAT. The estimated savings also assume people who need help to administer the insulin will be prescribed one dose of NPH insulin per day and the rest will be prescribed two doses per day. Total estimated savings are just under 2 million. Type of saving The savings are likely to be cash releasing Any costs required to achieve the savings Some additional resources might be needed for those patients who cannot, for various reasons, self administer insulin (an estimated 26,539). The vast majority will probably be administered by a carer but some may need additional healthcare professional support. Other information The saving is likely to impact prescribing costs in the community. Potential impact on quality of NHS care Impact on clinical quality Not anticipated to have any impact on immediate clinical quality but improvements predicted through the redirection of savings accrued Impact on patient safety Not anticipated to have any impact on patient safety Impact on patient and carer experience Not anticipated to have any impact on patient and carer experience Page 4 of 5
Likely ease of implementation Time taken to implement Can be achieved in the medium term: 3 months to 1 year Healthcare sectors affected Affects a number of teams accross several departments and organisations Stakeholder support Likely to achieve good buy-in from key influencers Page 5 of 5