Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus.

BACKGROUND: In short acting insulin analogues the dissociation of hexamers is facilitated, achieving peak plasma concentrations about twice as high and within approximately half the time compared to regular human insulin. According to these properties this profile resembles the shape of non-diabetic patients more than that of regular human insulins. Despite this theoretical superiority of short acting insulin analogues over regular human insulin, the risk-benefit ratio of short acting insulin analogues in the treatment of diabetic patients is still unclear.

OBJECTIVES: To assess the effect of treatment with short acting insulin analogues versus regular human insulin.

SEARCH STRATEGY: A highly sensitive search for randomised controlled trials combined with key terms for identifying studies on short acting insulin analogues versus regular human insulin was performed using the Cochrane Library (issue 4, 2003), MEDLINE and EMBASE. Date of last search was December 2003.

SELECTION CRITERIA: We included randomised controlled trials with diabetic patients of all ages that compared short acting insulin analogues to regular human insulin. Intervention duration had to be at least 4 weeks.

DATA COLLECTION AND ANALYSIS: Trial selection as well as evaluation of study quality was done 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 Jadad.

MAIN RESULTS: Altogether 7933 participants took part in 42 randomised controlled studies. Most studies were of poor methodological quality. In patients with type 1 diabetes, the weighted mean difference (WMD) of HbA1c was estimated to be -0.1% (95% CI: -0.2% to -0.1%) in favour of insulin analogue, whereas in patients with type 2 diabetes the WMD was estimated to be 0.0% (95% CI: -0.1% to 0.1%). 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: -0.2% to -0.0%). The WMD of the overall mean hypoglycaemic episodes per patient per month was -0.2 (95% CI: -1.2 to 0.9) 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 diabetic patients the incidence of severe hypoglycaemia ranged from 0 to 247.3 (median 20.3) episodes per 100 person-years for insulin analogues and from 0 to 544 (median 37.2) for regular insulin, in type 2 the incidence ranged from 0 to 30.3 (median 0.6) episodes per 100 person-years for insulin analogues and from 0 to 50.4 (median 2.8) 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.

REVIEWERS' 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 available we suggest a cautious response to the vigorous promotion of insulin analogues. Due to fears of potentially carcinogenic and proliferative effects, most studies to date have excluded patients with advanced diabetic complications. For safety purposes, we need a long-term follow-up of large numbers of patients who use short acting insulin analogues. Furthermore, we need well designed studies in pregnant women to determine the safety profile for both the mother and the unborn child.