|Efficacy and safety of insulin analogues for the management of diabetes mellitus: a meta-analysis
|Singh S R, Ahmad F, Lal A, Yu C, Bai Z, Bennett H
This review concluded that differences between conventional insulins and insulin analogues were minimal for the management of type 1, type 2 and gestational diabetes mellitus. Overall, the authors' conclusions were supported by the evidence presented, but caution is advised given the limitations of the included evidence and, in particular, the poor quality of the included trials.
To compare the effectiveness of insulin analogues with conventional insulins for the treatment of type1, type 2 and gestational diabetes mellitus. This review updated the findings of two earlier systematic reviews (see Other Publications of Related Interest field for bibliographic details).
MEDLINE, EMBASE, BIOSIS Previews, PASCAL and the Cochrane Library were searched from 1990 to April 2007. Search terms and full search strategies were available in an appendix. Grey literature was also identified by searching the web pages of regulatory agencies, near-technology assessment agencies, Health Technology Assessment Agency, professional associations, associated conference sites, and other specialised databases (DARE and the Latin American and Caribbean Center on Health Sciences Information). Internet searches were also performed. Manufacturers and other stakeholders were consulted about additional evidence. Only English language data were eligible for inclusion.
Randomised controlled trials (RCT) comparing insulin analogues with conventional insulins, in patients with type 1, type 2 or gestational diabetes mellitus. Relevant comparisons were: premixed or regular rapid-acting insulin analogue versus regular human insulin; or another rapid-acting insulin analogue (premixed or regular); and long-acting insulin analogue versus neutral protamine Hagedorn insulin or another intermediate-acting conventional insulin; or another long-acting insulin analogue. Trials of insulin glulisine were excluded. Eligible outcomes included glycaemic control assessed by haemoglobin A1c level and blood glucose level, number of hypoglycaemic episodes, quality of life, mortality, patient satisfaction, adverse events and complications from diabetes mellitus.
Included interventions were single agent or combination treatments including: rapid-acting analogues (insulin lispro and insulin aspart) or long-acting insulin analogues (insulin glargine and insulin detemir); human insulin; and/or neutral protamine Hagedorn insulin. The majority of trials were in adults and most commonly assessed rapid-acting insulin analogues. Similar numbers of trials in children and adolescents assessed rapid-acting and long-acting insulin analogues. Trial duration ranged from four weeks to 30 months.
An undisclosed number of reviewers independently selected trials for inclusion in the review
Assessment of study quality
Trial quality was assessed using a modified Jadad scale, which assesses allocation concealment, blinding of assessors and the use of an intention-to-treat analysis. Each trial was awarded a score up to a maximum of 5 points.
Two reviewers independently assessed the quality of each study and any discrepancies were resolved through consensus or a third reviewer.
An undisclosed number of reviewers (at least two) independently extracted data from each trial using a structured form. Any discrepancies were resolved through consensus or another reviewer. For continuous outcomes, the mean and standard deviation were extracted. For dichotomous outcomes, relative risks with 95% confidence intervals were calculated.
Methods of synthesis
Trials were grouped according to the type of diabetes (gestational diabetes, paediatric type 1, adult type 1, paediatric type and adult type 2 diabetes) and weighted mean differences or pooled relative risks, with 95% confidence intervals, calculated using a random-effects model. Additional analyses were performed for different methods of administration for rapid-acting insulin analogues, type of bolus insulin administered with long-acting analogues; and the type of oral anti-diabetic agent administered with long-acting insulin analogues in the management of type 2 diabetes.
Statistical heterogeneity was assessed using the I2 statistic; any value over 50% was investigated further to try to determine possible causes for the observed heterogeneity. Data for premixed insulins and data for bolus insulins were included in the same meta-analyses. Where cross-over trials reported no evidence of carry-over effects, data were combined from both cross-over and parallel trials. The effect of trial quality was also assessed. Where analyses included five or more trials, the risk of publication bias was assessed using funnel plots.
Results of the review
Sixty-eight RCTs were included in the analysis of rapid-acting insulin analogues and 49 RCTs in the analysis of long-acting insulin analogues. Sample sizes ranged from 7 to 1,008. Most of the trials were of short to medium duration; the methodological quality was rated as poor (Jadad score 2 or 3).
Rapid-acting insulin analogues: In adults with type 1 diabetes, minimal differences were reported between rapid-acting insulin analogues and regular human insulin for haemoglobin A1c: for insulin lispro the weighted mean difference was –0.09% (95% confidence interval (CI):–0.16 to –0.02; 22 RCTs); for insulin aspart the weighted mean difference was –0.13% (95% CI: –0.20 to –0.07; seven RCTs). Similar differences were reported for patients with type 2 diabetes: for insulin lispro the weighted mean difference was –0.03% (95% CI: –0.12 to –0.06; 11 RCTs); for insulin aspart the weighted mean difference was –0.09% (95% CI: –0.21 to 0.04; six RCTs).
Long-acting insulin analogues: Only marginal differences between long-acting insulin analogues and neutral protamine Hagedorn insulin were reported for haemoglobin A1c in adults with type 1 diabetes: for insulin glargine weighted mean difference was –0.11% (95% CI: –0.21%, –0.02%; 11 RCTs); for insulin detemir weighted mean difference was –0.06% (95% CI: –0.13%, 0.02%, seven RCTs). Among adults with type 2 diabetes: insulin glargine weighted mean difference was –0.05% (95% CI: –0.13 to 0.04; nine RCTs); insulin detemir weighted mean difference was 0.13% (95% CI: 0.03%, 0.22%); three RCTs. No significant evidence of statistical heterogeneity was found.
No statistically significant differences or only very small differences between insulin analogues and conventional insulins, were reported for outcomes assessed in children and adolescents (11 RCTs) and in pregnant women (four RCTs).
Data relating to the incidence of hypoglycaemia were inconsistent. There were insufficient data to assess the effects of different types of insulin on long-term diabetes-related complications or death. There were no significant differences in the incidence of adverse events between insulin analogues and conventional insulins; the most commonly reported adverse events were upper respiratory tract infections, injection site reactions and weight gain.
Further results were reported in the review and appendices.
A related assessment of the cost-effectiveness of conventional insulins versus insulin analogues was published elsewhere (see Other Publications of Related Interest field for bibliographic details).
The evidence suggested that differences between conventional insulins and insulin analogues were minimal for the management of type 1, type 2 and gestational diabetes mellitus.
This review answered a clear research question supported by adequately described inclusion criteria. Extensive attempts were made to locate both published and unpublished data, but there was a risk of language bias, as only English language studies were included in the review. The authors did report that, in their opinion, the risk of language bias was minimal. Attempts were also made to reduce the risk of reviewer error and bias by the involvement of more than one reviewer in all stages of the review process.
Quality was assessed using a validated scale, but found to be generally poor. This suggests that the findings may not be reliable. The effects of differences in quality were considered along with a number of other potential confounding variables. Subgroup analyses were performed to take into account differences between the trials in terms of patients, interventions and outcomes. For a number of outcomes and pooled analyses, the number of included trials was low and, for some intended comparisons, there were no trials.
Overall, the authors' conclusions were supported by the evidence presented, but caution is advised given the limitations of the included evidence and, in particular, the poor quality of the included trials.
Implications of the review for practice and research
Practice: The authors stated that insulin analogues offered few clinical advantages over conventional insulins for the management of most patients with type 1, type 2 or gestational diabetes.
Research: The authors stated that further well-designed studies are required to better assess the effects of insulin analogues on long-term diabetes-related complications, death, quality of life and patient satisfaction. Further studies are also required in children with type 2 diabetes, patients with a prior history of significant hypoglycaemia, and pregnant women in the case of long-acting insulin analogues.
Singh S R, Ahmad F, Lal A, Yu C, Bai Z, Bennett H. Efficacy and safety of insulin analogues for the management of diabetes mellitus: a meta-analysis. CMAJ: Canadian Medical Association Journal 2009; 180(4): 385-397
Other publications of related interest
Cameron CG, Benett HA. Cost effectiveness of insulin analogues for diabetes mellitus. CMAJ 2009;180:400-7.
Canadian Optimal Medication Prescribing and Utilization Service (COMPUS). An Economic Evaluation of Insulin Analogues
for the Treatment of Patients with Type 1 and Type 2 Diabetes Mellitus in Canada. ON, Canada: Canadian Agency for Drugs and Technologies in Health. Optimal Therapy Report; 2(4). 2008.
Canadian Optimal Medication Prescribing and Utilization Service (COMPUS). Optimal Therapy Recommendations for the Prescribing and Use of Insulin Analogues. ON, Canada: Canadian Agency for Drugs and Technologies in Health. Optimal Therapy Report; 2(7). 2009.
Daneman D, Tran K, Banerjee S, et al. Rapid-acting insulin analogues for the treatment of diabetes mellitus: meta-analyses of clinical outcomes. Update of CADTH Technology Report No. 87. Ottawa, ON, Canada: Canadian Agency for Drugs and Technologies in Health. Optimal Therapy Report; 2(2). 2008.
Tran K, Banerjee S, Li H, et al. Long-acting insulin analogues for diabetes mellitus: meta-analysis of clinical outcomes and assessment of cost-effectiveness. Ottawa, ON, Canada: Canadian Agency for Drugs and Technologies in Health. Technology Report; 92. 2007.
Subject indexing assigned by NLM
Diabetes Mellitus /drug therapy; Humans; Hypoglycemic Agents /adverse effects /therapeutic use; Insulin /adverse effects /analogs & derivatives /therapeutic use; Randomized Controlled Trials as Topic
Database entry date
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.