Combination of Metformin plus Insulin May Not Reduce Mortality Compared to Insulin Alone in Patients with Type 2 Diabetes

DynaMed Weekly Update - Volume 7, Issue 19

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For patients with type 2 diabetes mellitus inadequately treated with lifestyle modifications and oral antidiabetic agents, combined use of metformin and insulin is recommended by the American Diabetes Association and the European Association for the Study of Diabetes as part of a consensus treatment algorithm (Diabetologia 2009 Jan;52(1):17). A new systematic review of 26 randomized trials compared the effects of combination therapy vs. insulin alone on clinical outcomes in 2,286 patients with type 2 diabetes.

Trial durations ranged from 3 months to 4.3 years, with a median duration of 6 months. Most of the trials had some methodologic limitations including incomplete blinding, baseline differences between randomized groups, and unclear allocation concealment. In meta-analyses, there were no significant differences in all-cause mortality (risk ratio 1.3, 95% CI 0.57-2.99) or cardiovascular mortality (risk ratio 1.7, 95% CI 0.35-8.3) comparing the combination of metformin plus insulin to insulin alone (level 2 [mid-level] evidence). No deaths occurred in 11 of 16 trials that reported mortality as an outcome. There were also no significant differences in the incidence of severe or mild hypoglycemia. Combination therapy was associated with significant reductions in HbA1c, weight gain and insulin dose (BMJ 2012 Apr 19;344:e1771).

Follow-up was too short in most trials to draw reliable conclusions about mortality, and the statistical power was limited by the low event rates in all trials. However, the findings from the meta-analysis were consistent with the findings in the trial with the largest sample and longest follow-up. While these data cannot definitively rule out a mortality or cardiovascular benefit from continuing metformin in patients treated with intensive insulin, the systematic review establishes that to date, any such benefit remains unproven.

For more information, see the Metformin for diabetes topic in DynaMed.