A Cochrane review included 347 comparative trials and cohort studies. Pooled data revealed no cases of fatal or nonfatal lactic acidosis in 70 490 patient-years of metformin use or in 55 451 patients-years in the non-metformin group. Using Poisson statistics the upper limit for the true incidence of lactic acidosis per 100 000 patient-years was 4.3 cases in the metformin group and 5.4 cases in the non-metformin group. There was no difference in lactate levels, either as mean treatment levels or as a net change from baseline, for metformin compared to placebo or other non-biguanide therapies. The mean lactate levels were slightly lower for metformin treatment compared to phenformin (WMD –0.75 mmol/l, 95% CI –0.86 to –0.65).
Comment: The quality of evidence is downgraded by indirectness (the studies may have included healthier patients with fewer comorbidities than those treated in clinical practice).