A Cochrane review [Abstract] 1 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.
A community-based cohort study 2 assessing hospitalization due acidosis included over 150 000 patients. Compared with alternative diabetes management, time-dependent metformin use was not associated with incident acidosis overall (adjusted hazard ratio [HR], 0.98; 95% CI 0.89 to 1.08) or in patients with eGFR 45 to 59 mL/min/1.73 m2 (adjusted HR, 1.16; 95% CI 0.95 to 1.41) and eGFR 30 to 44 mL/min/1.73 m2 (adjusted HR, 1.09; 95% CI 0.83 to 1.44). On the other hand, metformin use was associated with an increased risk of acidosis at eGFR less than 30 mL/min/1.73 m2 (adjusted HR, 2.07; 95% CI,1.33 to 3.22). Results were consistent when new metformin users were compared with new sulfonylurea users (adjusted HR for eGFR 30 to 44 mL/min/1.73 m2, 0.77; 95% CI 0.29 to 2.05), in a propensity-matched cohort (adjusted HR for eGFR 30 to44 mL/min/1.73 m2, 0.71; 95% CI 0.45 to 1.12), when baseline insulin users were excluded (adjusted HR for eGFR 30 to 44 mL/min/1.73 m2, 1.16; 95% CI 0.87 to 1.57), and in the replication cohort (adjusted HR for eGFR 30 to 44 mL/min/1.73 m2, 0.86; 95% CI 0.37 to 2.01).
A population-based cohort study 3 analyzed whether treatment with metformin in patients with renal impairment is associated with a higher risk of lactic acidosis. A cohort of 223 968 metformin users and 34 571 diabetic patients who had never used metformin were identified from the Clinical Practice Research Datalink (CPRD). The crude incidence of lactic acidosis or elevated lactate concentrations in current metformin users was 7.4 per 100 000 person-years (vs. 2.2 per 100 000 person-years in nonusers). Compared with nonusers, risk of lactic acidosis or elevated lactate concentrations in current metformin users was significantly associated with a renal function <60 mL/min/1.73 m² (adjusted HR 6.37, 95% CI 1.48 to 27.5). The increased risk among patients with impaired renal function was further increased in users of ≥730 g of metformin in the preceding year (adjusted HR 11.8, 95% CI 2.27 to 61.5) and in users of a recent high daily dose (>2 g) of metformin (adjusted HR 13.0, 95% CI 2.36 to 72.0).
A retrospective cohort combined data 4 followed new users of metformin or sulfonylureas from development of reduced kidney function (eGFR <60 mL/min/1.73 m2 or serum creatinine≥1.4 mg/dL for female or 1.5 mg/dL for male) through hospitalization for lactic acidosis, death, loss to follow-up, or study end. The weighted cohort included 24 542 metformin users and 24 662 sulfonylurea users who developed reduced kidney function (median age 70 years, median eGFR 55.8). There were 4.18 (95% CI 3.63 to 4.81) vs. 3.69 (95% CI 3.19 to 4.27) lactic acidosis hospitalizations per 1000 person-years among metformin and sulfonylurea users, respectively (adjusted hazard ratio 1.21, 95% CI 0.99 to 1.50).
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).
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