Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus: systematic review and meta-analysis.
BACKGROUND
Metformin therapy for type 2 diabetes mellitus has been shown to reduce total mortality rates compared with other antihyperglycemic treatments but is thought to increase the risk of lactic acidosis. The true incidence of fatal and nonfatal lactic acidosis associated with metformin use is not known.


METHODS
A comprehensive search was performed to identify all comparative trials or observational cohort studies published between January 1, 1959, and March 31, 2002, that evaluated metformin therapy, alone or in combination with other treatments, for at least 1 month. The incidence of fatal and nonfatal lactic acidosis was recorded as cases per patient-years for metformin treatment and for placebo or other treatments. In a second analysis, lactate levels were measured as a net change from baseline or as mean treatment values for metformin and comparison groups.


RESULTS
Pooled data from 194 studies revealed no cases of fatal or nonfatal lactic acidosis in 36 893 patient-years in the metformin group or in 30 109 patients-years in the nonmetformin group. Using Poisson statistics with 95% confidence intervals, the probable upper limit for the true incidence of lactic acidosis in the metformin and nonmetformin groups was 8.1 and 9.9 cases per 100 000 patient-years, respectively. There was no difference in lactate levels for metformin compared with placebo or other nonbiguanide therapies.


CONCLUSIONS
There is no evidence to date that metformin therapy is associated with an increased risk of lactic acidosis or with increased levels of lactate compared with other antihyperglycemic treatments if the drugs are prescribed under study conditions, taking into account contraindications.
Salpeter
Shelley R
SR
Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. salpeter@stanford.edu
Greyber
Elizabeth
E
Pasternak
Gary A
GA
Salpeter
Edwin E
EE
D000140:Acidosis, Lactic / Q000453:epidemiology*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008687:Metformin / Q000627:therapeutic use*; D010629:Phenformin / Q000627:therapeutic use; D018570:Risk Assessment
D007004:Hypoglycemic Agents; D008687:Metformin; D010629:Phenformin