SYSTEMATIC REVIEW
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Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus.

BACKGROUND: Metformin is an oral anti-hyperglycemic agent used in the treatment of type 2 diabetes mellitus. The results of the UK Prospective Diabetes Study indicate that metformin treatment is associated with a reduction in total mortality compared to other anti-hyperglycemic treatments. Metformin, however, is thought to increase the risk of lactic acidosis, and is considered to be contraindicated in many chronic hypoxemic conditions that may be associated with lactic acidosis, such as cardiovascular, renal, hepatic and pulmonary disease, and advancing age.

OBJECTIVES: To assess the incidence of fatal and nonfatal lactic acidosis with metformin use compared to placebo and other glucose-lowering treatments in patients with type 2 diabetes mellitus. A secondary objective was to evaluate the blood lactate levels for those on metformin treatment compared to placebo or non-metformin therapies.

SEARCH STRATEGY: A search was performed of the Cochrane Controlled Trials Register and the Database of Abstracts of Reviews of Effectiveness (up to 4/2000), Medline (up to 11/2000), Embase (up to 11/2000), Oldmedline, and Reactions (up to 5/2000), in order to identify all studies of metformin treatment from 1966 to November 2000. The Cumulated Index Medicus was used to search relevant articles from 1959 to 1965. The search was augmented by scanning references of identified articles, and by contacting principal investigators. Date of latest search: November 2000.

SELECTION CRITERIA: Prospective trials in patients with type 2 diabetes that lasted longer than one month were included if they evaluated metformin, alone or in combination with other treatments, compared to placebo or any other glucose-lowering therapy. Observational cohort studies of metformin treatment lasting greater than one month were also included.

DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials to be included, assessed study quality and extracted data. The incidence of fatal and nonfatal lactic acidosis was recorded as cases per patient-years, for metformin treatment and for placebo or other treatments. The upper limit for the true incidence of cases in the metformin and non-metformin groups were calculated using Poisson statistics. In a second analysis lactate levels were measured as a net change from baseline or as mean treatment values (basal and stimulated by food or exercise) for treatment and comparison groups. The pooled results were recorded as a weighted mean difference (WMD) in mmol/L, using the fixed effects model for continuous data.

MAIN RESULTS: Pooled data from 176 comparative trials and cohort studies revealed no cases of fatal or nonfatal lactic acidosis in 35,619 patient-years of metformin use or in 30,002 patients-years in the non-metformin group. Using Poisson statistics with 95% confidence intervals the upper limit for the true incidence of metformin-associated lactic acidosis was 8.4 cases per 100,000 patient-years, and the upper limit for the true incidence of lactic acidosis in the non-metformin group was 9 cases per 100,000 patient-years. 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 -0.15).

REVIEWER'S CONCLUSIONS: There is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared to other anti-hyperglycemic treatments if prescribed under the study conditions, taking into account contra-indications.

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