Does metformin cause lactic acidosis?
There is no evidence that metformin causes lactic acidosis, even in patients with renal insufficiency or other comorbidities. Although caution is still indicated in patients with multiple or severe comorbidities, it appears that the initial concern about lactic acidosis with this drug was misplaced.
Unlike other agents used in the treatment of type 2 diabetes mellitus, metformin has been shown to reduce mortality in obese patients. (1) It is therefore being used increasingly often for the treatment of type 2 diabetes. However, many physicians are concerned about a possible increase in the risk of lactic acidosis, particularly in patients who have cardiovascular disease, renal disease, liver problems, chronic respiratory disease, or advanced age. Phenformin, another biguanide, was withdrawn from the market after a rate of 40 to 64 cases of lactic acidosis per 100,000 patient-years was reported.
Salpeter and colleagues found 176 studies that met their inclusion criteria, of which 118 were prospective clinical trials. The 176 studies followed 26,099 patients who took metformin for a total of 65,621 patient-years, and 8,943 control patients who did not take metformin for 30,002 patient-years.
Although many studies excluded patients with comorbidities, a significant number did not. For example, 81 did not exclude patients with renal insufficiency. Remarkably, there was not a single case of fatal or nonfatal lactic acidosis in any of the patients, whether or not they took metformin. Therefore, the upper limit of a 95 percent confidence interval with zero at the lower end is 8.4 cases per 100,000 patient-years in patients taking metformin and 9.0 cases per 100,000 patient-years in patients not taking it. There was no difference in intermediate physiologic outcomes, such as change in lactate levels, and no evidence of publication bias. The authors cite data showing that contraindications to the use of metformin are largely ignored in clinical practice. It appears that, in this case, physicians are correct.
(1.) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group [published correction appears in Lancet 1998;352:1557]. Lancet 1998;352:854-65.
MARK EBELL, M.D., M.S. Salpeter S, et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 2004;(3):CD002967.
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