Does metformin increase the risk of fatal or nonfatal lactic acidosis?

Practice Pointers The first-line treatments recommended for type 2 diabetes are lifestyle changes and metformin, which is a biguanide antihyperglycemic agent.2 Demonstrated benefits of metformin include lower cardiovascular mortality than other oral diabetes medications3 and a reduced risk of death or myocardial infarction in overweight patients with type 2 diabetes.4 However, because an earlier biguanide, phenformin, was removed from the market after being linked to several cases of lactic acidosis, there have been concerns that metformin may predispose patients to lactic acidosis as well. In light of this, metformin is considered contraindicated in patients with chronic renal insufficiency, pulmonary disease, or hypoxic conditions; abnormal hepatic function; peripheral vascular disease; and in those older than 65 years. The use of metformin in patients with heart failure continues to be controversial.1 The authors of this Cochrane review found no cases of fatal or nonfatal lactic acidosis in 347 prospective trials and cohort studies with more than 70,490 patient-years of metformin use.1 Although the presence or absence of metformin contraindications among participants was not addressed in all studies, the authors note that 97 percent of the studies allowed for at least one metformin contraindication among included patients, and that 26 percent of all participants were estimated to be older than 65 years. Furthermore, one trial specifically studied 393 patients with at least one contraindication to metformin and found no cases of lactic acidosis. All patients in this trial had serum creatinine values ranging from 1.5 to 2.5 mg per dL (132.60 to 221.00 μmol per L).5 Because metformin has demonstrated benefits for patient-oriented outcomes in the treatment of type 2 diabetes, the absence of any cases of lactic acidosis among all patients included in the reviewed studies is reassuring regarding the safety of metformin in general. Considering that there was no standardized reporting across the studies of metformin use in the presence of contraindications, definitive conclusions about the safety of metformin in the presence of contraindications are not possible. Nevertheless, the review authors suggest that concerns for lactic acidosis with metformin use may be overstated for the following three reasons. First, despite chemical similarities, phenformin and metformin have different mechanisms of action. Whereas phenformin can impair hepatic oxidative phosphorylation and increase anaerobic Does Metformin Increase the Risk of Fatal or Nonfatal Lactic Acidosis?