Like other
biguanide agents,
metformin is an anti-hyperglycemic agent with lower tendency towards
hypoglycemia compared to other anti-diabetic drugs. Given its favorable effects on serum
lipids, obese body habitus,
cardiovascular disease, and mortality,
metformin is recommended as the first-line pharmacologic agent for
type 2 diabetes in the absence of
contraindications. However, as
metformin accumulation may lead to type B non-hypoxemic
lactic acidosis, especially in the setting of kidney injury,
chronic kidney disease, and overdose, regulatory agencies such as the United States Food and Drug Administration (FDA) have maintained certain restrictions regarding its use in kidney dysfunction. Case series have demonstrated a high fatality rate with
metformin-associated
lactic acidosis (MALA), and the real-life incidence of MALA may be underestimated by observational studies and clinical trials that have excluded patients with moderate-to-advanced kidney dysfunction. A recent study of advanced
diabetic kidney disease patients in Taiwan in Lancet Endocrinology and Diabetes has provided unique insight into the potential consequences of unrestricted
metformin use, including a 35% higher adjusted mortality risk that was dose-dependent. This timely study, as well as historical data documenting the toxicities of other
biguanides,
phenformin and
buformin, suggest that the recent relaxation of FDA recommendations to expand
metformin use in patients with kidney dysfunction (i.e., those with estimated glomerular filtration rates ≥30 instead of our recommended ≥45 ml/min/1.73 m2) may be too liberal. In this article, we will review the history of
metformin use; its pharmacology, mechanism of action, and potential toxicities; and policy-level changes in its use over time.