Is Metformin Associated With Lactic Acidosis?

Jodi H. Walker, BS, PharmD


January 19, 2010


The use of metformin in patients with renal impairment is associated with an increased risk for lactic acidosis. Why is this and what is the mechanism? Are sulfonylureas associated with lactic acidosis?

Response from Jodi H. Walker, BS, PharmD
Adjunct Faculty, Albany College of Pharmacy, Albany, New York; Clinical Pharmacy Specialist, VA Medical Center, Bath, New York

Metformin is one of most commonly prescribed medications for the treatment of type 2 diabetes mellitus. Metformin exerts its activity by increasing peripheral glucose uptake and utilization, and decreasing hepatic gluconeogenesis. By decreasing pyruvate dehydrogenase activity and mitochondrial reducing agent transport, metformin enhances anaerobic metabolism and increased production of tricarboxylic acid cycle precursors. Inhibition of pyruvate dehydrogenase subsequently decreases the channeling of these precursors into aerobic metabolism and causes increased metabolism of pyruvate to lactate and ultimately lactic acid production.[1]

In a patient with normal renal function, the excess lactic acid is simply cleared through the kidneys. However, in a patient with renal impairment, both metformin and lactic acid are cleared less effectively and may result in further accumulation of both.[1] The complication of lactic acidosis is serious and potentially fatal.

Increased risk for lactic acidosis associated with metformin is controversial. A Cochrane Systematic Review of over 200 trials evaluated the incidence of lactic acidosis among patients prescribed metformin vs non-metformin antidiabetes medications. Of 100,000 people, the incidence of lactic acidosis was 5.1 cases in the metformin group and 5.8 cases in the non-metformin group. The authors concluded that metformin is not associated with an increased risk for lactic acidosis.[2]

To compare the occurrence of lactic acidosis between metformin and sulfonylureas, Bodmer and colleagues conducted a nested, case-controlled analysis of 50,048 patients with type 2 diabetes receiving an oral antidiabetes agent. They found that per 100,000 patients, the crude incidence of lactic acidosis in patients treated with metformin was 3.3, while the incidence in patients treated with sulfonylureas was 4.8. All patients in whom lactic acidosis developed had underlying conditions that are known risk factors for lactic acidosis.[3]

Risk factors for lactic acidosis include any disease state that has the potential to either increase the production or decrease the removal of lactic acid. Conditions that may increase risk include congestive heart failure, liver disease, shock, alcohol use, hypoxic states, renal failure, sepsis, and advanced age.[4,5,6]

It appears that metformin itself may not increase the risk for lactic acidosis. And although metformin use has increased over the years, the incidence of lactic acidosis has not increased.[4] Additionally, there is no evidence to suggest that sulfonylureas alone increase the risk for lactic acidosis. Rather, the presence of underlying conditions and concomitant use of other medications may elevate an individual's risk level.

Some suggest that diabetes mellitus, rather than specific antidiabetes medications, may predispose a patient to lactic acidosis. The mechanisms for this increased risk are unknown. In practice, it may be important to consider diabetes mellitus as a risk factor for developing lactic acidosis and examine each patient's medication profile as well as other underlying conditions to determine a patient’s overall risk.[7]

The author acknowledges PharmD students, Erin Meyer and Zachary Kennedy, for their contributions in researching and compiling this response.