Is Metformin Safe in Patients With Mild Renal Insufficiency?

Among the first million patients who received metformin in the U.S., 47 patients developed metformin-associated lactic acidosis (MALA), with 43 having predisposing factors for lactic acidosis (including moderate to severe renal failure and congestive heart failure) (1). Although there was initial concern, studies have suggested that MALA is secondary to underlying conditions and represents a coincidental finding (2,3). While the current consensus is that the risk of lactic acidosis is negligible when metformin is used as labeled (4), we present a patient who developed MALA in the absence of currently recognized contraindications to metformin.

A 55-year-old man with hypertension, type 2 diabetes, and mild renal insufficiency (measured creatinine clearance 91 ml/min) presented with sudden onset of fatigue, vomiting, and altered mental status after performing strenuous yard work without sufficient hydration. His medications included nifedipine, captopril, hydrochlorothiazide, glyburide, and metformin.

The patient rapidly developed respiratory distress and hypotension necessitating intubation and vasoactive agents. Laboratory studies revealed a serum creatinine level of 9.4 mg/dl, pH 6.98, CO₂ <6 mmol/l, and lactic acid 27 mmol/l. Evaluation using a computed tomography scan and magnetic resonance angiography of the abdomen/pelvis, various cultures and cardiac echocardiogram could not reveal an etiology for lactic acidosis. Serum metformin level (ARUP Laboratories, Salt Lake City, UT) was 8 mg/l (therapeutic range 1–2). Continuous venovenous hemofiltration was initiated immediately. Conservative management was followed by rapid amelioration of his general status. He was extubated within 24 h, continuous venovenous hemofiltration was stopped after 36 h, and he was discharged 6 days after presentation without deficits.

This case is unique in that MALA developed in the absence of currently recognized risk factors or predisposing conditions. Although this patient had mild impairment of kidney function, contraindication criteria for the use of metformin were not met (5). The patient was taking 2 g metformin per day, which is within the recommended therapeutic range.

In our opinion, a threshold serum creatinine level above normal range should not be considered safe for metformin use because renal function can rapidly deteriorate in patients with even mild underlying kidney disease, resulting in accumulation of metformin and development of MALA. We suggest that consideration be given to avoiding metformin in patients with any degree of renal dysfunction.