COMMENTARY

Metformin in Patients With CKD: A New Analysis

Tejas P. Desai, MD

Disclosures

March 23, 2015

Metformin in Patients With Type 2 Diabetes and Kidney Disease

Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK
JAMA. 2014;312:2668-2675

Background: Metformin and Chronic Kidney Disease

Diabetes mellitus is the leading cause of chronic kidney disease (CKD) in the United States. For decades, a mainstay of therapy against diabetes has been metformin. Metformin has the advantage of being an effective antihyperglycemic agent that also facilitates weight loss; however, it is considered unsafe in patients with renal insufficiency because of fears about lactic acid accumulation. Thus, since its approval by the US Food and Drug Administration in 1994, healthcare providers have been cautioned against the use of metformin in patients with CKD, a measure that has prevented these patients from availing themselves of the beneficial effects of metformin.

Fears about metformin use in patients with CKD stem from the theoretical ability of the drug to generate large amounts of lactic acid. Metformin inhibits the respiratory chain within the mitochondria, forcing cells in the body to perform anaerobic metabolism (metabolism that does not use oxygen). A large by-product of anaerobic metabolism is lactic acid, which acidifies the blood and, if present in a high concentration, can cause multiorgan dysfunction.

Because the kidneys excrete metformin, any degree of kidney dysfunction would increase the level of metformin and the subsequent lactic acid produced. Now, a large systematic review calls into question whether this theoretical concern is supported by empirical real-world data.

The Study

Inzucchi and colleagues analyzed results of clinical and observational studies to suggest that reservations about using metformin in patients with CKD are not borne out in the data. Empirical data[1] have indeed shown a reduction in metformin clearance as kidney dysfunction worsens (a 23%-33% reduction when the creatinine clearance is 60-90 mL/min, and a 74%-78% reduction when the creatinine clearance is 30-60 mL/min). Of interest, in that study, metformin levels were maintained within the therapeutic range (4-20 μmol/L) regardless of the creatinine clearance, suggesting that despite a reduction in drug clearance, there is no increase in metformin toxicity.

In another independent study,[2] the observed metformin levels at various stages of CKD were measured, and all were within the drug's broad therapeutic range (4.5 μmol/L for an estimated glomerular filtration rate [eGFR] > 60 mL/min/1.73 m2; 7.71 μmol/L for an eGFR of 30-60 mL/min/1.73 m2; and 8.88 μmol/L for an eGFR < 30 mL/min/1.73 m2).

Unfortunately, the authors of the current study were unable to find equally robust data regarding the levels of lactic acid generated in patients with various degrees of kidney function who were taking metformin. Many of the studies that focused on lactic acid production excluded patients with CKD; other studies did not perform propensity-score adjustments to account for confounding. The available data suggest that the degree of lactic acidosis seen in diabetic patients taking metformin is similar to that in patients taking other antidiabetic medications (eg, sulfonylureas) or in those taking no medications at all.

Commentary

Despite these shortcomings, this systematic review revisits the notion that metformin is unequivocally unsafe in patients with CKD. Given its low cost, proven effectiveness against hyperglycemia, and positive secondary effects (eg, weight loss), metformin is an attractive drug for many patients with diabetes, including those with kidney disease. The authors recognize the value of using metformin in patients with CKD and offer an alternative dosing strategy that opens its use to more patients, with doses ranging from 2550 mg for patients with an eGFR ≥ 90 mL/min/1.73 m2 down to 1000 mg for those with an eGFR of 30 to < 45 mL/min/1.73 m2, and recommendations to avoid use in those with an eGFR below 30 mL/min/1.73 m2.

Compiling all of the available data into a systematic review offers a concise perspective on the question of the safety of metformin in patients with CKD. Although some providers may continue to wonder whether long-term metformin use could lead to the deleterious effects initially feared, this review opens the possibility of welcoming back metformin into the family of antihyperglycemic drugs that many kidney disease patients need.

Abstract

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