Study supports less-restrictive metformin labeling

Last Updated: 2017-01-04

By Megan Brooks

NEW YORK (Reuters Health) - Metformin appears to be associated with lower mortality in patients with mild to moderate chronic kidney disease, congestive heart failure, and chronic liver disease, according to a review of relevant research.

Metformin is widely recommended as a first-line agent for type 2 diabetes, but, until recently, it was contraindicated in patients with certain chronic conditions due to concerns about lactic acidosis, first author Dr. Matthew J. Crowley told Reuters Health by email.

"However, the US Food and Drug Administration (FDA) now says that metformin may be used safely for patients with mild-moderate chronic kidney disease and other historical contraindications like congestive heart failure," said Dr. Crowley, of the Durham VA Center for Health Services Research and Duke University Medical Center in Durham, North Carolina.

"Now that the lactic acidosis question has been addressed for these groups, our VA-funded review asked, what do we know about how metformin affects mortality and other clinical outcomes for patients with historical contraindications and precautions?" he explained.

As reported online January 2 in Annals of Internal Medicine, the study team did a systematic review of metformin use and its effect on several relevant clinical outcomes, including all-cause mortality and major cardiovascular events in patients with kidney disease (eGFR <60 mL/min/1.73 m2), congestive heart failure, or chronic liver disease with hepatic impairment.

They reviewed 17 studies comparing treatment regimens that included metformin with those that did not and found that metformin use was associated with lower all-cause mortality among patients with each of the three chronic conditions.

Metformin was also associated with a lower risk for hospital readmission for heart failure in patients with heart failure and kidney disease.

There was no evidence that the risks associated with metformin exceed those of other diabetes medications in patients with kidney disease, heart failure or liver disease.

"Our findings support FDA's recent expansion of metformin use," Dr. Crowley told Reuters Health.

"As we note in our review, existing studies have some limitations, but overall it is very encouraging that metformin use is associated with reduced mortality for these patients with historical contraindications and precautions," he said.

"Despite this well-conducted review, the benefits of metformin use in patients with kidney, heart, or liver dysfunction remain somewhat uncertain," writes Dr. Kasia J. Lipska in a linked editorial. "The available studies were all observational and could not completely account for confounding by indication or other biases. Moreover, metformin use was determined primarily at baseline, attrition was not evaluated completely, and outcome assessment was not blinded. As a result, the authors correctly concluded that the strength of the evidence remains low."

"Because metformin is widely used and inexpensive, a better understanding of its effect on outcomes in contemporary practice, as well as among subgroups of patients with commonly occurring comorbid conditions, is imperative," notes Dr. Lipska from Yale School of Medicine, New Haven, Connecticut.

She adds, "Comparative effectiveness evidence for metformin with respect to cardiovascular disease in the modern era is either insufficient or of low quality. In contrast, evidence for newer glucose-lowering agents (that is, those introduced after 2008) is now emerging from several modern cardiovascular outcomes trials, which typically include thousands of high-risk diabetic patients with many prespecified and independently adjudicated outcomes. These postapproval trials are required by the FDA to reasonably exclude cardiovascular risk associated with new glucose-lowering agents."

"The resulting imbalance in the available evidence may potentially lead to greater use of newer medications, in lieu of metformin, and cost an already taxed health care system billions of dollars," Dr. Lipska writes. "In light of the recently relaxed contraindications for its use, bolstering the evidence base for metformin might be a wise investment."

The study was funded by the U.S. Department of Veterans Affairs. The authors have disclosed no conflicts of interest.

SOURCE: http://bit.ly/2iFk4Jp and http://bit.ly/2iFk7oz

Ann Intern Med 2017.