Metformin use associated with improved outcomes in patients with historical contraindications

Metformin appears to improve certain outcomes in patients with moderate chronic kidney disease (CKD), congestive heart failure (CHF), or chronic liver disease with hepatic impairment, according to a recent systematic review.

The FDA recently modified its boxed warning for metformin, removing CHF as a contraindication and basing use in patients with CKD on estimated glomerular filtration rate rather than serum creatinine. Researchers from the U.S. Department of Veterans Affairs performed a systematic review of the literature to help promote informed prescribing of metformin in these previously contraindicated populations. Studies were included in the review if they were published in English and included adults with type 2 diabetes and CKD, CHF, or chronic liver disease with hepatic impairment; compared regimens with metformin and those without; and reported outcomes of interest including all-cause mortality and major adverse cardiovascular events. The study results were published online Jan. 3 by Annals of Internal Medicine.

Seventeen observational studies were included in the review. Of these, 5 involved patients with moderate to severe CKD, 11 involved patients with CHF, 3 involved patients with chronic liver disease and hepatic impairment, and 3 involved patients with CKD and those with CHF. The researchers performed quantitative and qualitative data syntheses and found that metformin appeared to be associated with lower all-cause mortality in patients with all three of the studied conditions, with fewer readmissions for heart failure in patients with CKD or CHF, and with lower hypoglycemia rates in patients with moderate CKD.

The authors noted that their review may have been affected by the observational design of the included studies, that they did not examine all outcomes of interest, and that most of the included studies defined metformin use only at baseline, among other limitations. However, they concluded that based on limited evidence, metformin appears to improve certain clinical outcomes in patients in whom it had previously been contraindicated, supporting the recent labeling changes by the FDA. They called for future trials comparing metformin with specific alternative therapies in these populations to help refine prescribing guidelines.

The author of an accompanying editorial said the review was well-conducted but called the benefits of metformin use in patients with kidney, heart, or liver dysfunction “still somewhat uncertain.” Clinicians and patients are in need of higher-quality evidence about benefits and harms of available treatment options and must also consider the potential effect of each treatment on patients' lives and budgets, she said.

“The particularly vulnerable patients with kidney, heart, or liver failure need specific information about the safety and effectiveness of treatment in the context of these comorbid conditions and about any interactions between drugs or conditions that may nullify the benefits or accentuate the harms of treatment,” the editorialist wrote. “This type of evidence is sorely lacking.”

The editorialist also pointed out that newer glucose-lowering agents have more evidence available on cardiovascular risk because the FDA has required postapproval trials to help determine their safety. “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,” the editorialist wrote. “In light of the recently relaxed contraindications for its use, bolstering the evidence base for metformin might be a wise investment.”