Metformin Benefits Patients Historically Kept From Using It

Miriam E Tucker

January 03, 2017

Metformin treatment in patients with type 2 diabetes who have historical contraindications to the drug's use is associated with improved clinical outcomes, new research shows.

Matthew J Crowley, MD, from Durham Veteran's Affairs Medical Center and Duke University, Durham, North Carolina, and colleagues published the results of their systematic review of 17 observational studies online January 3 in the Annals of Internal Medicine.

The evidence, albeit limited to observational data, suggests metformin is associated with reduced all-cause mortality in patients with type 2 diabetes with chronic kidney disease (CKD), congestive heart failure (CHF), and chronic liver disease (CLD) with hepatic impairment.

Metformin also appears to reduce CHF admissions in patients with moderate CKD and CHF and to lower hypoglycemia risk in patients with CKD.

Metformin has been recommended as first-line therapy for type 2 diabetes by professional diabetes societies in the United States and Europe for more than a decade, and that recommendation has just been reaffirmed by the American College of Physicians in guidelines that were also published online January 3 in the Annals of Internal Medicine.

The renewed support comes on the heels of emerging data demonstrating that prior concerns about lactic acidosis in patients with moderate CKD, CHF, or CLD have been largely unfounded.

The US Food and Drug Administration (FDA) removed CHF as a contraindication to metformin use in 2006. Moreover, in April 2016, the agency revised its CKD warning to restrict metformin use only in patients with severe CKD (estimated glomerular filtration rate [eGFR] <30 mL/minute per 1.73 m2), thereby allowing it for those with moderate CKD (30–60 mL/minute per 1.73 m2).

The current study looked at the flip side, Dr Crowley told Medscape Medical News.

"Recent FDA statements and reviews addressing metformin have focused on rates of lactic acidosis with historical contraindications and precautions. With this [Veterans Affairs]-funded project, we explored another issue: Now that the lactic-acidosis question has been addressed, what do we know about how metformin affects long-term clinical outcomes for patients with historical contraindications and precautions?"

The investigators found the drug has several positive effects. "Keeping in mind that confounding by indication and other factors can introduce bias into our estimates, we didn't just find a neutral effect with metformin. It actually appeared to be associated with lower mortality and certain cardiovascular outcomes.

"Those are really exciting findings and definitely encourage the use of metformin clinically for these groups, and continued exploration of long-term outcomes in comparison to other therapies," Dr Crowley said.

Will Metformin Ever Get an RCT?

In an accompanying editorial, Yale University endocrinologist Kasia J Lipska, MD, points out that metformin has many overall advantages, including low cost and low risks for weight gain or hypoglycemia. However, she says, better-quality studies are needed for metformin to compete with data from recent FDA-mandated randomized controlled outcomes trials showing cardiovascular benefits from both the sodium-glucose cotransporter type 2 (SGLT2) inhibitor empagliflozin and the glucagonlike peptide 1 (GLP-1) agonist liraglutide.

"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. In light of the recently relaxed contraindications for its use, bolstering the evidence base for metformin might be a wise investment," writes Dr Lipska, who led a group at Yale that had filed a citizen's petition to the FDA, lobbying for the metformin label change regarding moderate CKD.

Dr Crowley agrees, but notes that such studies might be difficult, given that they would require large numbers of patients be followed for a long time and could face ethical barriers, as metformin is already the standard of care. Whereas the ethics problem might, in theory, be addressed by studying different doses of metformin or comparing it with effective alternatives, "studies like that are very expensive," he said.

"Industry funders aren't going to line up" to study the generic metformin, he added.

In any case, he said, "I think it's a great area for discussion. I think this will be a hot topic for the American Diabetes Association and thought leaders going forward, and it's a pretty exciting discussion to have."

Several Metformin Benefits Found for Patients With CKD

Data for CKD came from six observational trials with sample sizes ranging from 1246 to 11,481 patients with moderate to severe CKD, with follow-up times ranging from 1 to 3.9 years. A meta-analysis of five studies that examined all-cause mortality in 33,442 subjects showed a 22% reduction in relative risk of dying with metformin than without (hazard ratio [HR], 0.78; P < .001).

One study of 5859 subjects also found a slightly lower CHF readmission rate with metformin use among patients with CKD and CHF (HR, 0.91).

Moreover, in a study of 1644 patients with eGFR lower than 60 mL/minute per 1.73 m2, both glyburide (adjusted odds ratio, 6.0) and insulin (adjusted odds ratio, 7.9) were associated with more hypoglycemia than metformin, and those results persisted in patients with lower eGFR levels.

In Patients With CHF and CLD, Metformin Was Associated With All-Cause Mortality

In 11 observational studies with sample sizes ranging from 346 to 13,930 and follow-up from 1 to 4.7 years, metformin was associated with a 22% lower risk for death compared with no metformin (HR, 0.78; P = .003).

In addition, the relative risk for readmission for CHF during follow-up "was 13% lower for patients receiving metformin than for those not receiving it" (HR, 0.87; P = .009).

Although there was a trend toward a reduction in major adverse cardiovascular outcomes and cardiovascular mortality in the CHF group, the differences between those receiving and not receiving metformin did not reach statistical significance (HR, 0.87 and 0.77, respectively).

There were three observational cohort studies of patients with CLD with cirrhosis, ranging from 82 to 250 patients (total, 432), with follow-up ranging from 4.5 to 5.7 years. Although a meta-analysis could not be performed because two studies included only unadjusted event rates, one study of 250 patients with a low risk for bias found significantly longer survival associated with metformin use (HR, 0.43), regardless of cirrhosis severity.

"There's clearly a strong rationale for using metformin from a cost perspective," Dr Crowley told Medscape Medical News. "The idea that a low-cost therapy like metformin could provide some of the same mortality benefits that newer drugs seem to would be huge. It would be really valuable for patients with diabetes all across the country and the world."

The study was funded by the US Department of Veterans Affairs. Dr Crowley is supported by a Career Development Award from VHA Health Services Research and Development. Dr Lipska receives support from the National Institute on Aging and the American Federation of Aging Research. The other authors and editorialists have disclosed no relevant financial relationships.

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Ann Intern Med. Published online January 3, 2017. Abstract, Editorial

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