A systematic review of 17 observational studies found that metformin was associated with a reduction in all-cause mortality in patients with type 2 diabetes and chronic kidney disease, congestive heart failure or chronic liver disease with hepatic impairment.

Metformin was also associated with fewer heart failure readmissions in patients with chronic kidney disease or congestive heart failure.

Lead researcher Matthew J. Crowley, MD, MHS, of Duke University and the Durham Veterans Affairs Medical Center in North Carolina, and colleagues published their results online Jan. 2 in the Annals of Internal Medicine. The U.S. Department of Veterans Affairs funded the study.

When the FDA approved metformin in 1994, the drug became the initial treatment option for many people with type 2 diabetes in the U.S., according to the researchers. However, the FDA required a label warning against using metformin in patients with chronic kidney disease and recommended caution for patients with congestive heart failure and chronic liver disease.

The researchers noted that the FDA in 2006 removed congestive heart failure as a contraindication to metformin use, although the agency still cautions against the drug’s use in patients with acute or unstable congestive heart failure. They also noted that the FDA in April 2016 revised its warning regarding metformin use in patients with chronic kidney disease. By switching to a more inclusive criteria based on estimated glomerular filtration rate, an estimated one million additional patients with moderate chronic kidney disease are eligible to receive metformin, although the drug remains contraindicated in patients with severe chronic kidney disease.

For this analysis, the researchers searched databases, the ClinicalTrials.gov website and other publications for trials published from 1994 to 2016. They identified 17 observational studies of adults with type 2 diabetes and moderate to severe chronic kidney disease, congestive heart failure or chronic liver disease with hepatic impairment.

Of the studies, five included patients with moderate to severe chronic kidney disease, 11 included patients with congestive heart failure and three included patients with chronic liver disease with hepatic impairment. Three of the studies included patients with chronic kidney disease and congestive heart failure.

Based on the 17 studies, the researchers noted that metformin was associated with reduced all-cause mortality in all three patient groups, fewer congestive heart failure readmissions for patients with moderate chronic kidney disease or congestive heart failure and a lower rate of hypoglycemia among patients with moderate chronic kidney disease.

“Although data were limited, we found no evidence to suggest that metformin's benefits do not extend to patients with moderate [chronic kidney disease], [congestive heart failure], or [chronic liver disease] with impaired hepatic function,” the researchers wrote. “Together with reports regarding the safety of metformin with respect to lactic acidosis, our findings support the FDA's recent actions.”

The researchers cited a few limitations of the study, including that they did not examine all outcomes of potential interest and relied on observational evidence. They mentioned there was a lack of randomized trial data evaluating the use of metformin in patients with chronic kidney disease, congestive heart failure or chronic liver disease with hepatic impairment. They also noted there was no much information on precaution severity in patients with congestive heart failure and chronic liver disease. In addition, they suggested that future research should compare metformin with alternative medications in patients with historical contraindications or precautions to the drug.

“Available data provide no evidence that the risks associated with metformin exceed those of other antihyperglycemic medications in these populations,” the researchers wrote. “Our findings support the recent FDA labeling changes, point toward areas for future research, and may help inform clinical practice and revision of clinical guidelines.”