Effects of Metformin Exposure on Survival in a Large National Cohort of Patients With Diabetes and Cirrhosis

Abstract

Background & Aims: Type II diabetes mellitus worsens the prognosis of cirrhosis. Multiple medications including metformin and statins often are co-administered to manage patients with diabetes. The aim of this study was to assess the impact of metformin exposure on mortality, hepatic decompensation, and hepatocellular carcinoma in individuals with diabetes and cirrhosis, controlling for multiple concomitant exposures. Methods: We performed a retrospective cohort study of patients with cirrhosis diagnosed between January 1, 2008, through June 30, 2016, in the Veterans Health administration. Marginal structural models and propensity-matching approaches were implemented to quantify the treatment effect of metformin in patients with pre-existing diabetes with or without prior metformin exposure. Results: Among 74,984 patients with cirrhosis, diabetes mellitus was present before the diagnosis of cirrhosis in 53.8%, and was diagnosed during follow-up evaluation in 4.8%. Before the diagnosis of cirrhosis, 11,114 patients had active utilization of metformin. In these patients, metformin, statin, and angiotensinogen-converting enzyme inhibitor/angiotensin-2–receptor blocker exposure were associated independently with reduced mortality (metformin hazard ratio, 0.68; 95% CI, 0.61–0.75); metformin was not associated with reduced hepatocellular carcinoma or hepatic decompensation after adjustment for concomitant statin exposure. For patients with diabetes before a diagnosis of cirrhosis but no prior metformin exposure, metformin similarly was associated with reduced mortality (hazard ratio, 0.72; 95% CI, 0.35–0.97), but not with reduced hepatocellular carcinoma or hepatic decompensation. Conclusions: Metformin use in patients with cirrhosis and diabetes appears safe and is associated independently with reduced overall, but not liver-related, mortality, hepatocellular carcinoma, or decompensation after adjusting for concomitant statin and angiotensinogen-converting enzyme inhibitor/angiotensin-2–receptor blocker exposure.