Long‐term metformin use may improve clinical outcomes in diabetic patients with non‐alcoholic steatohepatitis and bridging fibrosis or compensated cirrhosis

Abstract

Summary Background Metformin may protect against hepatocellular carcinoma and mortality among patients with type 2 diabetes. Aim To investigate whether long‐term use of metformin improves survival and reduces liver‐related outcomes among patients with type 2 diabetes and non‐alcoholic steatohepatitis. Methods A total of 191 diabetic patients with biopsy‐proven non‐alcoholic steatohepatitis and bridging fibrosis or compensated cirrhosis were retrospectively identified at Indiana University Medical Center between October 2004 and January 2016. Of them, 110 were users and 81 never‐users of metformin. Primary outcomes were transplant‐free survival, development of hepatocellular carcinoma or a first event of hepatic decompensation. Results Cirrhosis was present in 85% of metformin users and 88% of nonusers. Metformin dose was greater than or equal to 1 g/d in 104 out of 110 users and its median duration of use was 6 (95% CI: 4.4‐7.9) years. The mean follow‐up was 6.92 and 6.80 years for metformin users and non‐users, respectively. During follow‐up, 28 patients developed hepatocellular carcinoma (metformin users: 7, nonusers: 21), and 52 died (metformin users: 7, nonusers: 24) or were transplanted (metformin users: 13, non‐users: 13). Metformin use was associated with lower risk of overall mortality or transplant (HR: 0.42; 95% CI: 0.24‐0.74, P = 0.003) and hepatocellular carcinoma (sHR: 0.25; 95% CI: 0.11‐0.58, P = 0.001), and remained independently associated with both outcomes after propensity‐score and covariate‐adjusted analyses. No instances of hepatotoxicity or lactic acidosis were observed. Conclusion Our study demonstrated an association between long‐term metformin use and reduced the risk of all‐cause mortality/transplant and hepatocellular carcinoma in diabetics with non‐alcoholic steatohepatitis and advanced fibrosis.

Letter: metformin treatment and hepatocellular carcinoma risk in non‐alcoholic fatty liver disease. Authors’ reply

“…We thank Dogru et al for their insightful comments on our recent article. 1,2 We demonstrated that long term and continued use of metformin lowers risk of death or transplant and hepatocellular carcinoma (HCC) in type 2 diabetic patients with non-alcoholic steatohepatitis (NASH) and advanced fibrosis. Dogru et al suggested that benefits of metformin intake on adverse clinical outcomes might be mediated by improving insulin sensitivity and perhaps regulating insulin-like growth factor/ insulin axis.…”

“…Eight studies involving 134 202 metformin users and 60 352 non-users were included (Table 1). 1,2,[4][5][6][7][8][9] The mean follow-up ranged from 2.8 to 6.8 years. The incidence rate of HCC ranged from 0.03% to 7.69% among metformin users, and 0.046% to 50% among nonusers.…”

Letter: improvement of clinical outcomes by metformin in metabolic liver disease—a microbiota‐dependent mechanism?

“…EDITORS, Vilar-Gomez et al found that the long-term use of metformin is positively associated with a decrease in the risk of overall mortality, the need for liver transplantation and the development of hepatocellular carcinoma (HCC) in diabetic patients with non-alcoholic steatohepatitis (NASH) and bridging fibrosis or compensated cirrhosis. 1 The authors hypothesize several pathways that potentially define the beneficial effects of metformin, including decrease in insulin-like growth factor-1, activation of AMP-activated protein kinase, inhibition of mammalian target rapamycin, downregulation of human epidermal growth factor receptor-2, reduction in endogenous production of reactive oxygen species and associated DNA damage, and others. [2][3][4][5] Increasing evidence suggests that intestinal dysbiosis plays a key role in the development and progression of metabolic liver disorder.…”

Letter: metformin reduces the risk of hepatocellular carcinoma in diabetic patients

“…2 Therefore, the incidence rate of HCC was 6.36% (7/110) and 25.93% (21/81) among diabetic patients with or without long-term metformin treatment. 1 This raises a question about the intensity of surveillance for HCC in such patients. Current HCC surveillance guidelines propose biannual liver ultrasound for patients with cirrhosis.…”

“…Eight studies involving 134 202 metformin users and 60 352 non-users were included (Table 1). 1,2,[4][5][6][7][8][9] The mean follow-up ranged from 2.8 to 6.8 years. The incidence rate of HCC ranged from 0.03% to 7.69% among metformin users, and 0.046% to 50% among nonusers.…”