Metformin improves survival, reduces HCC risk in diabetics with NASH and fibrosis
Type 2 diabetes (T2D) patients with nonalcoholic steatohepatitis (NASH) and advanced fibrosis may fare well with long-term use of metformin, as the drug confers marked benefits for transplant-free survival and helps prevent the development of hepatocellular carcinoma (HCC), according to a recent study.
“The continued use of metformin showed between 56 percent and 59 percent decrease in all‐cause mortality or transplantation rates … [and] between 75 percent and 78 percent [HCC] risk reduction,” the investigators said.
The analysis included 191 T2D patients (average age, 57 years; 57.6 percent female) with biopsy‐proven NASH and bridging fibrosis or compensated cirrhosis, including 110 who were metformin users (dosing ≥1 g/d in 104 users; median duration of use, 6 years). Cirrhosis was present in 85 percent of metformin users and 88 percent of nonusers.
Over a mean follow up of nearly 7 years, 52 patients died (seven users, 24 nonusers) or received liver transplants (13 users, 13 nonusers) and 28 developed HCC (seven users, 21 nonusers). Compared with nonusers, metformin users had markedly lower 10-year cumulative rates of transplant-free survival (35 percent vs 64 percent) and HCC incidence (12 percent vs 40 percent). [Aliment Pharmacol Ther 2019;doi:10.1111/apt.15331]
In unadjusted Cox proportional hazards models, metformin exerted a significant protective effect on the risks of overall mortality or transplant (hazard ratio, 0.42, 95 percent CI, 0.24–0.74; p=0.003) and HCC (subhazard ratio, 0.25, 0.11–0.58; p=0.001). These risk-reduction benefits were consistently observed on subsequent analyses adjusting for several confounders, including a rigorous propensity score and a clinically rich set of prognostic variables. No instances of hepatotoxicity or lactic acidosis were recorded.
It is important to note that metformin use, possibly along with cumulative duration of therapy and dose, was associated not only with decreased incidence of HCC but also with early tumour stages based on Barcelona Clinic Liver Cancer (BCLC) classification at the time of diagnosis, according to the investigators.
“Among metformin users, 71 percent and 29 percent of HCCs were detected at early/very early or intermediate BCLC stages, which are associated with high expectation for long‐term survival. In contrast, 52 percent of liver cancer diagnoses were done at intermediate or advanced BCLC stages among nonexposed patients, which are clearly associated with worse prognosis and survival rates,” they said.
“We hypothesized that metformin use might modify the tumour biology of the HCC, slowing its growth and progression, which may partly explain the liver tumour detection at early stages in patients undergoing HCC surveillance,” the investigators said, adding that the hypothesis is consistent with previous studies reporting the glucose-lowering drug to be associated with less aggressive disease in patients with lung or prostate cancer. [World J Surg Oncol 2018;16:60; Clin Transl Oncol 2015;17:819‐824; Ann Oncol 2016;27:2184‐2195]
Another potentially important observation is that combining metformin with vitamin E may improve outcomes in the study population beyond that observed with either of them individually. However, the investigators advised caution in the interpretation of this finding due to the small number of patients included in the combination group, which precluded controlling for covariates.