Metformin counters risks associated with diabetes in NASH cirrhosis patients

Type 2 diabetes mellitus (T2DM) contributes to a heightened risk of death, hepatic decompensation, and hepatocellular carcinoma (HCC) among patients with nonalcoholic steatohepatitis (NASH) and cirrhosis, but the good news is that metformin may cut the risk of these adverse outcomes, a study has found.

“Our data clearly demonstrates that in the presence of compensated cirrhosis, T2DM identifies an at-risk group at high probability of developing liver related morbidity and mortality over the medium term, thereby indicating a need for heightened surveillance and prioritization for effective therapy,” according to the investigators.

The analysis included 299 patients with biopsy-proven NASH with Child-Pugh A cirrhosis from tertiary hospitals in Spain, Australia, Hong Kong, and Cuba. A total of 212 patients had diabetes at baseline, and this group were older (mean age, 58.9 vs 52.5 years; p<0.01) and more likely to have hypertension, gastroesophageal varices, and poorer renal function compared with nondiabetics (n=87).

Over a median follow-up of 5.1 years, eight patients developed T2DM. The majority of diabetic patients (79 percent) were on glucose-lowering medications, including metformin (n=111), sulphonylureas (n=61), and insulin (n=87). Insulin users showed higher HbA1c and creatinine levels than those on metformin and sulphonylureas.

Cox proportional and competing risk models revealed T2DM to be associated with an increased risk of adverse outcomes among NASH cirrhosis patients. Significantly fewer patients with vs without diabetes survived the entire follow-up (38 percent vs 81 percent; adjusted hazard ratio [aHR], 4.23, 95 percent confidence interval [CI], 1.93–9.29). [Clin Gastroenterol Hepatol 2020;doi:10.1016/j.cgh.2020.04.083]

Furthermore, higher proportions of patients with diabetes developed hepatic decompensation (51 percent vs 26 percent; aHR, 2.03, 95 percent CI, 1.005–4.11) and HCC (25 percent vs 7 percent; aHR, 5.42, 95 percent CI, 1.74–16.80). Averaged annual HbA1c levels over time did not affect outcomes.

“There was an unexpected low rate of death from cardiovascular disease in T2DM patients with NASH cirrhosis, which may reflect the reduction in blood pressure, body weight, and cholesterol which occurs with progressive fibrosis, or due to competing risks from liver disease limiting opportunity for cardiovascular disease to manifest,” the investigators noted.

Meanwhile, metformin use over time showed a protective effect on the risks of death or liver transplantation (aHR, 0.41, 95 percent CI, 0.26–0.45), hepatic decompensation (aHR, 0.80, 95 percent CI, 0.74–0.97), and HCC (aHR, 0.78, 95 percent CI, 0.69–0.96). The benefits conferred for hepatic decompensation and HCC were only seen among patients with HbA1c levels >7.0 percent (aHR, 0.97, 95 percent CI, 0.95–0.99 and aHR, 0.67, 95 percent CI, 0.43–0.94, respectively).

“Notably, no patient developed lactic acidosis or serious complications from metformin use, in line with other reports. However, the safety and efficacy of metformin in decompensated cirrhosis is not clear, and caution should be applied using it,” the investigators said. [Hepatology 2014;60:2008-2016]

Results from clinical trials are mixed regarding the impact of metformin on liver histology in noncirrhotic NASH patients, and a lack of adequately powered randomized controlled trials has hampered recommendation for use of the drug in patients with NASH. [Hepatology 2018;67:328-357; J Hepatol 2016;64:1388-1402]

“[O]ur data provides rationale to examine the impact of [the glucose-lowering drug] in a prospective randomized clinical trial on NASH cirrhosis outcomes,” they added.