CHARLOTTE, N.C.—Survival rates of patients with cirrhosis and diabetes may improve if they take a combination of metformin and a glucagon-like peptide-1 receptor agonist (GLP1-RA) rather than metformin alone, according to a recent study.
While these second-line antidiabetic agents can help patients who need more than metformin to stabilize their glycemic indexes, little is known about their use in patients with cirrhosis and diabetes.
Although current clinical and preclinical studies have shown that the use of GLP1-RAs is associated with reduced liver fibrosis, inflammation markers, serum alanine and aspartate aminotransferase, as well as improved glycemic indexes, in patients with nonalcoholic steatohepatitis and type 2 diabetes, those studies have excluded patients with cirrhosis.
“We wanted to know if there is an improvement in mortality and hepatic compensation outcomes in patients with cirrhosis and diabetes who are on metformin and a GLP1-RA versus those on metformin alone. We also wanted to know how dual therapy affects patients who have cirrhosis, and particularly those who have cirrhosis due to NASH,” said Daniel Huynh, a second-year medical student at the Renaissance School of Medicine at Stony Brook University, in New York, presenting the research at the 2022 annual meeting of the American College of Gastroenterology.
Mono Versus Dual Therapy
To answer these questions, Mr. Huynh and his co-investigators conducted a retrospective study of a propensity score–matched cohort from the TriNetX research platform to investigate the impact of dual-therapy with metformin and a GLP1-RA in patients with cirrhosis and diabetes (oral abstract 67). Their primary outcome was three-year all-cause mortality, and three-year composite hepatic decompensation was a secondary outcome.
After propensity score matching, the researchers identified 1,087 patients with type 2 diabetes and cirrhosis taking both metformin and a GLP1-RA (33.6% men and 66.4% women), and matched them with an equal number of patients receiving only metformin.
The researchers found that patients with type 2 diabetes and cirrhosis receiving metformin monotherapy had a higher risk for mortality than those on dual metformin–GLP1-RA therapy (relative risk, 2.88; 95% CI, 2.16-3.65; P<0.001) and a lower three-year survival rate (86.64% vs. 93.11%, respectively; P<0.0001).
“The risk of mortality was nearly threefold higher in those on metformin monotherapy,” Mr. Huynh said.
They did not find a statistically significant difference in the probability of hepatic decompensation at three years (P=0.086). “However, we did find that those on mono metformin therapy were more likely to have a higher probability of decompensating at six months and one year, possibly suggesting a short-term benefit,” Mr. Huynh said.
Cirrhosis Due to NASH
In a subgroup of 185 patients with type 2 diabetes and cirrhosis due to NASH (34% men and 72% women), the researchers found no statistically significant difference between the monotherapy and dual-therapy groups in either mortality or hepatic decompensation.
According to the research team, the positive impact on survival in patients undergoing dual therapy can be attributed to GLP1-RA’s effect on diabetes-associated comorbidities. “We know that GLP1-RAs are indicated for type 2 diabetes treatment if patients have an atherosclerotic cardiovascular history, such as prior stroke or myocardial infarction,” Mr. Huynh said.
“Our findings do need to be confirmed by prospective studies that include the use of a GLP1-RA in cirrhotic patients and other underrepresented groups,” Mr. Huynh added. But they “suggest a role for the use of GLP1-RA in the setting of type 2 diabetes and cirrhosis.”
Absence of FDA-Approved Medication for Cirrhosis
Mitchell Mah’moud, MD, a professor of medicine at Duke University School of Medicine, in Durham, N.C., called the researchers’ abstract an exciting piece of research with tremendous clinical application, especially in the absence of an FDA-approved medication for cirrhosis, with physicians having little to offer patients besides dietary and glycemic control.
“In patients with cirrhosis, there is an unmet and urgent need to avert decompensation, particularly those who may not be candidates for liver transplant,” he said. “Hence, this paper offers an encouraging opportunity to use a dual therapy of metformin and GLP1-RA to mitigate the disease progression to decompensated phase.”
Noting that cirrhosis is a dynamic state, Dr. Mah’moud speculated that the effectiveness of the GLP1-RA may be due to several factors, including its ability to increase fatty acid oxidation, decrease lipogenesis and improve hepatic glucose metabolism.
He also suggested that even though no large-scale studies have been conducted on dual therapy, the topic warrants a prospective study.
“It is possible that the dual therapy results in decreased hepatic steatosis and subsequent fibrogenesis, and thus reduced portal pressure,” he noted. “It would be interesting to identify patients at even higher risk for hepatic decompensation based on the liver or splenic stiffness measurements and offer them dual therapy at the time of the diagnosis.”
—Monica J. Smith
Mr. Huynh and Dr. Mah’moud reported no relevant financial disclosures.
This article is from the February 2023 print issue.