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Treatment with glucagon-like peptide-1 (GLP-1) receptor agonists may reduce the risk of developing cirrhosis, liver cancer, and other adverse liver outcomes in adults with type 2 diabetes and chronic liver disease, new research suggested.

Using an emulated target trial design, researchers observed a 49% lower 10-year risk for major adverse liver outcomes (MALO) in patients with any chronic liver disease and type 2 diabetes who initiated a GLP-1 agonist and adhered to treatment, compared with peers who did not initiate GLP-1 therapy.

"Our results give some support to the hypothesis that GLP-1 agonists could be a treatment option" to reduce the risk for MALO in this patient population, first author Axel Wester, MD, PhD, Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden, told Medscape Medical News.

"Randomized trials have so far only assessed histological outcomes (surrogate markers of liver outcomes), but we were able to investigate hard clinical outcomes in our study, which is a strength. It is, however, difficult to draw strong conclusions from a single study," Wester cautioned.

The study was published online in Gut.

Mixed Findings

The researchers emulated a nationwide target trial to estimate the long-term impact of GLP-1 agonist therapy on MALO in adult patients with any chronic liver disease and type 2 diabetes using observational data from Swedish healthcare registries from 2010 to 2020. They included 1026 GLP-1 initiators and 15,633 non-initiators.

In the intention-to-treat analysis, the 10-year risk for MALO was 13.3% in initiators vs 14.6% in non-initiators (risk ratio [RR], 0.91). These estimates were "imprecise" with a 95% CI for the RR ranging from 0.50 to 1.32, the authors noted.

In the corresponding per-protocol analysis, the risk for MALO at 10 years was 7.4% and 14.4%, respectively, yielding an RR of 0.51. The per-protocol risk estimates at 6 years were 5.4% and 9% (RR, 0.60), and at 8 years were 7.2% and 11.7% (RR, 0.61).

Wester and colleagues noted that their findings do not support a protective effect of GLP-1 agonists in the subgroup with compensated cirrhosis — in line with a recent phase 2 trial in patients with metabolic dysfunction-associated steatohepatitis (MASH)-related compensated cirrhosis, as reported by Medscape Medical News.

A limitation of the study is a lack of data on fibrosis stage, beyond classifying patients as cirrhotic (F4) or non-cirrhotic (F0-F3). The researchers also had no laboratory data, such as glycated hemoglobin, to assess diabetes severity and the need for escalating to second-line treatment with GLP-1 agonists.

Promising but Preliminary

There currently are no drugs approved in the United States for metabolic dysfunction-associated steatotic liver disease (MASLD), so GLP-1 agonists represent "a promising drug class," Jamile Wakim-Fleming, MD, who directs the Center for Metabolic Steatosis of the Liver at the Cleveland Clinic, Cleveland, Ohio, told Medscape Medical News.

While results comparing MALO between the groups were "favorable among initiators of GLP-1 receptor agonists, these drugs were not protective in the intention-to-treat analysis, leading to my opinion that longitudinal randomized controlled studies are needed in order to draw a firm conclusion regarding adverse liver-related outcomes in individuals who take GLP-1 receptor agonists," said Wakim-Fleming, who was not involved in the current study.

Phase 2 studies suggest GLP-1 agonists resolve MASH in patients with MASLD but do not cause fibrosis regression, she noted.

"Large phase 3 trials that aim to estimate the effect of GLP-1 agonists on resolving MASH or reducing hepatic fibrosis, cirrhosis, and its complications are underway," Wakim-Fleming said.

Along with phase 3 trials, large observational studies using appropriate methodology could further delineate the effect of GLP1 agonists on the risk for MALO, the study authors wrote.

The study had no commercial funding. Wester and Wakim-Fleming had no relevant disclosures.