GLP-1 RA Linked to Lower Risk of Cirrhosis Development in Patients with MASLD

A recent study linked glucagon-like peptide 1 receptor agonist (GLP-1 RA) use to a reduced risk of cirrhosis development among patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and diabetes.¹

“…we observed protective associations between GLP-1 RA use and subsequent development of cirrhosis, cirrhosis complications, and overall mortality,” wrote investigators, led by Fasiha Kanwal, MD, MSHS, from the section of gastroenterology and hepatology at Baylor College of Medicine in Houston. “This chemopreventive activity became apparent 18 to 24 months after treatment initiation and increased over time.”

MASLD is the fastest-growing cause of cirrhosis, and this end-stage of chronic liver disease increases the risk of hepatocellular carcinoma. Studies have shown antiviral treatments can significantly reduce cirrhosis-related complications of chronic viral hepatitis, but they do not show the same benefit for patients with MASLD. Evidence supporting chemoprevention of cirrhosis in patients with MASLD remains limited.

GLP-1 RA, a treatment for diabetes and obesity, presents a potential chemopreventive option for MASLD. Medications in this class reduce body weight, glycemia, and inflammation, possibly lowering the risk of MASLD progression.

Research has supported the effectiveness of GLP-1 RAs in improving liver inflammation in patients with MASLD.² In this study, investigators sought to determine whether GLP-1 RAs use is linked to a lower risk of cirrhosis development and its complications, such as decompensation and hepatocellular cancer, among patients with MASLD.¹

The retrospective cohort study leveraged national Veterans Health Administration Corporate Data Warehouse and Central Cancer Registry data. The study included patients with MASLD and diabetes who initiated either a GLP-1 RA or dipeptidyl peptidase 4 inhibitor between January 1, 2006, and June 30, 2022, at 130 Veterans Health Administration hospitals and associated ambulatory clinics. Participants were followed up from baseline until either they reached a study outcome or the end of the study period (December 31, 2022), whichever came first.

Among the 16,058 patients who initiated GLP-1 RAs, 14,606 did not have cirrhosis (mean age, 60.56 years; 89.1% male), and 1452 had cirrhosis (mean age, 66.99 years; 93.7% male). GLP-1 RA new users were 1:1 propensity score matched to a patient who initiated a DDP-4i during the same month.

The primary outcome for patients without cirrhosis was progression to cirrhosis defined by validated diagnosis codes or a noninvasive marker of liver fibrosis. Secondary outcomes included cirrhosis complications, such as decompensation, HCC, liver transplant, and all-cause mortality. For patients with cirrhosis, the primary outcome was a composite outcome of cirrhosis complications, and secondary outcomes were examined for decompensation, HCC, and all-cause mortality.

Among patients without cirrhosis, GLP-1 RA use, compared with DPP-4i use, was linked to a lower cirrhosis risk (9.98 vs 11.10 events per 1000 person-years; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75 – 0.98). Investigators observed similar results with secondary outcomes, with GLP-1 RA use linked to a lower risk of the composite outcome of cirrhosis complications (1.89 vs 2.55 events per 1000 person-years; HR, 0.78; 95% CI,0.59 – 1.04) and mortality (21.77 vs 24.43 events per 1000 person-years; HR, 0.89; 95% CI, 0.81-0.98).

“Notably, the reduction in mortality associated with GLP-1 RA use (2.66 events per 1000 person-years) exceeded the association with cirrhosis prevention (1.12 events per 1000 person-years),” investigators wrote. “The present data suggest that among patients with MASLD, GLP-1 RAs may offer other survival benefits than those conferred by slowing the risk of liver disease progression.”

As for patients with cirrhosis, the study found no association between GLP-1 RA use and primary or secondary outcomes.

“…there was limited benefit in patients with established cirrhosis,” investigators explained. “These data highlight the potential consequences of delaying treatment—either by lack of access or by patient or health care professional choice—on subsequent risk of cirrhosis complications."

Investigators wrote the study was limited by potential unmeasured confounding, misclassification, no validated definition for decompensated cirrhosis, the MASLD definition relying on ≥ 2 elevated ALT levels which may limit the generalizability of the sample, and the absolute risk of some outcomes, such as HCC, was low. Other limitations mentioned included the short follow-up period and the sample including mostly male patients.

“While cirrhosis is a clear risk factor for HCC and reducing cirrhosis by GLP-1RAuse should prevent HCC, an independent confirmation of this relationship requires even larger studies than this one,” investigators concluded. “In the meantime, the presence of MASLD can help with the prioritization of GLP-1RA therapy in persons with diabetes.”

References

1. ^{Kanwal, F, Kramer, J, Li, L, et al. GLP-1Receptor Agonists and Risk for Cirrhosis and Related Complications in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease. JAMA Intern Med. doi:10.1001/jamainternmed.2024.4661. Published online September 16, 2024.}
2. ^{Wester A, Shang Y, Toresson Grip E, Matthews AA, HagströmH. Glucagon-likepeptide-1 receptor agonists and risk of major adverse liver outcomes in patients with chronic liver disease and type 2 diabetes. Gut. 2024;73 (5):835-843. doi:10.1136/gutjnl-2023-330962}