GLP-1 Therapies Reduce Risk of Cirrhosis, Complications of MASLD

The use of glucagon-like peptide-1 (GLP-1) receptor agonists—in particular, semaglutide—may be associated with a lower risk of progression to cirrhosis and other complications of metabolic dysfunction-associated steatotic liver disease (MASLD), according to research results published in JAMA Internal Medicine.¹

In a retrospective cohort study, investigators sought to determine if the use of GLP-1 receptor agonists leads to a lower risk of developing cirrhosis and related complications—such as decompensation and/or hepatocellular cancer—in patients with MASLD. Using data from Veterans Health Administration hospitals and ambulator care clinics, researchers identified a cohort of adults diagnosed with MASLD and T2D who initiated either a GLP-1 receptor agonist or a dipeptidyl peptidase-4 inhibitor (DPP-4i) between 2006 and 2022. Eligible patients who initiated GLP-1 therapy were propensity score matched 1:1 with eligible patients who initiated a DPP-4i within the same year and calendar month.

The primary study outcome was progression to cirrhosis; secondary outcomes included cirrhosis complications, including decompensation, hepatocellular carcinoma, or liver transplant, and all-cause mortality. For patients with cirrhosis, the primary outcome was a composite outcome of cirrhosis complications, with secondary outcomes including decompensation, hepatocellular carcinoma, and all-cause mortality.

Investigators identified a total of 16,058 patients who initiated GLP-1 receptor agonist therapy, 14,606 of whom did not have cirrhosis (cirrhosis n=1452) at baseline. Mean age of those in the GLP-1 group was 60.47±10.31 years (89.1% men); patients were receiving care for a mean of 10.80±5.52 years before baseline, and were prescribed treatment at a mean of 7.93±4.46 years after MASLD diagnosis. Those who had cirrhosis were older and were receiving care longer than those without cirrhosis.

The majority of patients were prescribed semaglutide (75.6%), followed by liraglutide (33.7%), dulaglutide (27.7%), and exenatide (6.6%). During the course of the study, 55.1% of patients switched from one GLP-1 therapy to another. Mean duration of treatment with a GLP-1 agonist was 3.20±2.19 and 2.96±1.87 years in patients with and without cirrhosis, respectively; in the non-cirrhosis group, 31.2% of patients switched from a DPP-4i to a GLP-1 therapy, while only 6.6% of GLP-1 patients switched to a DPP-4i therapy during the follow-up period.

READ MORE: Semaglutide Reduces Weight, Truncal Fat in Patients with MASLD

Among patients without cirrhosis, the use of GLP-1 receptor agonist therapy was associated with a 14% lower risk of cirrhosis vs the DPP-4i group (9.98 vs 11.10 events per 1000 person-years; HR, 0.86; 95% CI, 0.75-0.98). Risk of the composite secondary outcome was 22% lower in the GLP-1 group vs the DPP-4i group (1.89 vs 2.55 events per 1000 person-years), and GLP-1 use was associated with a 30% lower risk of cirrhosis decompensation vs DPP-4is (1.80 vs 2.26 events per 1000 person-years) and an 11% lower risk of all-cause mortality (21.77 vs 24.43 events per 1000 person-years); risk of developing hepatocellular carcinoma was also slightly lower (0.24 vs 0.27 events per 1000 person-years).

Following stratification by specific GLP-1 therapy, semaglutide was associated with lower hazard ratios for progression to cirrhosis, with no association between the use of dulaglutide or liraglutide and MASLD. No statistically significant interactions by age, sex, body mass index, diabetes complications, or FIB-4 score were noted.

Among patients with cirrhosis, there was no statistically significant difference in the risk of developing cirrhosis complications between the GLP-1 and DPP-4i groups (18.64 vs 15.31 events per 1000 person years). Findings were similar for decompensated cirrhosis, hepatocellular carcinoma, and risk of all-cause mortality (14.45 vs 13.32 events, 5.32 vs 3.20 events, and 54.75 vs 61.91 events per 1000 person-years, respectively).

Several study limitations were noted, including the potential for unmeasured confounding; the definition of MASLD that was applied, which may limit generalizability; and imprecise estimates of some outcomes, such as hepatocellular carcinoma, due to a low absolute risk of these outcomes.

“These results support the need for long-term randomized clinical trials to test the benefits of GLP-1 [receptor agonist] use for primary prevention of cirrhosis in patients with MASLD,” the researchers concluded. “While cirrhosis is a clear risk factor for [hepatocellular carcinoma] and reducing cirrhosis by GLP-1 RA use should prevent [hepatocellular carcinoma], an independent confirmation of this relationship requires even larger studies.”

READ MORE: Digestive Health Resource Center

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Reference

1. Kanwal F, Kramer JR, Li L, et al. GLP-1 receptor agonists and risk for cirrhosis and related complications in patients with metabolic dysfunction-associated steatotic liver disease. JAMA Intern Med. Published online September 16, 2024. doi:10.1001/jamainternmed.2024.4661