Glucagon-like peptide-1 (GLP-1) receptor agonists, especially semaglutide, may significantly lower the risk of developing cirrhosis and its complications in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). This is according to a retrospective cohort study published in JAMA Internal Medicine.
The study, utilizing data from Veterans Health Administration hospitals and ambulatory care clinics, examined over 16,000 adults diagnosed with MASLD and type 2 diabetes who initiated either a GLP-1 receptor agonist or a dipeptidyl peptidase-4 inhibitor (DPP-4i) between 2006 and 2022. The primary outcome was progression to cirrhosis, while secondary outcomes included cirrhosis complications such as decompensation, hepatocellular carcinoma, or liver transplant, and all-cause mortality.
Impact on Cirrhosis Progression
In patients without cirrhosis at baseline, GLP-1 receptor agonist therapy was associated with a 14% reduced risk of progressing to cirrhosis compared to DPP-4i therapy (HR, 0.86; 95% CI, 0.75-0.98). Specifically, 9.98 events per 1000 person-years were observed in the GLP-1 group versus 11.10 events in the DPP-4i group. The risk of the composite secondary outcome was also 22% lower in the GLP-1 group (1.89 vs 2.55 events per 1000 person-years).
Reduction in Cirrhosis Complications and Mortality
GLP-1 use was linked to a 30% lower risk of cirrhosis decompensation (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) compared to DPP-4is. The risk of developing hepatocellular carcinoma was slightly lower as well (0.24 vs 0.27 events per 1000 person-years).
Specific GLP-1 Therapies
Stratification by specific GLP-1 therapy revealed that semaglutide was associated with lower hazard ratios for progression to cirrhosis. However, no significant association was found between dulaglutide or liraglutide and MASLD progression. There were no statistically significant interactions noted by age, sex, body mass index, diabetes complications, or FIB-4 score.
Findings in Patients with Existing Cirrhosis
Among patients who already had cirrhosis at the beginning of the study, 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). Similar results were observed for decompensated cirrhosis, hepatocellular carcinoma, and all-cause mortality.
Study Limitations and Future Directions
The study acknowledges several limitations, including the potential for unmeasured confounding, the applied definition of MASLD which may limit generalizability, and imprecise estimates for some outcomes like hepatocellular carcinoma due to their low absolute risk. The researchers emphasized the need for long-term randomized clinical trials to validate the benefits of GLP-1 receptor agonists for primary prevention of cirrhosis in MASLD patients. They stated that while reducing cirrhosis with GLP-1 RAs should prevent hepatocellular carcinoma, independent confirmation requires larger studies.
