Importance: Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasing cause of cirrhosis. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are effective in improving liver inflammation in patients with MASLD.

Objective: To determine whether use of GLP-1 RAs is associated with lower risk of developing cirrhosis and its complications, including decompensation and hepatocellular cancer (HCC), among patients with MASLD.

Design, setting, and participants: This retrospective cohort study with an active comparator, new-user design used data from the national Veterans Health Administration Corporate Data Warehouse and Central Cancer Registry. Patients with MASLD and diabetes who were seen at 130 Veterans Health Administration hospitals and associated ambulatory clinics and who initiated either a GLP-1 RA or dipeptidyl peptidase 4 inhibitor (DPP-4i) between January 1, 2006, and June 30, 2022, were included. Patients were followed up from baseline until one of the study outcomes or the end of the study period (December 31, 2022), whichever came first.

Exposures: Each GLP-1 RA new user was propensity score matched in 1:1 ratio to a patient who initiated a DPP-4i during the same month. Separate analyses were conducted among patients without and with cirrhosis at baseline.

Main outcomes and measures: For patients without cirrhosis, the primary outcome was progression to cirrhosis defined by validated diagnoses codes or a noninvasive marker of liver fibrosis, and secondary outcomes were cirrhosis complications defined both as a composite and individual complications, including decompensation, HCC, or liver transplant, and all-cause mortality. For patients with cirrhosis, the primary outcome was a composite outcome of cirrhosis complications, and secondary outcomes were decompensation, HCC, and all-cause mortality.

Results: Of 16 058 patients who initiated GLP-1 RAs, 14 606 did not have cirrhosis (mean [SD] age, 60.56 [10.31] years; 13 015 [89.1%] male), and 1452 had cirrhosis (mean [SD] age, 66.99 [7.09] years; 1360 [93.7%] male) at baseline. These patients were matched to an equal number of patients who initiated a DPP-4i. In patients without cirrhosis, GLP-1 RA use, compared with DPP-4i use, was associated with a lower risk of cirrhosis (9.98 vs 11.10 events per 1000 person-years; hazard ratio [HR], 0.86; 95% CI, 0.75-0.98). Similar results were seen for the secondary outcomes. GLP-1 RA use, compared with DPP-4i use, was associated with 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). There were no associations between GLP-1 RA use and outcomes in patients with cirrhosis.

Conclusions and relevance: In this cohort study, GLP-1 RA use was associated with a lower risk of progression to cirrhosis and mortality among patients with MASLD and diabetes. The protective association was not seen in patients with existing cirrhosis, underscoring the importance of treatment earlier in the disease course.