Association of GLP-1 Receptor Agonists With Hepatic Decompensation in the All of Us Research Program

To evaluate the association between glucagon-like peptide-1 receptor agonist (GLP-1RA) initiation and the risk of hepatic decompensation compared with dipeptidyl peptidase 4 inhibitors (DPP4is) in a racially and ethnically diverse cohort of adults with Type 2 diabetes.

This retrospective active-comparator new-user cohort study utilised data from the National Institutes of Health's All of Us Research Program. Adult participants with Type 2 diabetes initiating GLP-1RAs or DPP4is without prior hepatic decompensation or competing causes of chronic liver disease were identified. Stratified propensity score matching (1:1) was employed to balance baseline covariates. The primary outcome was a composite of hepatic decompensation events (oesophageal varices with bleeding, ascites, hepatic encephalopathy, hepatic failure, or liver transplantation). Hazard ratios (HRs) were estimated using Cox proportional hazards regression.

The matched cohort included 7854 participants (mean age 57.3 years; 58.8% female; 24.8% Black or African American). GLP-1RA use was associated with a significantly reduced risk of hepatic decompensation compared with DPP4i use (HR 0.67; 95% CI 0.47-0.95; p = 0.026), corresponding to an absolute rate difference of -1.66 events per 1000 person-years. Estimates were directionally similar in prespecified sensitivity analyses.

In this diverse nationwide cohort, initiation of GLP-1RAs was associated with a significantly reduced risk of hepatic decompensation compared with DPP4is. These findings extend prior evidence by demonstrating this association in a cohort enriched for populations historically underrepresented in biomedical research.