Glucagon-like peptide-1 receptor agonists, but not dipeptidyl peptidase-4 inhibitors, reduce alcohol intake.

Summary

Using a large VA cohort with propensity score matching and reverse translational rodent experiments, GLP-1 receptor agonists were associated with greater reductions in AUDIT-C drinking scores than both unexposed comparators and DPP-4 inhibitor recipients. In mice and alcohol-dependent rats, DPP-4 inhibitors did not reduce alcohol intake despite lowering glucose, confirming specificity. Findings support GLP-1RA repurposing for alcohol use disorder.

Key Findings

• GLP-1RA recipients had greater AUDIT-C score reductions than unexposed (DiD 0.09; 95% CI 0.03–0.14; P=0.0025) and DPP-4I recipients (DiD 0.11; 95% CI 0.05–0.17; P=0.0002).
• Effects were larger among individuals with baseline AUD and hazardous drinking (e.g., DiD up to 1.38 vs unexposed; P<0.0001).
• DPP-4 inhibitors showed no reduction in alcohol intake in humans and did not reduce drinking in mice or alcohol-dependent rats, despite lowering blood glucose.
• Reverse translational rodent studies confirmed target engagement for DPP-4Is (glucose lowering) but no effect on alcohol intake, underscoring pathway specificity.

Clinical Implications

Consider GLP-1RA therapy in patients with AUD (especially with comorbid T2DM/obesity) while awaiting RCTs; do not expect DPP-4 inhibitors to reduce alcohol consumption. Screening for AUD in patients started on GLP-1RAs may identify additional benefit.

Limitations

• Observational human data with potential residual confounding and reliance on self-reported AUDIT-C.
• Generalizability may be limited by the VA population; mechanisms within the GLP-1RA class and dose-response require RCTs.

Future Directions

Conduct randomized controlled trials testing specific GLP-1RAs for AUD, define mechanisms (central vs peripheral), and identify patient subgroups most likely to benefit.