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

This study investigates whether glucagon-like peptide-1 receptor agonists (GLP-1RAs)—a class of medications widely used for type 2 diabetes and obesity—can be repurposed to treat alcohol use disorder (AUD). Additionally, the researchers examined whether dipeptidyl peptidase-4 inhibitors (DPP-4Is), which increase endogenous GLP-1 levels, share these potential anti-alcohol effects.

The researchers employed a two-pronged methodology. First, they conducted a large-scale pharmacoepidemiologic study using electronic health records from the U.S. Department of Veterans Affairs (2008–2023). They used propensity-score matching to compare changes in Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) scores among GLP-1RA recipients, DPP-4I recipients, and unexposed individuals. Second, they used a reverse translational approach, testing two DPP-4Is (linagliptin and omarigliptin) in mouse and rat models of alcohol consumption to see if these drugs could replicate the anti-alcohol effects previously observed with GLP-1RAs.

In the human cohort, GLP-1RA recipients showed a significantly greater reduction in AUDIT-C scores compared to both unexposed individuals and DPP-4I recipients. These reductions were most pronounced in individuals with baseline AUD or hazardous drinking patterns. Conversely, DPP-4I recipients showed no significant difference in alcohol consumption compared to unexposed individuals. The rodent experiments confirmed these findings: while the DPP-4Is successfully engaged their biological targets by lowering blood glucose, they failed to reduce alcohol intake in either mice or rats, regardless of whether the drugs could cross the blood-brain barrier.

These findings provide strong, convergent evidence that GLP-1RAs may be effective for treating AUD, while suggesting that simply increasing endogenous GLP-1 levels via DPP-4 inhibition is insufficient. This distinction is critical for clinicians and researchers, as it narrows the focus for future clinical trials and helps clarify the mechanisms—likely involving direct GLP-1 receptor activation—through which these medications influence addictive behaviors.