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GLP-1 Receptor Agonists and All-Cause Overdose Risk in Veterans With Type 2 Diabetes and Opioid Use Disorder
Kevin P Kennedy1,2,3, Ryan Bremseth-Vining1, Kevin G Lynch1,2
1VISN 4 Mental Illness Research, Education, and Clinical Center (MIRECC), Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania.
The Journal of Clinical Psychiatry
|July 20, 2026
Summary
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) show promise in reducing opioid overdoses among patients with type 2 diabetes. These findings suggest a potential role for GLP-1RAs in opioid use disorder treatment.
Area of Science:
- Pharmacology
- Public Health
- Addiction Medicine
Background:
- Opioid overdoses represent a significant public health crisis.
- Glucagon-like peptide-1 receptor agonists (GLP-1RAs) show preclinical promise for treating opioid use disorder (OUD).
- Observational data suggests GLP-1RAs may reduce opioid overdose risk, requiring further validation.
Purpose of the Study:
- To evaluate the association between GLP-1RAs (semaglutide, tirzepatide) and all-cause overdose risk in Veterans with type 2 diabetes and OUD.
- To compare overdose risk between GLP-1RA users and users of other common diabetes medications.
Main Methods:
- Target trial emulation study using Veterans Health Administration (VA) data.
- Inclusion of Veterans diagnosed with type 2 diabetes mellitus and OUD initiating semaglutide/tirzepatide or comparator diabetes medications (insulin, metformin, sulfonylurea, SGLT2 inhibitor, DPP4 inhibitor).
- Propensity score matching and Cox proportional hazards regression to analyze 12-month all-cause overdose events.
Main Results:
- Semaglutide and tirzepatide were associated with significantly lower overdose risk compared to insulin (HR=0.32) and SGLT2 inhibitors (HR=0.25).
- No significant difference in overdose risk was observed when compared to metformin, sulfonylureas, or DPP4 inhibitors.
- The study included substantial patient numbers for each comparison group post-matching.
Conclusions:
- GLP-1RAs (semaglutide, tirzepatide) are linked to reduced all-cause overdose risk versus insulin and SGLT2 inhibitors in a Veteran population.
- These findings support the potential utility of GLP-1RAs in managing OUD.
- Randomized controlled trials are necessary to confirm these associations and establish causality.
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