The Journal of clinical psychiatryJul 20, 2026

GLP-1 Receptor Agonists and Risk of Any Overdose in Veterans with Type 2 Diabetes and Opioid Use Disorder

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 21, 2026

Abstract

Semaglutide and tirzepatide are associated with a significantly lower risk of all-cause overdose compared to insulin and SGLT2 inhibitors.

In a study involving Veterans with type 2 diabetes and opioid use disorder, semaglutide and tirzepatide showed a hazard ratio of 0.32 for overdose compared to insulin.
When compared to SGLT2 inhibitors, semaglutide and tirzepatide had a hazard ratio of 0.25 for all-cause overdose.
No significant differences in overdose risk were observed when comparing semaglutide and tirzepatide to metformin, sulfonylureas, or DPP4 inhibitors.
The findings highlight a potential role for GLP-1 receptor agonists in managing opioid use disorder but indicate the need for further randomized controlled trials.

Simplified

Objective: Overdoses remain a major public health challenge. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been proposed as a treatment for opioid use disorder (OUD) based on preclinical research. Early observational research suggests that GLP-1RAs are associated with reduced opioid overdoses but warrants replication in different patient populations. Methods: This target trial emulation study used Veterans Health Administration (VA) data to include Veterans with a diagnosis of type 2 diabetes mellitus and OUD who initiated semaglutide and tirzepatide or a comparison diabetes medication (insulin, metformin, a sulfonylurea, a sodium-glucose transport 2 (SGLT2) inhibitor, or a dipeptidyl-peptidase 4 [DPP4] inhibitor) between January 1, 2020, and December 31, 2024. Each set of comparison groups was propensity score matched on relevant variables. Cox proportional hazards regression models were used to compare the time to all-cause overdose events in the 12 months after medication initiation. Results: After propensity score matching, semaglutide and tirzepatide were associated with significantly lower risk of all-cause overdose compared to insulin (hazard ratio [HR]=0.32; 95% CI=0.14-0.71; P=.006; n=630) and SGLT2 inhibitors (HR=0.25; 95% CI=0.09-0.68; P=.006; n=432). Semaglutide and tirzepatide were not associated with significantly lower risks than metformin (HR=0.75; 95% CI=0.38-1.45; n=1,016), sulfonylureas (HR=0.82; 95% CI=0.33-1.96; n=710), or DPP4 inhibitors (HR=1.20; 95% CI=0.52-2.78; n=858). Conclusion: Collectively, semaglutide and tirzepatide were associated with lower risk of all-cause overdose compared to insulin and SGLT2 inhibitors, but not metformin, sulfonylureas, or DPP4 inhibitors. These results suggest the possible role of GLP-1RAs in OUD but underscore the need for randomized controlled trials.

Funding

Competing interests

Relevant Financial Relationships: Mr Reville is Executive Director of CASPR, which provided funding for this research. All other authors report no financial or other relationship relevant to the subject of this article. Drs Kennedy, Zhang, and Oslin and Mr Bremseth-Vining are salaried employees of the US Department of Veterans Affairs.

PubMed

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GLP-1 Receptor Agonists and Risk of Any Overdose in Veterans with Type 2 Diabetes and Opioid Use Disorder

Abstract

Funding

Competing interests

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