# GLP-1 Drugs and Overdose Risk: Five Comparators in VA Data | This GLP A VA target trial emulation found lower drug overdose risk on GLP-1 drugs against insulin (HR 0.32) and SGLT2 inhibitors, but not against metformin, sulfonylureas or DPP4 inhibitors. Publisher: This GLP Editorial Team Canonical: https://thisglp.com/research/overdose-depends-on-the-comparator Updated: 2026-09-18 Published: 2026-09-17 [← Research](https://thisglp.com/research) Evidence # GLP-1 Drugs and Overdose Risk: Five Comparators in VA Data The same GLP-1 drugs, the same veterans' database, the same twelve months, and five comparison groups that do not agree. One estimate points the other way. [This GLP Editorial Team](https://thisglp.com/about)September 20266 min readUpdated September 2026 Same drug, five comparison groups · 1.0 · vs insulin · vs SGLT2 · vs metformin · vs sulfonylurea · vs DPP4 **Research, not medical advice.** This GLP is independent and educational. Nothing here is a substitute for individualized care from a licensed clinician, and reading it creates no doctor–patient relationship. Talk to your own provider before starting, stopping, or changing any medication, peptide, or therapy. See our [methodology](https://thisglp.com/methodology) and [terms](https://thisglp.com/terms). ## Key takeaways - Veterans with type 2 diabetes and opioid use disorder were followed for 12 months after starting a GLP-1 drug or a comparison diabetes medication. - Against insulin, overdose risk was lower (HR 0.32, 95% CI 0.14-0.71). Against SGLT2 inhibitors, also lower (HR 0.25, 95% CI 0.09-0.68). - Against metformin (0.75), sulfonylureas (0.82) and DPP4 inhibitors (1.20), there was no significant difference — and the DPP4 estimate points the other way. - Insulin users are the sickest group in any diabetes cohort, so the two comparisons that worked are the two most vulnerable to confounding. Preclinical work suggested GLP-1 drugs might reduce opioid craving, and observational studies have reported fewer overdoses. A target trial emulation in Veterans Health Administration data tested it again in people carrying both type 2 diabetes and opioid use disorder, who started semaglutide or tirzepatide against one of five other diabetes medications between 2020 and 2024 [\[1\]](https://thisglp.com/research/overdose-depends-on-the-comparator#ref-1). The trial evidence in this area is covered separately in [the alcohol trials](https://thisglp.com/research/does-semaglutide-reduce-alcohol-use), which asked a related question with a randomized design. Against insulin, the hazard ratio for all-cause overdose over 12 months was 0.32 (95% CI 0.14–0.71). Against SGLT2 inhibitors it was 0.25 (95% CI 0.09–0.68). Both are large reductions and both are statistically significant. Against the other three comparators, nothing. Metformin gave 0.75 (95% CI 0.38–1.45), sulfonylureas 0.82 (95% CI 0.33–1.96), and DPP4 inhibitors 1.20 (95% CI 0.52–2.78), an estimate that sits on the wrong side of 1 entirely. Same drug, same outcome, same database, same 12 months. Which comparison a study picks decides what it finds Insulin is what people get when other drugs have failed or their diabetes is advanced, so insulin users are sicker on average than anyone else in a diabetes cohort. SGLT2 inhibitors sit closer to the middle. The two comparisons where the GLP-1 arm won are the two where the comparison group had most reason to fare badly for reasons unrelated to overdose, and propensity matching on recorded variables does not fix that. The intervals themselves say something worth noticing. An interval running from 0.09 to 0.68 is not a precise estimate; it is a small number of rare events in a matched set of a few hundred people. Overdose is uncommon even in this population, and the width of every interval in the study reflects that. The authors conclude by calling for randomized controlled trials, which is the correct reading of their own result, and puts them in the same position as the team in [the Crohn's disease cohort](https://thisglp.com/research/do-glp1-drugs-help-crohns-disease) who published a dramatic number and then told readers not to believe it. None of this makes the hypothesis wrong. A real effect on craving could plausibly show up first against the comparators with the most room to move, and two of five estimates landing below 1 with three inconclusive is not evidence of absence. It is evidence that the question is still open, and that a headline built from the insulin comparison alone would be describing a choice of control group rather than a property of the drug. The same reasoning applies whenever a study picks its own comparator, as in [the tirzepatide network comparison](https://thisglp.com/research/is-tirzepatide-better-than-dulaglutide) and in [the carpal tunnel cohort](https://thisglp.com/research/do-glp1-drugs-help-carpal-tunnel-syndrome), where two comparison groups gave two different answers about the same drug. ## Frequently asked Do GLP-1 drugs reduce overdose risk? This study cannot settle that. Risk was lower against insulin and SGLT2 inhibitors but not against metformin, sulfonylureas or DPP4 inhibitors, and the authors call for randomized trials. Why does the comparison drug matter so much? Insulin is prescribed when diabetes is advanced or other drugs have failed, so insulin users are sicker on average. A comparison group with more underlying risk makes any drug look better. Were these large studies? No. The matched sets ranged from a few hundred to about a thousand people and overdose is rare, which is why the confidence intervals are wide — one runs from 0.09 to 0.68. ## Sources 1. \[1\] Kennedy KP, Bremseth-Vining R, Lynch KG, Reville N, et al. (2026). GLP-1 Receptor Agonists and All-Cause Overdose Risk in Veterans With Type 2 Diabetes and Opioid Use Disorder The Journal of Clinical Psychiatry. [PMID 42474323](https://pubmed.ncbi.nlm.nih.gov/42474323/) ## Where to get it ### Best GLP-1 injections Every injectable seller we can verify, with the price each one publishes and an honest read of what the trials measured. [Compare providers →](https://thisglp.com/best/compounded-semaglutide) ## More in Evidence - [ 150 minutes · Weekly activity goal · 2 days · Muscle strengthening · Adapt · Symptoms and ability ### Exercise on Ozempic: Building Strength Without Ignoring Symptoms ](https://thisglp.com/research/exercise-on-ozempic) - [ STEP 1, semaglutide 2.4 mg vs placebo, % change at 68 weeks · LDL cholesterol · −2.5% vs +1.3% · Total cholesterol · −3.3% vs +0.1% · HDL cholesterol · +5.2% vs +1.4% · Triglycerides · −21.9% vs −7.3% · Wegovy label, Table 13. Adults without diabetes. Ozempic doses are lower. ### Does Ozempic Lower Cholesterol? 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