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Semaglutide (Ozempic, Wegovy) may help reduce the risk of an opioid overdose in certain people, an emulation target trial suggested.

Over a 1-year follow-up, people with comorbid type 2 diabetes and opioid use disorder (OUD) who took the GLP-1 receptor agonist for their diabetes had a significantly lower risk of an opioid overdose compared with those taking other antidiabetic medications, found Rong Xu, PhD, of the Center for Artificial Intelligence in Drug Discovery in Cleveland, and colleagues.

This was the case when semaglutide was compared with virtually all other antidiabetic classes:

• Insulin (HR 0.42, 95% CI 0.29-0.60)
• Metformin (HR 0.46, 95% CI 0.31-0.68)
• DPP-4 inhibitors (HR 0.37, 95% CI 0.23-0.61)
• SGLT2 inhibitors (HR 0.58, 95% CI 0.38-0.87)
• Sulfonylureas (HR 0.49, 95% CI 0.31-0.78)
• Thiazolidinediones (HR 0.32, 95% CI 0.12-0.89)

These findings suggest that semaglutide holds "potential therapeutic value for preventing overdoses," Xu's group said in a research letter.

Also, semaglutide was associated with a significantly lower risk for opioid overdose when compared with other GLP-1 receptor agonists (HR 0.56, 95% CI 0.36-0.87). This was largely driven by its comparison with liraglutide (Victoza; HR 0.45, 95% CI 0.25-0.84). Another drug in the class, dulaglutide (Trulicity), was the only antidiabetic included in the analysis that semaglutide didn't outperform for opioid overdose risk reduction (HR 0.71, 95% CI 0.43-1.15).

The researchers cited a few anecdotal reports of semaglutide users reporting reduced drug cravings. Some studies have also suggested a benefit for people with and tobacco use disorder as well. "GLP-1 receptor agonists, used for type 2 diabetes and obesity, modulated dopamine reward signaling and decreased drug rewards, including heroin in rodents," they noted.

"This led us to investigate whether semaglutide could protect against overdoses in patients with OUD," they said. While medications exist for OUD, like buprenorphine and methadone, only around 25% of those with the condition receive recommended medications and about half discontinue treatment within 6 months.

"There is an urgency for alternative treatments for OUD," Xu's group underscored.

Injectable semaglutide (Ozempic) was first approved in 2017 for type 2 diabetes, followed by oral semaglutide (Rybelsus) in 2019.

In 2021, a higher-dose version (Wegovy) was approved for chronic weight management in adults with obesity or with overweight plus at least one weight-related condition, which was later expanded to include children ages 12 and up. The weight-loss formulation most recently landed approval as a preventive for major heart disease in people with overweight and a history of cardiovascular disease.

Xu and colleagues' cohort study included 33,006 patients: 3,034 prescribed semaglutide and 29,972 prescribed other antidiabetic medications between December 2017 (when semaglutide was first approved) and 2023. After propensity-score matching, the average age was 58 years, 55% were female, and over 60% were white.

Each comparison of the target trial was emulated using electronic health records from the TriNetX Analytics Platform, which includes deidentified data on 116.6 million U.S. patients.

All patients had diagnoses of both type 2 diabetes and OUD with a history of obesity, hypertension, hypercholesterolemia, hyperlipidemia, heart diseases, or stroke. Those with a history of bariatric surgery, pancreatitis, type 1 diabetes, thyroid cancer, or gastroparesis were excluded.

Xu's group pointed out the limitations that come with conducting an electronic health record-based observational study, such as potential confounding and biases. They suggested a randomized clinical trial to more fully assess semaglutide's potential benefit for OUD.

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