Semaglutide May Ease Tobacco Use, Study Suggests

Among patients with type 2 diabetes and tobacco use disorder (TUD), results from a real-world study suggest new users of semaglutide (Ozempic; Novo Nordisk) could require fewer healthcare resources to treat their addiction than those on other antidiabetic medications.

This, according to researchers led by William Wang (Case Western Reserve University School of Medicine, Cleveland OH), points to a possible additional benefit of the already-popular drug.

Use of the glucagon-like peptide-1 (GLP-1) receptor agonist was associated with fewer medical encounters related to a TUD diagnosis and prescriptions for smoking-cessation medications, even when compared against other GLP-1 receptor agonists in a target trial emulation using a large number of electronic health records (EHRs).

For most comparisons, the differences emerged within 30 days of starting treatment, with findings that were generally similar irrespective of obesity status, the investigators report in a study published online this week in Annals of Internal Medicine.

The findings are consistent with both anecdotal reports that users of semaglutide have a decreased desire to smoke tobacco and preclinical research indicating that GLP-1 receptor agonism has that effect, senior author Rong Xu, PhD (Case Western Reserve University School of Medicine), told TCTMD. She noted, too, that prior work by her group has yielded similar findings when examining semaglutide use and cannabis and alcohol use disorders.

These results, however, do not support off-label use of semaglutide—which has indications for the treatment of type 2 diabetes and obesity and for a reduction in cardiovascular events—for the purpose of smoking cessation, the researchers say.

“This is an observational study, and we cannot use these findings to justify any clinical practice changes, which will require randomized clinical trials, but our study supports future randomized clinical trials,” Xu said. And taken together with their previous studies, she added, “this gives us more confidence that semaglutide could represent a new type of treatment for addiction.”

Commenting for TCTMD via email, Bettina Winzeler, MD (University Hospital Basel, Switzerland), said that even though the study suggests semaglutide may influence smoking behavior, the main limitation is that “we do not know whether ‘less encounters’ also means ‘less smoking or more successful smoking cessation.’”

Agreeing with Xu, she indicated that a randomized trial would be needed to provide a definitive answer. She noted that two RCTs exploring the impact of GLP-1 receptor agonism and smoking cessation have been published previously: a pilot study that yielded positive results with exenatide and a larger trial that failed to establish a benefit with dulaglutide.

Winzeler, who was the senior author of the latter study, said it could be that semaglutide is more potent than dulaglutide, “which as a larger molecule may have limited blood brain barrier permeability and a lower central effect on reward.” In addition, she said, the dulaglutide trial had “a very high abstinence rate in the placebo group, which may have masked the dulaglutide effect.”

Differences vs Several Other Types of Drugs

The investigators performed a target trial emulation using data from the TriNetX Analytics platform, which contains EHRs from about 113 million patients cared for at 64 large healthcare organizations. The analysis included data spanning December 2017 and March 2023 on patients with type 2 diabetes and TUD, including 5,967 new users of semaglutide and 216,975 new users of other classes of antidiabetes medications—insulins, metformin, dipeptidyl-peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors, sulfonylureas, thiazolidinediones, and other GLP-1 receptor agonists.

After propensity-score matching, there were 5,954 patients prescribed semaglutide and an equal number prescribed the other medications (mean age 59; 51% women).

Semaglutide was associated with a significantly lower risk for medical encounters related to the TUD diagnosis through 1 year of follow-up compared with all the other classes of medications, with the strongest relationship seen versus insulins (HR 0.68; 95% CI 0.63-0.74) and the weakest versus other GLP-1 receptor agonists (HR 0.88; 95% CI 0.81-0.96). The findings were generally consistent in patients with or without obesity, although the comparison with other GLP-1 receptor agonists was not significant in patients without obesity.

Semaglutide also was associated with significantly fewer prescriptions for smoking-cessation medications, again with the strongest relationship seen when compared against insulins (HR 0.32; 95% CI 0.28-0.38) and the weakest versus other GLP-1 receptor agonists (HR 0.62; 95% CI 0.52-0.74). Obesity status did not influence the findings.

The likelihood of counseling for smoking cessation was significantly lower with semaglutide only when compared with insulins, metformin, and DPP-4 inhibitors.

“The lower risks for TUD-related measures at follow-up for patients who were prescribed semaglutide are consistent with preclinical and preliminary clinical evidence in support of its potential beneficial effects as well as that of other GLP-1 receptor agonist medications for the treatment of TUD,” Wang et al write.

No Direct Clinical Implications—Yet

As for a potential mechanism to explain the findings, Xu pointed to preclinical data suggesting that GLP-1 receptor agonism likely affects the dopamine reward system in the brain. That system, she noted, “is involved in addiction in general, not just specifically nicotine addiction.”

She and her colleagues call for confirmation of the findings in future trials, acknowledging that these observational results are subject to several limitations, including documentation bias, residual confounding, and missing data on current smoking behavior, TUD severity, body mass index, and adherence to medications.

They note, too, that even though “a reduction in TUD-related encounters could potentially suggest a reduction in tobacco use or relapse,” this difference “could also reflect other scenarios, such as a reduced willingness to seek help to quit smoking.”

For Winzeler, the study “emphasizes that semaglutide (and other GLP-1 receptor agonists) could be a very interesting therapy for smoking cessation, that further research in this direction is worthwhile, and that—despite our negative results—further and larger RCTs should be conducted (especially with semaglutide, which is the most interesting candidate from all GLP-1 receptor agonists).”

She added, “Unfortunately, the results do not (yet) have direct clinical implications.”