Adults who smoked daily and received semaglutide had greater reductions in nicotine craving and body weight than those who received placebo, although the glucagon-like peptide-1 receptor agonist did not significantly reduce cigarettes smoked per day or improve the trial’s co-primary laboratory smoking outcomes.
In the phase 2a randomized clinical trial, researchers enrolled 24 non–treatment-seeking adults who smoked at least 5 cigarettes daily and randomly assigned them to once-weekly semaglutide or placebo for 9 weeks. Participants completed laboratory smoking sessions before treatment and again after 8 weeks of therapy.
Semaglutide dosing escalated from 0.25 mg weekly during weeks 1 to 4 to 0.5 mg weekly during weeks 5 to 8. A 1.0-mg dose was administered during week 9 when tolerated. Participants smoked about 15 cigarettes daily at baseline, and 83% were women.
The co-primary outcomes were laboratory measures of smoking resistance, defined as delay time before smoking, and cigarette self-administration during a laboratory session. Researchers also evaluated weekly cigarette consumption, nicotine craving, withdrawal symptoms, body weight, and hemoglobin A1c levels.
Prespecified analyses showed no statistically significant differences between groups in smoking resistance or laboratory cigarette consumption. Cigarettes smoked per day also declined over time in both groups without a statistically significant between-group difference.
However, semaglutide was associated with greater reductions in weekly nicotine craving compared with placebo in the trial’s preplanned mixed-model analysis.
Because the trial randomized fewer participants than originally planned, the researchers also used change-score analyses to assess baseline-to-posttreatment changes; in those analyses, semaglutide-treated participants showed larger reductions in laboratory cigarette consumption following treatment. The study was originally powered for 36 participants but randomized 24 because of budgetary and logistical constraints. Twenty-one participants completed the primary outcome assessment.
Participants who received semaglutide lost about 5% of body weight through week 10, whereas participants who received placebo had a small weight increase. Semaglutide-treated participants also had lower hemoglobin A1c levels during treatment.
Exploratory analyses suggested larger reductions in withdrawal symptoms among semaglutide-treated participants, particularly on craving and hunger subscales; the researchers noted that the withdrawal finding was unexpected because participants were not attempting to quit or reduce smoking. Researchers also observed relative increases in smoking abstinence self-efficacy and readiness to quit during the second month of treatment, although the study was not powered to evaluate those outcomes definitively.
Most adverse events were mild, including expected gastrointestinal effects. One participant in the semaglutide group discontinued treatment because of adverse events.
Researchers said the findings should be interpreted cautiously because the single-center study was small, short in duration, and tested relatively low semaglutide doses compared with those commonly used for obesity management. Most participants received treatment primarily in the 0.25-mg to 0.5-mg range, with limited exposure to the 1.0-mg dose. Participants also were not attempting smoking cessation and did not receive nicotine replacement therapy or counseling, limiting generalizability to patients actively trying to quit smoking. The predominantly female sample with obesity-range mean body mass index further limits applicability to smokers broadly.
“In this phase 2a randomized clinical trial of non–treatment-seeking people who smoke, semaglutide monotherapy did not significantly improve laboratory smoking reinstatement or reduce weekly [cigarettes per day] but led to greater reductions in laboratory cigarette intake and reduced weekly nicotine craving, also reducing body weight and HbA1c,” wrote Christian S. Hendershot, PhD, of the Keck School of Medicine of the University of Southern California, and colleagues.
Disclosures: Researchers reported relationships with Eli Lilly, Apollo Therapeutics, Elsevier, Novo Nordisk, Roche, Bayer, Antag Therapeutics, Boehringer Ingelheim, Carmot, Diasome, Gentibio, Rhythm, and vTv Therapeutics outside the submitted work. The study was funded by the National Institute on Drug Abuse, and the funders had no role in study design, analysis, or manuscript preparation.
Source: JAMA Network Open
