IMPORTANCE: People who smoke cigarettes face increased risk of morbidity and mortality, in part due to elevated rates of cardiometabolic disease. Preclinical and early clinical data indicate that glucagon-like peptide-1 receptor agonists (GLP-1RAs) warrant consideration for smoking cessation and prevention of associated cardiometabolic risks.
OBJECTIVE: To evaluate the effects of semaglutide vs placebo on cigarette smoking, craving, and weight outcomes in people who smoke.
DESIGN, SETTING, AND PARTICIPANTS: This parallel-arm phase 2a randomized clinical trial with embedded human laboratory sessions was conducted at an academic medical center, with enrollment occurring from October 2022 to April 2024. Participants were non-treatment-seeking adults consuming at least 5 cigarettes per day. Data were analyzed in 2025.
INTERVENTION: Nine weeks of subcutaneous of semaglutide (0.25 mg for 4 weeks, 0.5 mg for 4 weeks, 1.0 mg for 1 week) vs placebo.
MAIN OUTCOMES AND MEASURES: The co-primary outcomes were laboratory measures of smoking resistance and reinstatement and self-administration, assessed before and after treatment. Changes in cigarette use, cigarette craving, body weight, and other outcomes were assessed weekly.
RESULTS: Of 45 participants enrolled, 24 participants (mean [SD] age, 44 [12] years; 20 [83%] female; mean [SD] body mass index, 33.5 [7.2]; mean [SD] cigarettes per day, 15.4 [7.9]) were randomized to placebo (12 participants) or semaglutide (12 participants), of whom 21 participants (88%) completed the primary outcome assessment. Primary treatment-by-time interactions on laboratory measures of smoking resistance (23 participants; β = 0.16 [95% CI, -0.07 to 0.40]; P = .16) and number of cigarettes (22 participants; β = -0.08 [95% CI, -0.25 to 0.08]; P = .30) were not significant. Supplementary change score analyses indicated significantly greater reductions in laboratory smoking (β = -0.69 [95% CI, -1.26 to -0.13]; P = .02; d = 0.67) in the semaglutide group vs the placebo group after treatment. Semaglutide reduced cigarette craving (treatment-by-time interaction: β = -0.11 [95% CI, -0.20 to -0.03]; P = .01) and body weight (β = -0.04 [95% CI, -0.05 to -0.03]; P < .001) over treatment weeks. Exploratory effect size analyses indicated potential effects on withdrawal symptoms.
CONCLUSIONS AND RELEVANCE: In this phase 2a randomized clinical trial, semaglutide monotherapy did not significantly increase laboratory smoking resistance or reduce weekly cigarettes per day but reduced nicotine craving and body weight. Larger trials should evaluate effects of GLP-1RA therapies on cessation, postcessation weight gain, and cardiometabolic outcomes in people who smoke.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05530577.
