A randomized controlled trial of once-weekly semaglutide for limiting post-smoking cessation weight gain in smokers with overweight/obesity: Study protocol.

Background: Smoking and obesity are the two leading causes of preventable morbidity and mortality in the U.S. While smoking cessation has tremendous health benefits, most smokers gain weight post-cessation, which may partially attenuate these benefits. Semaglutide 2.4 mg once-weekly, a glucagon-like peptide-1 receptor agonist (GLP-1RA) approved for weight management in adults with overweight/obesity, leads to clinically meaningful reductions in body weight and may thus have utility for preventing weight gain in the context of smoking cessation.

Methods: This parallel group, two-arm, double-blind clinical trial will randomize 177 treatment-seeking smokers with a body mass index of ≥30 kg/m or ≥ 27 kg/m with at least one weight-related comorbidity to semaglutide 2.4 mg once-weekly or placebo (2:1) for 28 weeks, including 16 weeks of semaglutide dose escalation, followed by 12 weeks at target, 2.4 mg, dose. Both groups will receive 10 weeks of nicotine patches (dose based on baseline number of cigarettes smoked daily) and brief individual smoking cessation counseling. The primary outcome is percent body weight change at the end of treatment. Secondary outcomes are changes in total body weight and fat mass (kg) and waist circumference. Exploratory outcomes are changes in daily energy intake and food choices, food cravings and appetite/satiety, and smoking abstinence rates.

Conclusion: We anticipate that semaglutide 2.4 mg once-weekly will provide a clinically meaningful effect on weight management in the context of smoking cessation. If our hypotheses are confirmed, this GLP-1RA could move forward as a pharmacotherapeutic for helping smokers achieve abstinence without weight gain. Universal trial number (UTN): U1111-1270-1737.

Clinical Trial Registration: NCT06173778.