Once Weekly Semaglutide for Daily Cigarette Use: Trial Results

Key Takeaways

• The co-primary laboratory smoking resistance and laboratory cigarette self-administration treatment-by-time interaction tests were not significantly improved with semaglutide.
• Greater reductions were observed in laboratory smoking change scores and weekly cigarette craving, while weekly cigarettes per day did not significantly separate by treatment over time.
• Body weight and HbA1c were lower with semaglutide, adverse events were mostly mild and largely gastrointestinal, one participant discontinued because of adverse effects, and the findings remain early phase 2a results from a small non-treatment-seeking sample.

A 24-participant phase 2a randomized trial compared once-weekly semaglutide with placebo in non-treatment-seeking adults who smoked daily. The prespecified laboratory treatment-by-time tests were not significant, though semaglutide was associated with larger reductions in laboratory smoking change scores, craving, weight, and HbA1c. Weekly cigarettes per day also did not separate by treatment over time, leaving a mixed signal that does not establish cessation benefit.

At an academic medical center, the parallel-arm phase 2a trial with embedded laboratory sessions enrolled 45 participants; 24 were randomized equally to semaglutide or placebo, and 21 completed posttreatment testing. Eligible adults were non-treatment-seeking, were 21 to 65 years old, smoked at least five cigarettes daily, and had biochemical verification at baseline. Among randomized participants, mean age was 44 years, 83% were female, mean BMI was 33.5, and mean cigarette consumption was 15.4 per day. Semaglutide was injected subcutaneously at 0.25 mg in weeks 1-4, 0.5 mg in weeks 5-8, and 1.0 mg in week 9; no cessation therapy was provided. Laboratory smoking sessions occurred before treatment and again after eight treatment weeks.

The co-primary outcomes were laboratory smoking resistance and laboratory cigarette self-administration, each measured before and after treatment. The planned treatment-by-time interaction was not significant for smoking resistance, with beta 0.16, 95% CI -0.07 to 0.40, and P=.16. The corresponding interaction for laboratory cigarettes smoked was also not significant, with beta -0.08, 95% CI -0.25 to 0.08, and P=.30. Separate change-score analyses linked semaglutide to a greater reduction in laboratory smoking, with beta -0.69, 95% CI -1.26 to -0.13, P=.02, and d=0.67. In the laboratory, smoking change scores favored semaglutide, but the planned interaction tests did not.

Outside the laboratory, weekly cigarette craving declined more with semaglutide than with placebo, with beta -0.11, 95% CI -0.20 to -0.03, and P=.01. Weekly cigarettes per day did not show a significant treatment-by-time interaction, with beta -0.01, 95% CI -0.04 to 0.03, and P=.65. Exploratory analyses suggested improvements in withdrawal, self-efficacy, and readiness to change, with larger effects during weeks 5 to 8 than weeks 1 to 4. Craving and some secondary behavioral measures changed more than daily cigarette count.

Weight changed more with semaglutide than placebo, with a significant treatment-by-time interaction of beta -0.04, 95% CI -0.05 to -0.03, and P<.001. Through week 10, mean body weight changed by -5.11% with semaglutide and +1.58% with placebo, and HbA1c was lower during treatment in the semaglutide group. Adverse events were mostly mild and largely gastrointestinal, and one semaglutide participant discontinued because of adverse effects. Blood pressure and CES-D differences were not significant, and the short treatment period limited assessment at higher semaglutide doses. The investigators noted the small, non-treatment-seeking sample and underpowered interaction tests, and described the findings as early and hypothesis-generating rather than evidence of long-term efficacy, safety, or cessation benefit.