GLP-1 receptor agonists and smoking cessation: therapeutic promise beyond glycemia.

OBJECTIVES

Tobacco use remains the leading preventable cause of morbidity and mortality worldwide, with current cessation therapies yielding suboptimal long-term abstinence. This systematic review evaluates the efficacy, tolerability, and neurobiological rationale of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual GLP-1/glucose-dependent insulinotropic peptide (GIP) agonists in treating nicotine use disorder (NUD), with particular attention to smoking abstinence, craving reduction, weight gain mitigation, and mechanistic insights.

METHODS

Following PRISMA guidelines, a comprehensive search was conducted across PubMed, Embase, CENTRAL, PsycINFO, and Web of Science through April 2025. Eligible studies included randomized controlled trials (RCTs), observational cohorts, and preclinical rodent studies evaluating GLP-1 or GLP-1/GIP agonists in nicotine-related outcomes. Risk of bias was assessed using Cochrane RoB2, ROBINS-I, and SYRCLE tools. Narrative synthesis was conducted due to heterogeneity in study designs and outcome definitions.

RESULTS

Twelve studies met inclusion criteria—eight human and four preclinical. Preclinical studies demonstrated consistent attenuation of nicotine-seeking behavior and mesolimbic dopaminergic signaling via GLP-1R agonism. Among human studies, exenatide showed the most robust efficacy in enhancing abstinence and reducing craving and weight gain. Dulaglutide did not improve abstinence, though it conferred metabolic benefits. Semaglutide showed indirect behavioral benefits in real-world observational data. Adverse events were predominantly mild gastrointestinal symptoms.

CONCLUSION

GLP-1 RAs—particularly exenatide and semaglutide—exhibit promising neurobehavioral and metabolic effects in smoking cessation. Their dual mechanism may address key limitations of current pharmacotherapies. Larger, mechanistically enriched trials are warranted to validate efficacy and guide clinical translation for nicotine dependence and related substance use disorders.