Multi Site Randomized Trial of a GLP-1/GIP Receptor Agonist for Smoking Cessation

Cigarette smoking and obesity are the two leading preventable causes of morbidity and mortality in the United States. Despite historical declines in smoking rates, cigarette smoking continues to account for an estimated 480,000 U.S. deaths per year, and available pharmacotherapies for smoking cessation are only moderately effective. Obesity rates continue to rise dramatically: nearly one-half of U.S. adults will live with obesity by 2030. The emergence of highly effective incretin-based therapies for diabetes and obesity, including long-acting glucagon-like-peptide 1 (GLP-1) receptor agonists and dual GLP-1/GIP (gastric inhibitory peptide) receptor agonists, is leading to rapid advances in the clinical management of obesity and other cardiometabolic disorders. Importantly, preclinical and emerging clinical findings indicate that GLP-1 receptor agonists reduce the intake of addictive drugs, including nicotine. Data from early studies with people who smoke suggest that GLP-1RA may increase cigarette abstinence and prevent post-cessation weight gain. Consistent with this evidence, our Phase II clinical trial data indicate that low-dose treatment with a long-acting GLP-1 receptor agonist leads to prospective reductions in cigarette craving and cigarettes per day in non-treatment-seeking people who smoke. Larger randomized trials are now needed to determine the efficacy of incretin-based therapies for smoking cessation in treatment-seeking samples. Tirzepatide, the first dual GLP-1/GIP receptor agonist, shows superior efficacy for weight loss compared to semaglutide. Evidence further indicates that tirzepatide has protective effects on cardiovascular risk outcomes. Therefore, tirzepatide is a promising candidate therapy with potential applications for cessation, reduction of cardiovascular risks, and prevention of post-cessation weight gain. This multi-site, 24-week clinical trial seeks to expedite data on the efficacy of tirzepatide for smoking cessation and associated outcomes (e.g., cigarettes per day, post-cessation weight gain, cardiovascular risk factors) in treatment-seeking people who smoke. Expediting Phase II clinical data on the efficacy of tirzepatide in treatment-seeking people who smoke will help to inform dose selection and populations of focus for pivotal Phase III clinical trials.