PROJECT ABSTRACT
Despite reductions in prevalence over the last few decades, over 34 million Americans currently smoke
cigarettes, and tobacco use remains the leading preventable cause of death, disability, and disease. Among
smokers who achieve abstinence, post-cessation weight gain (PCWG) is common and attributed to increased
energy intake in the first weeks and months after quitting. PCWG is problematic for three reasons. First, many
smokers, especially women, report fear of PCWG as a major barrier to quitting. Second, PCWG can precipitate
a relapse. Third PCWG can contribute to the onset of a chronic illness, such as obesity or type 2 diabetes
mellitus. First-line treatments, i.e. nicotine replacement therapies (NRT), varenicline and bupropion help
people quit smoking but do not provide a clinically meaningful impact on PCWG. Our recent pilot work showed
that a 6-week treatment with a glucagon-like peptide-1 receptor (GLP-1R) agonist, extended-release exenatide,
as an adjunct to nicotine patch, improved abstinence and decreased PCWG in prediabetic and/or overweight
treatment-seeking smokers. These findings, which are consistent with preclinical reports that GLP-1R agonists
decrease the rewarding effects of nicotine and food, support GLP-1R as a promising target for facilitating
smoking cessation and decreasing PCWG. The proposed research will assess the efficacy of extended-release
exenatide as an adjunct to nicotine patch on smoking abstinence and PCWG during the first 3 months after
quitting, when most weight gain occurs. A double-blind trial is proposed in which treatment-seeking smokers
will be randomized to receive either 2 mg exenatide (once a week) or placebo as an adjunct to nicotine patch for
14 weeks, starting 2 weeks prior to target quit day. The primary outcome measures will be end-of-treatment
smoking abstinence (4-week continuous) and PCWG. We predict that exenatide will improve abstinence and
mitigate PCWG relative to placebo. Exploratory aims will examine the long-term (6 months) impact of
exenatide on the primary study outcomes and the effect of exenatide on neuroaffective responses to food- and
nicotine-related stimuli. Innovative aspects of this research include: 1) targeting GLP-1R to facilitate smoking
cessation and decrease PCWG; 2) testing an approved medication that could be deployed quickly as an
adjunctive treatment for use in combination with NRT; 3) providing the impetus for conducting pivotal Phase 3
clinical trials to establish the efficacy of exenatide-NRT combinations and 4) exploring a putative mechanism
implicated in exenatide's effects on smoking and PCWG. This project stands to contribute significantly to
current treatments for smoking cessation by identifying a first-in-class adjunct pharmacotherapeutic that
uniquely targets both cessation and weight gain. This R01 resubmission application is proposed by an early-
stage investigator who has assembled a team of scientists with relevant expertise and access to resources,
including two-site recruitment capabilities, to ensure timely enrollment and successful completion of a large
sample size (N=216).
