Exenatide Adjunct to Nicotine Patch Facilitates Smoking Cessation and May Reduce Post-Cessation Weight Gain: A Pilot Randomized Controlled Trial

Abstract

Introduction Approved pharmacological treatments for smoking cessation are modestly effective, underscoring the need for improved pharmacotherapies. Glucagon-like peptide-1 receptor (GLP-1R) agonists attenuate the rewarding effects of nicotine in preclinical studies. We examined the efficacy of extended-release exenatide, a GLP-1R agonist, combined with nicotine replacement therapy (NRT, patch) for smoking cessation, craving and withdrawal symptoms, with post-cessation body weight as secondary outcome. Methods Eighty-four prediabetic and/or overweight smokers were randomized (1:1) to once-weekly placebo or exenatide, 2 mg, subcutaneously. All participants received NRT (21 mg) and brief smoking cessation counseling. Seven-day point prevalence abstinence (expired CO level ≤5 ppm), craving, withdrawal and post-cessation body weight were assessed following 6 weeks of treatment. A Bayesian approach for analyzing generalized linear models yielded posterior probabilities (PP) to quantify the evidence favoring hypothesized effects of treatment on the study outcomes. Results Exenatide increased the risk for smoking abstinence compared to placebo (46.3% and 26.8%, respectively), (RR = 1.70; 95% credible interval = [0.96, 3.27]; PP = 96.5%). Exenatide reduced end-of-treatment craving in the overall sample and withdrawal among abstainers. Post-cessation body weight was 5.6 pounds lower in the exenatide group compared to placebo (PP=97.4%). Adverse events were reported in 9.5% and 2.3% of participants in the exenatide and placebo groups, respectively. Conclusions Exenatide, in combination with the NRT improved smoking abstinence, reduced craving and withdrawal symptoms, and decreased weight gain among abstainers. Findings suggest that the GLP-1R agonist strategy is worthy of further research in larger, longer duration studies. Implications Despite considerable progress in tobacco control, cigarette smoking remains the leading cause of preventable disease, disability, and death. In this pilot study, we showed that extended-release exenatide, a glucagon-like peptide-1 receptor agonist, added to the nicotine patch, improved abstinence and mitigated post-cessation body weight gain compared to patch alone. Further research is needed to confirm these initial positive results.

The role of glucagon‐like peptide 1 (GLP‐1) in addictive disorders

“…According to ClinicalTrials.gov, three human clinical trials are investigating the potential effects of a GLP‐1 receptor agonist against tobacco use disorder (Table 2), and one randomized clinical pilot trial has investigated the effects of exenatide, 2.0 mg once weekly, in combination with transdermal nicotine replacement therapy on smoking cessation. They have reported that exenatide increased smoking abstinence and reduced craving (Yammine et al, 2021). Two other clinical trials investigating subcutaneous liraglutide, 3.0 mg daily (ClinicalTrials.gov identifier NCT03712098), and subcutaneous dulaglutide, 1.5 mg once weekly (ClinicalTrials.gov identifier NCT03204396), are still recruiting.…”

The Effect of Smoking Cessation on Body Weight and Other Metabolic Parameters with Focus on People with Type 2 Diabetes Mellitus

“…In a pilot study, extended-release exenatide, a GLP-1R agonist, added to the nicotine patch, improved abstinence, reduced craving and withdrawal symptoms and decreased PSCWG among abstainers. Findings suggested that the GLP-1R agonist strategy is worthy of further research in larger studies with longer durations [ 165 ].…”

Exenatide once weekly for alcohol use disorder investigated in a randomized, placebo-controlled clinical trial

“…Importantly, exenatide crosses the blood brain barrier (20), and a similar dosing regiment, i.e. 2 mg subcutaneously once weekly, has recently shown efficacy in other neuropsychiatric disorders including nicotine dependence (21) and Parkinson's disease (20) suggesting a central engagement, possibly mediated, at least in part, by dopamine signaling (22).…”

“…Since the pharmacodynamics and pharmacokinetics of a GLP-1 receptor agonist in patients with AUD have not been investigated, we chose a dosing regimen consistent with established tolerability and efficacy in treatment of type 2 diabetes, i.e., exenatide, 2 mg subcutaneously once weekly. Importantly, exenatide crosses the blood-brain barrier ( 20 ), and a similar dosing regimen, i.e., 2 mg subcutaneously once weekly, has recently shown efficacy in other neuropsychiatric disorders, including nicotine dependence ( 21 ) and Parkinson’s disease ( 20 ), suggesting a central engagement, possibly mediated, at least in part, by dopamine signaling ( 22 ).…”