Glucagon‐like Peptide-1 Agonists and Smoking Cessation: A Brief Review

Richard A. Robbins MD

Phoenix Pulmonary and Critical Care Research and Education Foundation

Gilbert, AZ USA

Abstract

The glucagon‐like peptide 1 (GLP-1) agonists such as semaglutide (Ozempic®, Wegovy®) and tirzepatide (Mounjaro®) have shown efficacy inducing weight loss in both diabetics and non-diabetics. According to the incentive sensitization theory of addiction, these drugs may prove useful in addictive disorders such as nicotine addiction. Animal data has been suggestive of a potential positive effect but early human studies have been mixed. This manuscript reviews the theory of addiction as well as the few animal and human studies available. Further human studies are needed to show GLP-1 agonist efficacy in smoking cessation.

GLP-1

Glucagon‐like peptide 1 (GLP‐1) has received much attention because of its association with weight loss (1). Endogenous GLP‐1 is produced by cleavage of the prohormone proglucagon in the intestinal endocrine L cells and is released into the bloodstream in response to food intake. It is rapidly inactivated with a half‐life of just 1–2 min by the enzyme, dipeptidyl peptidase 4 (DPP‐4). GLP‐1 receptors are present in many tissues throughout the body. GLP‐1 potentiates insulin secretion, inhibits glucagon secretion, slows gastric emptying and reduces appetite (2). GLP‐1 is also produced in the nucleus tractus solitarius (NTS) of the brain stem and is released as a neurotransmitter in several brain regions. GLP‐1 receptors are expressed in brain regions believed to be involved in reward and addiction (3). Studies in mice indicate that several GLP‐1 receptor agonists can cross the blood–brain barrier at least to some extent when administered systemically (4).

Incentive Sensitization Theory of Addiction

Many neurocircuits and neurochemicals, such as dopamine, opioid peptides, corticotropin‐releasing factor (CRF), dynorphin, glutamate, gamma-aminobutyric acid (GABA) and vulnerability factors such as genetics, initial drug exposure and social environment have been proposed to play a role in addiction (5-10). Attention has also been directed to the behavioral, cognitive and neurobiological heterogeneity of different substance abuse disorders (6). Among the most dominant theories is ‘incentive sensitization’ which underlies the excessive ‘wanting’ triggered by reward cues in addicted individuals (5). The rewarding effects of nicotine and food are both mediated by the mesolimbic dopamine reward system (10).

Nicotine Addiction

Tobacco use is one of the largest preventable causes of premature death, but still, six million people die due to tobacco‐related diseases every year (11). Despite the available treatment options, many smokers attempt to quit without medication or support, with a failure rate of 95–98% (12). There is also a high prevalence of co‐use of two or more substances. This has consequences for the associated disease burden, treatment strategies and outcomes.

FDA approved treatments for smoking cessation, including nicotine replacement therapy (NRT), varenicline, and bupropion, decrease smoking relapse. However, their long-term efficacy is modest with success rates of <40% at one year (12). Furthermore, these treatments delay, but do not prevent, body weight gain during smoking abstinence (13,14).

Studies of GLP-1 and Smoking Cessation

Recent preclinical studies indicated that GLP-1 agonists decreased the rewarding and reinforcing effects of nicotine in rodents (15). In a series of experiments the effects of the GLP-1 receptor agonist, exendin-4 (Ex4), blocked nicotine-induced expression of locomotor sensitization in mice (16). Similarly, a recent study found that systemic administration of liraglutide (25 μg/kg, intraperitoneally) attenuated nicotine self-administration in rats (17). Together, these preclinical studies suggest that GLP-1 agonists may attenuate the reinforcing efficacy of nicotine.

Human studies to date have been mixed. A randomized study of 84 prediabetic and/or overweight smokers treated with once-weekly placebo or exenatide, 2 mg, subcutaneously was encouraging (18). All participants received nicotine replacement therapy (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. Exenatide increased the risk for smoking abstinence compared to placebo (46.3% and 26.8%, respectively), (risk ratio [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%).

However, a recent single-center, randomized, double-blind, placebo-controlled, parallel group trial showed no effect on smoking cessation (19). Patients were assigned to either a 12-week treatment with dulaglutide 1.5 mg or placebo subcutaneously once weekly in addition to standard of care smoking cessation therapy (varenicline 2 mg/day and behavioral counselling). After 12 weeks, dulaglutide or placebo injections were discontinued and the participants were followed up at week 24 and 52. Dulaglutide did not improve long-term smoking abstinence, but modestly counteracted weight gain 12 weeks after quitting. However, 3 months of treatment did not have a sustained beneficial effect on weight at 1 year.

A trial of 40 smokers who are overweight were treated with liraglutide (escalating doses of 0.6–3.0 mg weekly) or placebo in addition to smoking cessation counseling has been completed (20). However, the results are not yet published.

Nicotine Addiction Combined with Other Addictions

Consistent with the incentive sensitization theory of addiction, a review based on preclinical and clinical studies has shown that co‐use of alcohol and nicotine potentiates craving and self‐administration of both substances (20,21). In addition, 50-90% of people who use cocaine also consume alcohol simultaneously (22). Eighty per cent of individuals who use cocaine or opioids are also smoking tobacco (23). GLP-1 agonists may prove useful in these situations since these agonists have shown promise in treating alcohol and narcotic addition (1).

Further evidence of GLP-1 agonists in addictive disorders is provided by a predefined secondary analysis of a double-blind, randomized, placebo-controlled trial evaluating the GLP-1 agonist dulaglutide as a therapy for smoking cessation (24). The main objective was to assess differences in alcohol consumption after 12 weeks of treatment with dulaglutide compared to placebo. In the primary analysis, participants out of the cohort who completed 12 weeks of treatment (n = 151; placebo n = 75, dulaglutide = 76) were included. Participants receiving dulaglutide drank 29% less (relative effect = 0.71, 95% CI 0.52–0.97, P = 0.04) than participants receiving placebo. Changes in alcohol consumption were not correlated with smoking status at week 12.

GLP-1 agonists have also been reported to be of benefit in obstructive sleep apnea (OSA) (25). The authors conducted two phase 3, double-blind, randomized, controlled trials involving adults with moderate-to-severe OSA (apnea-hypopnea index [AHI] >15 events/hour) and obesity. 469 participants who were not receiving treatment with positive airway pressure (PAP) were randomly assigned to tirzepatide (234) or placebo (235). After 52 weeks there a 50%-60% reduction in the severity of OSA (p<0.001). This reduction is quite impressive and clinically significant (25).

Practical Considerations

GLP-1 agonists such as semaglutide (Ozempic®, Wegovy®), tirzepatide (Mounjaro®), and dulaglutide (Trulicity®) remain quite expensive. For example, Ozempic® costs around $900 per month for off-label use and patients without diabetes may have difficulty obtaining these drugs for weight loss (26). It seems likely that similar difficulties may occur with smoking cessation. Furthermore, there may be differences in efficacy between different GLP-1 agonists in different conditions. For example, in patients with type 2 diabetes, tirzepatide was superior to semaglutide in lowering hemoglobin A1C and weight loss (27). It seems likely that differences might also exist in smoking cessation.

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Cite as: Robbins RA. Glucagon‐like Peptide-1 Agonists and Smoking Cessation: A Brief Review. Southwest J Pulm Crit Care Sleep. 2024;29(5):48-52. doi: https://doi.org/10.13175/swjpccs041-24 PDF