GLP and Nicotine: The 46% vs. 27% Signal, and Its Contradiction

A headline claiming a diabetes drug can help people quit smoking is the kind of thing that sounds implausible until you check the actual trial. The trial is real. So is a second trial that found nothing.

The pilot that produced the headline number

Researchers at MD Anderson Cancer Center ran a randomized, double-blind, placebo-controlled pilot trial testing exenatide, a GLP receptor agonist, as an add-on to standard nicotine replacement therapy for smoking cessation. Eighty-four smokers who were prediabetic and/or overweight were randomized to receive either exenatide or placebo, once weekly, alongside a nicotine patch and brief cessation counseling.

After six weeks of treatment, 46.3% of the exenatide group had achieved smoking abstinence, verified by expired carbon monoxide level, compared to 26.8% of the placebo group. Exenatide also reduced end-of-treatment craving across the sample and reduced withdrawal symptoms among people who successfully quit. The rationale behind testing this in the first place came from preclinical work showing that GLP receptor agonists blunt the rewarding effects of nicotine in animal models, the same underlying logic used to justify testing this drug class against alcohol and opioid craving.

The trial that didn’t replicate it

A separate, independent research group ran a similarly designed randomized, double-blind, placebo-controlled trial, this time testing dulaglutide, a different GLP receptor agonist, for the same purpose: supporting smoking cessation. The result did not match the exenatide finding. The researchers found no significant effect on craving or abstinence rates, and explicitly noted that their results were not consistent with the hypothesis that GLP analogues influence nicotine reward-seeking behavior, directly referencing the earlier exenatide trial as the result they failed to replicate.

Same idea, two different drugs, two different outcomes

This is worth sitting with rather than smoothing over. Exenatide and dulaglutide are both GLP receptor agonists, but they’re not identical molecules, and they don’t necessarily produce identical effects just because they share a receptor target. A secondary analysis of the original exenatide data found that the benefit was more pronounced in heavier smokers, people without prediabetes or obesity, and people without depressive symptoms, which suggests the effect, where it exists, may depend heavily on which population is being studied, not just which drug is being tested.

The honest state of the evidence right now: one well-designed pilot trial found a real and fairly large effect with exenatide. A separate well-designed trial with a different GLP drug found nothing. Both results are legitimate data points, and the responsible conclusion isn’t that GLP drugs work or don’t work for smoking cessation. It’s that this specific question, which drug, at what dose, in which population, hasn’t been answered yet, and a single 46% versus 27% headline number from one trial was never enough to answer it on its own.

References

Lüthi, H., et al. “Effect of Dulaglutide in Promoting Abstinence During Smoking Cessation: A Single-Centre, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Trial.” eClinicalMedicine, 2023.

Yammine, Luba, et al. “Exenatide Adjunct to Nicotine Patch Facilitates Smoking Cessation and May Reduce Post-Cessation Weight Gain: A Pilot Randomized Controlled Trial.” Nicotine & Tobacco Research, vol. 23, no. 10, 2021, pp. 1682-1690.