7625 Functional and structural neuronal changes of dulaglutide compared to placebo during smoking cessation - a randomized placebo-controlled trial
Authors: Sailer Clara Odilia , Lengsfeld Sophia , Coynel David , Baur Fabienne , Bologna Katja , Vukajlovic Tanja , Jeanloz Nica A , Bathelt Cemile , Zanchi Davide , Christ-Crain Mirjam , Winzeler Bettina Felicitas 
Published: October 2024

Disclosure: C.O. Sailer: None. S. Lengsfeld: None. D. Coynel: None. F. Baur: None. K. Bologna: None. T. Vukajlovic: None. N.A. Jeanloz: None. C. Bathelt: None. D. Zanchi: None. M. Christ-Crain: None. B.F. Winzeler: None.

Introduction: Nicotine activates reward-related brain regions and chronic cigarette smoking can lead to functional and structural neuronal changes. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), known for their anti-obesity effects, have emerged as potential treatments for addictive disorders. A pilot study of exenatide vs placebo revealed increased short-term smoking abstinence rates and reduce smoking craving. We previously reported the results of a clinical trial (n=255) investigating the effect of dulaglutide vs placebo on smoking cessation. Herein, we report the functional magnetic resonance imaging (fMRI) results of a subset of participants. This substudy aimed to investigate the influence of dulaglutide on smoking craving, functional and structural neuronal changes of smokers aiming to quit smoking. Methods: This single-center, randomized, double-blind, placebo-controlled trial enrolled 71 participants with at least a moderate nicotine dependence, all committed to quitting smoking. Of these, 35 participants received 12 weeks dulaglutide 1.5mg, and 36 participants placebo, alongside varenicline treatment and behavioral counselling. An fMRI session was conducted at baseline and 12 weeks. The primary outcomes included smoking craving assessed on a visual analogue scale (VAS, range 0-7), differences in blood oxygen level dependent (BOLD) signal (whole brain and regions of interests, e.g., nucleus accumbens, amygdala, thalamus) and gray matter changes between sessions and groups when exposed to smoking and neutral video cues. Secondary outcomes assessed the above in quitters vs persistent smokers. Results: In line with the primary study findings, abstinence rates at 12 weeks were comparable in the dulaglutide (54%) and placebo (68%) groups (p=0.27). In a mixed effect model, smoking craving significantly decreased at 12 weeks vs baseline (-2.13 (95% CI -2.46, -1.80), p&lt;0.001) and were lower for neutral vs smoking cues (-2.02 (-2.34, 1.70,), p&lt;0.001). However, no significant inter-group difference was observed (-0.09 (-0.53, 0.33), p=0.65). Persistent smokers exhibited higher smoking craving at 12 weeks vs quitters (0.48 (0.06, 0.90), p=0.028), particularly when exposed to smoking cues (2.02 (1.70, 2.34), p&lt;0.001). No significant differences were found in functional or structural analyses between interventions or smoking status. Conclusions: The smoking cessation intervention led to a significant reduction in smoking craving at 12 weeks without in-between group differences in behavioral, functional, or structural outcomes. Our findings challenge the hypothesis that GLP-1 RAs modulates smoking craving and behavior. It is plausible that a potential GLP-1 effect might have been masked by varenicline treatment and the unexpectedly high abstinence rate in the placebo group. Future studies should explore more potent GLP-1 RAs or dual agonists.

Presentation: 6/1/2024