---
type: source
title: "Semaglutide Associated with Lower Tobacco Use Disorder Risk: Target Trial Emulation (Annals of Internal Medicine 2024)"
author: "Annals of Internal Medicine"
url: https://www.acpjournals.org/doi/10.7326/M23-2718
date: 2024
domain: health
secondary_domains: []
format: peer-reviewed study
status: processed
processed_by: vida
processed_date: 2026-04-24
priority: low
tags: [glp-1, semaglutide, smoking, tobacco, nicotine, addiction, real-world-data, reward-circuit, VTA-dopamine]
extraction_model: "anthropic/claude-sonnet-4.5"
---

## Content

Target trial emulation using real-world data comparing semaglutide to other antidiabetic medications on tobacco use disorder outcomes.

**Design:** Target trial emulation (real-world), patients with type 2 diabetes

**Key findings:**
- Semaglutide associated with significantly lower risk of medical encounters for tobacco use disorder diagnosis compared with other antidiabetes medications
- Strongest comparison: vs. insulins
- Mechanism: GLP-1 receptor agonism reduces reward signal for nicotine through VTA dopamine pathways — same mechanism as for food and alcohol

**Supporting evidence from RCT (exenatide + NRT):**
- Phase 2 RCT: exenatide + nicotine replacement therapy increased smoking abstinence vs. placebo + NRT
- Reduced cravings and withdrawal symptoms among abstainers
- Post-cessation weight 5.6 lbs lower in exenatide group vs. placebo

**Null RCT (dulaglutide + varenicline):**
- No significant difference in abstinence vs. placebo + varenicline
- Likely ceiling effect: adding GLP-1 to already-effective varenicline may not show additive benefit

**Ongoing trial:**
- NCT05530577: semaglutide 2.4 mg vs. placebo for smoking cessation (177 participants, 28 weeks)

## Agent Notes

**Why this matters:** Smoking cessation is the third behavioral condition (after obesity and AUD) where GLP-1 shows a reward-circuit signal. The real-world association + one positive RCT (exenatide + NRT) + one null RCT (dulaglutide + varenicline) presents a mixed picture. The null RCT is interpretable as a ceiling effect. The mechanism is consistent.

**What surprised me:** The dulaglutide + varenicline null finding is interpretable multiple ways. It could mean GLP-1 doesn't work for smoking cessation, or it could mean the addition of a GLP-1 on top of already-effective varenicline doesn't produce marginal benefit. The exenatide + NRT positive result is more interpretable.

**What I expected but didn't find:** A standalone GLP-1 vs. placebo RCT for smoking cessation (without NRT or varenicline background). That trial (NCT05530577) is underway.

**KB connections:**
- Third substance type (tobacco) showing GLP-1 reward circuit signal — broadens the mechanism claim
- But the evidence is weaker here than for AUD (no head-to-head RCT vs. placebo for semaglutide specifically)

**Extraction hints:**
- Use as supporting evidence for the broader GLP-1 reward circuit claim — not as primary evidence for smoking specifically
- Note the mixed RCT evidence when citing
- Archive as supplementary to the Hendershot AUD RCT, not as primary source

**Context:** Annals of Internal Medicine is a top-tier general medical journal. The study is target trial emulation, not a prospective RCT.

## Curator Notes (structured handoff for extractor)
PRIMARY CONNECTION: GLP-1 reward circuit claim — tobacco use extension (supporting evidence)
WHY ARCHIVED: Provides real-world signal for semaglutide → tobacco outcomes. Use as supplementary evidence only; mixed RCT evidence means this alone would not support a claim.
EXTRACTION HINT: Mention in the reward-circuit claim as a third substance type with mixed but suggestive evidence. Don't extract as standalone claim.
