5E-04 - Comparative safety of glucagon-like peptide 1 receptor agonists (GLP-1-RAs) in chronic weight management patients without diabetes: a real-world data study

Background: GLP-1-RAs have been available in the U.S. for the treatment of type 2 diabetes (T2D) for almost 20 years. Due to new chronic weight management indications, GLP-1-RA prescribing has increased dramatically in recent years. Long-term use of these medications in individuals without T2D raises new questions about the risk-benefit assessment in this population, including possible effects on cardiovascular, biliary, and mental health.

Objectives: To assess serious clinical outcomes comparing GLP-1-RAs with naltrexone/bupropion (NalBup) or phentermine/topiramate (PhenTop) for chronic weight management in patients without diabetes.

Methods: We conducted a new user, active comparator cohort study in a large, US claims database. The study included adult, new users (>6 months continuous enrollment lookback) of GLP-1-RA, NalBup, or PhenTop from 01Jan2020 to 31Dec2023 who had no prior diagnoses of type 1 or type 2 diabetes, or prediabetes. Weight loss indication was defined as an obesity diagnosis within 6 months prior to treatment initiation, or an overweight diagnosis coupled with hypertension or dyslipidemia. Rate ratios (RR) and 6-month Kaplan-Meier-based number-needed-to-treat-or-harm (NNT/H) were estimated with propensity score weighting for 82 clinical and demographic covariates. We assessed 11 clinical outcomes: hospitalizations for gastrointestinal disorders, gastroparesis, bowel obstructions, gallbladder and biliary disease, acute pancreatitis, myocardial infarction (MI) or stroke, acute liver injury, or psychiatric diagnoses; thyroid cancer, suicidal ideation or self-harm, and all-cause mortality.

Results: This study included 25,489 GLP-1-RA users, 5,019 NalBup users, and 3,841 PhenTop users. GLP-1-RA users had higher rates of hospitalizations for gallbladder and biliary diseases (GLP-1-RA vs. NalBup RR 3.32, 95% CI: 1.44-7.64, 6-month NNT/H: 834; GLP-1-RA vs. PhenTop RR 2.17, 95% CI: 0.90-5.22, 6-month NNT/H: 2,858). No reduction in the rate of MI or stroke was observed for GLP-1-RA users (GLP-1-RA vs. NalBup RR 0.96, 95% CI: 0.46-2.00, 6-month NNT/H: 2,248; GLP-1-RA vs. PhenTop RR 0.92, 95% CI: 0.37-2.25, 6-month NNT/H: 998). GLP-1-RA users had lower rates of suicidal ideation or self-harm compared to NalBup users (RR 0.52, 95% CI: 0.30-0.93, 6-month NNT/H: 1,102) but not compared to PhenTop users (RR 1.21, 95% CI: 0.44-3.34, 6-month NNT/H: 1,303).

Conclusions: This study corroborates an increased risk of hospitalization for gallbladder and biliary conditions in GLP-1-RA users and found similar rates of MI or stroke when GLP-1-RAs were used for chronic weight management. Lower rates of suicidal ideation or self-harm in GLP-1-RA users compared to NalBup users is plausible given NalBup’s black box warning for suicidal ideation.