Glucagon-Like Peptide-1 Receptor Agonists and Risk of Parkinsonian Disorders in Patients with Obesity

IntroductionParkinsonism encompasses neurodegenerative disorders characterized by rigidity, tremor, and bradykinesia, with Parkinsons disease (PD) accounting for most cases. Emerging evidence suggests that metabolic dysfunction, including insulin resistance and neuroinflammation, may contribute to PD pathogenesis. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), approved for type 2 diabetes (T2D) and obesity, demonstrate neuroprotective effects in preclinical PD models. However, real-world evidence in individuals without T2D is limited. This study evaluated whether GLP-1RA use among adults with obesity or overweight is associated with the risk of PD and Parkinsonian disorders. MethodsWe conducted a retrospective cohort study using 2014-2024 electronic health record data from the OneFlorida+ Network. Adults with obesity (BMI [&ge;]30 kg/m2), overweight (BMI 25-29.9 kg/m2) with a weight-related comorbidity, or an obesity diagnosis were eligible. Exclusions included age <50 years, <30 days of follow-up, baseline PD or Parkinsonism, anti-Parkinson medication use, or T2D. GLP-1RA users were matched 1:1 to non-users using time-conditional propensity scores. Outcomes were a composite of (1) PD/Parkinsonism and (2) any Parkinsonian-related disorder, including PD, Parkinsonism, Lewy body dementias, and multiple system atrophy. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs). ResultsThe matched cohort included 11,683 GLP-1RA users and 11,683 non-users with balanced characteristics and a median follow-up of 286 days. GLP-1RA use was not associated with reduced risk of PD or Parkinsonism (22 vs. 33 events; HR 0.70, 95% CI 0.41-1.22) or any Parkinsonian-related disorder (98 vs. 108 events; HR 0.96, 95% CI 0.73-1.27). Findings were consistent in subgroup and sensitivity analyses. ConclusionAmong adults with obesity or overweight with a weight related condition, there was no difference in the risk of PD or Parkinsonian disorders between GLP-1 RA users and non-users. Longer follow-up and clinical trials are needed to clarify potential neuroprotective effects across populations.