# Efficacy and safety of glucagon-like peptide-1 receptor agonists in Parkinson’s disease: a systematic review and meta-analysis of randomized placebo-controlled clinical trials

## TL;DR

This study finds that GLP-1 receptor agonists, while showing promise in preclinical models, do not improve Parkinson’s disease symptoms in clinical trials and may cause weight loss.

## Contribution

A systematic review and meta-analysis of RCTs to evaluate the efficacy and safety of GLP-1 RAs in Parkinson’s disease.

## Key findings

- GLP-1 RAs did not improve motor or non-motor symptoms in Parkinson’s disease compared to placebo.
- GLP-1 RAs were associated with increased risk of weight loss and gastrointestinal adverse events.
- Preclinical evidence and subpopulation signals suggest further trials with brain-penetrant GLP-1 RAs may be warranted.

## Abstract

Converging lines of preclinical evidence support the neuroprotective properties of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in Parkinson’s disease (PD). Nevertheless, results from randomized-controlled clinical trials (RCTs) remain conflicting.

To assess the safety and efficacy of GLP-1 RAs in PD.

Systematic review and meta-analysis of randomized placebo-controlled clinical trials.

A systematic search of MEDLINE and Scopus databases was conducted on October 7, 2025, for randomized placebo-controlled clinical trials investigating GLP-1 RAs in adults with PD. Risk of bias was evaluated using the Cochrane Collaboration risk-of-bias (RoB2) tool.

Four RCTs comprising 667 PD patients (377 receiving GLP-1 RAs) were included. Between baseline and end-of-treatment, no differences were observed in the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III score change between GLP-1 RA- and placebo-treated patients in either off-medication (standardized mean difference (SMD): −0.16; 95% CI: −0.64 to 0.32; p = 0.52) or on-medication states (SMD: −0.13; 95% confidence interval (CI): −0.51 to 0.25; p = 0.49). No significant differences were uncovered in other MDS-UPDRS subscores, Non-Motor Symptoms Scale, Montreal Cognitive Assessment, or Parkinson’s Disease Questionnaire scores. The risk of serious adverse events and odds of treatment discontinuation were similar between groups, but GLP-1 RAs were associated with an increased risk of weight loss compared to placebo (risk ratio: 1.44; 95% CI: 1.04–1.99; p = 0.03).

GLP-1 RAs were not associated with improvements in motor or non-motor domains of PD. However, robust preclinical evidence and promising findings in select subpopulations warrant further RCTs to evaluate their neuroprotective potential, prioritizing long-acting and brain-penetrant agents that effectively engage central GLP-1 circuits for PD treatment.

The pre-specified protocol of the present systematic review and meta-analysis has been registered in the International Prospective Register of Ongoing Systematic Reviews PROSPERO (registration ID: CRD420251008703).

Efficacy and safety of glucagon-like peptide-1 receptor agonists in Parkinson’s disease: a systematic review and meta-analysis

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are medications approved for type 2 diabetes and obesity that have shown neuroprotective effects in preclinical models of Parkinson’s disease (PD). However, clinical trial results have been inconsistent. In this systematic review and meta-analysis, we evaluated the overall safety and effectiveness of GLP-1 RAs in people with PD by analyzing data from all available randomized placebo-controlled clinical trials. Our findings indicate that GLP-1 RAs do not lead to measurable improvements in motor symptoms, cognitive performance, or quality of life when compared to placebo. Although the risk of serious adverse events was similar between treatment and placebo groups, GLP-1 RAs were associated with an increased risk of weight loss and gastrointestinal adverse events. Despite the lack of demonstrated clinical benefit, strong preclinical evidence and exploratory signals in specific patient subgroups support the need for further high-quality trials, particularly with long-acting and brain-penetrant GLP-1 RAs in early-stage PD populations.