Antidiabetic drugs in Parkinson's disease: a comprehensive meta-analysis on efficacy and safety with trial sequential analysis and GRADE evaluation.

Recent studies highlighted the relation between type 2 diabetes and Parkinson's disease, suggesting a relation between insulin resistance and α-synuclein aggregation. Antidiabetic medications, including GLP-1 receptor agonists and PPAR-γ agonists, have shown potential neuroprotective effects. We conducted a comprehensive literature search retrieving randomized controlled trials (RCTs) comparing antidiabetic drugs and placebo. Key outcomes included motor and non-motor symptoms, along with the safety profile. Data were analyzed using RevMan, and trial sequential analysis as well as sensitivity analysis were conducted to ensure the robustness of our results. In addition, to ensure the reliability of our evidence, we conducted the GRADE evaluation approach. Seven RCTs, with 973 patients, were eligible for our inclusion criteria. Antidiabetic drugs have shown no significant difference from placebo concerning change in MDS-UPDRS scores while on medication in Parts I, II, III, IV (MD = -0.04, 95% CI [-0.74 to 0.66], p = 0.90), (MD = -0.88, 95% CI [-2.11 to 0.34], p = 0.16), (MD = -1.10, 95% CI [-2.61 to 0.42], p = 0.16), (MD = -0.09, 95% CI [-0.45 to 0.27], p = 0.64), respectively. However, for MATTIS-DRS and MADRS scores, results showed a significant difference favoring GLP-1 agonists (MD = 2.42, 95% CI [0.01 to 4.83], p = 0.05), (MD = -2.08, 95% CI [-3.93 to -0.23], p = 0.03) respectively. As for safety profile, results revealed significant differences favoring the placebo group. This meta-analysis concludes that antidiabetic drugs in early-to mid-stage Parkinson's disease show no significant benefit considering non-motor symptoms detected by MDS-UPDRS I, with TSA confirming this finding as a conclusive result. Similarly, no notable effects on motor symptoms were observed, although future trials are needed. GLP-1 agonists revealed potential antidepressant effects as well as improving cognitive functions detected by MADRS and MATTIS-DRS, respectively. However, antidiabetic drugs were associated with higher risks of gastrointestinal adverse effects such as nausea, vomiting, and weight loss.