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Antidiabetic medications, including GLP-1 receptor agonists and PPAR-<jats:italic>\u03b3<\/jats:italic> 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\u2009=\u2009\u22120.04, 95% CI [\u22120.74 to 0.66], <jats:italic>p<\/jats:italic>\u2009=\u20090.90), (MD\u2009=\u2009\u22120.88, 95% CI [\u22122.11 to 0.34], <jats:italic>p<\/jats:italic>\u2009=\u20090.16), (MD\u2009=\u2009\u22121.10, 95% CI [\u22122.61 to 0.42], <jats:italic>p<\/jats:italic>\u2009=\u20090.16), (MD\u2009=\u2009\u22120.09, 95% CI [\u22120.45 to 0.27], <jats:italic>p<\/jats:italic>\u2009=\u20090.64), respectively. However, for MATTIS-DRS and MADRS scores, results showed a significant difference favoring GLP-1 agonists (MD\u2009=\u20092.42, 95% CI [0.01 to 4.83], <jats:italic>p<\/jats:italic>\u2009=\u20090.05), (MD\u2009=\u2009\u22122.08, 95% CI [\u22123.93 to \u22120.23], <jats:italic>p<\/jats:italic>\u2009=\u20090.03) 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\u2019s 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.<\/jats:p>","DOI":"10.1007\/s10787-025-01873-0","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T11:09:35Z","timestamp":1754392175000},"page":"4577-4593","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Antidiabetic drugs in Parkinson\u2019s disease: a comprehensive meta-analysis on efficacy and safety with trial sequential analysis and GRADE evaluation"],"prefix":"10.1007","volume":"33","author":[{"given":"Amr M.","family":"Abou Elezz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kareem","family":"Khalefa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5802-2291","authenticated-orcid":false,"given":"Ahmed Farid","family":"Gadelmawla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7066-4374","authenticated-orcid":false,"given":"Youssef A.","family":"Khattab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8165-9470","authenticated-orcid":false,"given":"Mohamed","family":"Abo Zeid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,5]]},"reference":[{"key":"1873_CR1","doi-asserted-by":"publisher","first-page":"1843","DOI":"10.1210\/jc.2008-1296","volume":"94","author":"R Abu-Hamdah","year":"2009","unstructured":"Abu-Hamdah R, Rabiee A, Meneilly GS, Shannon RP, Andersen DK, Elahi D (2009) The extrapancreatic effects of glucagon-like peptide-1 and related peptides. 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