Newer Glucose-Lowering Drugs and Risk of Parkinson's Disease-A Meta-analysis of Randomized Outcome Trials

Background: Cumulative results from preclinical studies have shown that newer glucose-lowering drugs (GLDs), i.e., dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and sodium-glucose co-transporter-2 (SGLT2) inhibitors, have been associated with a decreased risk of Parkinson’s disease (PD). The findings from clinical and epidemiological studies are however mixed. We aimed to evaluate the potential effect of newer GLDs on the risk of PD through a meta-analysis of randomized outcome trial data. Methods: We systematically searched Pubmed, Embase, and CENTRAL up to December 2022 for published randomized placebo-controlled outcome trials evaluating DPP-4 inhibitors, GLP-1RAs, and SGLT2 inhibitors. We extracted PD outcomes from clinicaltrials.gov. We estimated pooled odds ratios (OR) and 95% confidence interval (CI) using the Peto method and we performed a subgroup analysis by type of newer GLDs. Results: Of 24 trials that qualified for inclusion, there were 33 incident PD cases among 185,305 participants with or without type 2 diabetes over a median follow-up of 2.2 years. Newer GLDs were significantly associated with a lower risk of PD than placebo (OR, 0.50; 95%CI, 0.25-0.98). Our subgroup analysis showed that DPP-4 inhibitors (OR, 0.71; 95%CI, 0.23-2.22), GLP-1RAs (OR, 0.51; 95%CI, 0.10 - 2.55), or SGLT2 inhibitors (OR, 0.37; 95%CI, 0.13-1.01) were all associated with a decreased risk of PD, but the differences were marginally or not statistically significant. Conclusion: Newer GLDs may be associated with a decreased risk of developing PD. Given the low number of events and short duration of follow-up of existing clinical trials, comparative effectiveness studies using real-world data (RWD) are warranted. These RWD-based studies can pave the way for evaluating the potential drug repurposing value of these newer GLDs for PD, before moving to large-scale randomized controlled trials. Disclosure H.Tang: None. Y.Lu: None. W.T.Donahoo: None. M.S.Okun: None. F.Wang: None. J.Bian: None. J.Guo: Consultant; Pfizer Inc., Research Support; PhRMA Foundation, NIH - National Institutes of Health. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK133465)