SGLT2 inhibitors vs. metformin for Parkinson's disease risk reduction in type 2 diabetes

Summary This study is the first large-scale, head-to-head comparison suggesting that sodium-glucose cotransporter-2 inhibitors (SGLT2is) may offer greater neuroprotection against Parkinson's disease (PD) compared to metformin in patients with type 2 diabetes mellitus (T2DM). Utilizing a 20-year real-world dataset and propensity score matching, we found that SGLT2i users had a 28% lower adjusted hazard ratio (aHR) for PD (0.72; 95% CI, 0.62–0.84) and reduced all-cause mortality. Unlike previous studies suggesting a potential increased PD risk with SGLT2is, our robust study design, stringent exclusion criteria, and competing risk adjustments support a protective association. The findings highlight the need for further prospective research to explore the neuroprotective benefits of SGLT2is, which may justify prioritizing their use in T2DM patients at risk for neurodegeneration. Background Type 2 diabetes mellitus (T2DM) is linked to an increased risk of Parkinson's disease (PD), likely mediated by insulin resistance, inflammation, and mitochondrial dysfunction. While metformin has shown neuroprotective effects, sodium-glucose cotransporter-2 inhibitors (SGLT2is) have emerging benefits in neurodegeneration. This study provides the first real-world head-to-head comparison of SGLT2is and metformin on PD risk in T2DM patients. Methods Using the TriNetX platform, we analyzed a 20-year dataset (2005–2025) from 142 healthcare organizations, identifying 913,428 T2DM patients (96,018 SGLT2i, 817,410 metformin users). Patients with prior PD, neurodegenerative diseases, or exposure to neuroprotective/neurotoxic antidiabetic drugs were excluded. Propensity score matching (1:1) balanced cohorts across demographic, clinical, and pharmacological variables. Cox proportional hazards models estimated adjusted hazard ratios (aHRs), validated by positive and negative controls. Results SGLT2i use was associated with a 28% lower PD risk than metformin (aHR = 0.72; 95% CI, 0.62–0.84; p < 0.0001). Dementia, a positive control, also showed reduced risk (aHR = 0.73; 95% CI, 0.68–0.78; p < 0.0001), reinforcing the neuroprotective effect. Negative controls confirmed specificity. SGLT2i users had significantly lower all-cause mortality (aHR = 0.85; 95% CI, 0.83–0.89; p < 0.0001). Conclusions This first large-scale comparison suggests SGLT2is provide superior neuroprotection against PD compared to metformin in T2DM patients, warranting further investigation.