Comparative risks of dementia and Parkinson's disease with GLP-1 RAs versus other oral glucose-lowering medications in obese patients with type 2 diabetes: a large real-world cohort study.

Abstract

This study evaluates dementia and Parkinson's disease (PD) risk among patients with type 2 diabetes (T2D) and obesity initiating GLP-1 receptor agonists (GLP-1 RAs) compared with other oral glucose-lowering medications, addressing the unclear comparative neurocognitive effects despite GLP-1 RAs' neuroprotective potential in preclinical studies. This historical prospective cohort study used electronic health records from Clalit Health Services. Adults with T2D and obesity (body mass index [BMI] ≥30 kg/m²) initiating non-insulin glucose-lowering medications between 2008-2021 were included. After exclusions and 1:1 nearest-neighbor matching, the final cohort comprised 46,962 patients. Associations were assessed using Cox proportional hazards models. Among 46,962 matched participants (mean age, 62.8 years; 52.6% women), median follow-up period was 7 years. Dementia occurred in 1125 GLP-1 RA users (4.8%) and 1822 non-GLP-1 users (7.8%) (adjusted hazard ratio [HR], 0.86 (0.75-0.99)). PD occurred in 231 GLP-1 RA users (1.0%) and 338 non-GLP-1 users (1.4%) (0.90 (0.67-1.22)). In the secondary analysis, GLP-1 RA use was associated with lower risks of dementia compared with sulfonylureas (0.75 (0.61-0.93)) and PD (0.56 (0.36-0.86)). No significant differences were observed compared with DPP-4 inhibitors or SGLT2 inhibitors. Subgroup analyses showed stronger protective associations for dementia among women (0.78 (0.65-0.94)) and participants aged ≥65 years (0.82 (0.69-0.97)). The use of GLP-1 RAs was associated with a lower risk of dementia compared with other glucose-lowering therapies. These findings support the neuroprotective potential of GLP-1 RAs and highlight the importance of incorporating brain health into diabetes management strategies.