Neurodegeneration and Stroke After Semaglutide and Tirzepatide in Patients With Diabetes and Obesity

Importance Glucagon-like peptide 1 receptor agonists (GLP-1RAs), such as semaglutide and tirzepatide, provide cardiometabolic benefits to patients with type 2 diabetes and obesity, but their potential benefits in mitigating neurodegenerative and cerebrovascular diseases remain unclear. Objective To evaluate the association of semaglutide and tirzepatide with the incidence of dementia, Parkinson disease, ischemic stroke, intracerebral hemorrhage, and all-cause mortality compared with other antidiabetic drugs in adults with type 2 diabetes and obesity. Design, Setting, and Participants This retrospective cohort study analyzed electronic health record–based data from the TriNetX US network (December 1, 2017, to June 30, 2024) in adults aged 40 years or older with type 2 diabetes and obesity initiating semaglutide, tirzepatide, or other antidiabetic drugs, excluding those with prior neurodegenerative or cerebrovascular diseases. Propensity score matching was used to balance the baseline characteristics. Exposures Patients treated with antidiabetic drugs were categorized as GLP-1RA (semaglutide or tirzepatide) or other antidiabetic drug (biguanides, sulfonylureas, dipeptidyl peptidase 4 inhibitors, sodium-glucose cotransporter 2 inhibitors, thiazolidinediones, and α-glucosidase inhibitors) users. Main Outcomes and Measures The primary outcomes were the incidence of neurodegenerative diseases (dementia, Parkinson disease, and mild cognitive impairment) and cerebrovascular (stroke and intracerebral hemorrhage) diseases, while the secondary outcome was all-cause mortality. Cox proportional hazard models were used to estimate hazard ratios (HRs) with 95% CIs. Results A total of 60 860 adults with type 2 diabetes and obesity were included, with 30 430 each in the GLP-1RA group (mean [SD] age, 57.9 [9.9] years; 50.2% female) and the other antidiabetic drug group (mean [SD] age, 58.0 [10.8] years; 51.4% female) after propensity score matching. During a 7-year follow-up, GLP-1RA users had a lower risk of dementia (HR, 0.63; 95% CI, 0.50-0.81), stroke (HR, 0.81; 95% CI, 0.70-0.93), and all-cause mortality (HR, 0.70; 95% CI, 0.63-0.78), with no significant differences in the risk of Parkinson disease or intracerebral hemorrhage. Subgroup analyses revealed greater benefits in patients aged 60 years or older, women, and patients with a body mass index of 30 to 40. Conclusions and Relevance In this cohort study, the use of GLP-1RAs semaglutide and tirzepatide was associated with a lower risk of dementia, stroke, and all-cause mortality in adults with type 2 diabetes and obesity. These findings suggest potential neuroprotective and cerebrovascular benefits of GLP-1RAs beyond glycemic control, warranting further trials to confirm these outcomes.