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

<jats:sec id="ab-zoi250630-4"><jats:title>Importance</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec id="ab-zoi250630-5"><jats:title>Objective</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec id="ab-zoi250630-6"><jats:title>Design, Setting, and Participants</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec id="ab-zoi250630-7"><jats:title>Exposures</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec id="ab-zoi250630-8"><jats:title>Main Outcomes and Measures</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec id="ab-zoi250630-9"><jats:title>Results</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec id="ab-zoi250630-10"><jats:title>Conclusions and Relevance</jats:title><jats:p>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.</jats:p></jats:sec>