GLP-1RAs protective against dementia, stroke in people with T2D, obesity

For adults with type 2 diabetes (T2D) and obesity, the use of glucagon-like peptide 1 receptor agonists (GLP-1RAs) semaglutide and tirzepatide provides substantial protection against dementia, stroke, and death, according to a large retrospective cohort study.

In the analysis of data from more than 60,000 adults enrolled in the TriNetX network, GLP-1RA users had a 37-percent lower risk of dementia (hazard ratio [HR], 0.63, 95 percent confidence interval [CI], 0.50–0.81) and 19-percent lower risk of stroke (HR, 0.81, 95 percent CI, 0.70–0.93) compared with users of other glucose-lowering drugs. This protective benefit was not observed for other dementia subtypes (ie, Alzheimer’s disease and vascular dementia) and for intracerebral haemorrhage. [JAMA Netw Open 2025;8:e2521016]

GLP-1RA users also had a 30-percent lower risk of all-cause mortality compared with users of other glucose-lowering drugs (HR, 0.70, 95 percent CI, 0.63–0.78). This finding persisted in supplementary analyses addressing death as a potential competing risk for neurodegenerative and cerebrovascular outcomes.

Looking at subgroups, the association between GLP-1RAs and neurodegenerative and cerebrovascular outcomes was pronounced among individuals aged 60 years or older (HR, 0.85, 95 percent CI, 0.74–0.99), women (HR, 0.85, 95 percent CI, 0.74–0.97), and those with a BMI of 30–40 kg/m² (HR, 0.82, 95 percent CI, 0.72–0.93).

Further comparison of GLP1-RAs showed a significantly lower risk of dementia with semaglutide (HR, 0.63, 95 percent CI, 0.50–0.79) and that of stroke with tirzepatide (HR, 0.69, 95 percent CI, 0.48–0.98) vs other glucose-lowering drugs. Tirzepatide was also associated with a substantially lower all-cause mortality risk (HR, 0.48, 95 percent CI, 0.35–0.66).

“Our findings align with previous studies supporting the neuroprotective potential of GLP-1RAs in dementia but not in mild cognitive impairment, suggesting that the neuroprotection offered by GLP-1RAs may become more evident during later stages of cognitive decline,” the investigators said. [Alzheimers Dement 2022;8:e12268; Alzheimers Dement 2024;20:8661-8672; Diabetes Metab Res Rev 2023;39:e3673]

Additionally, the mortality benefit seen with GLP-1RA corroborates earlier studies, suggesting that GLP-1RAs may not only improve cardiometabolic health but also enhance overall survival by way of metabolic modulation, decreased cardiovascular and stroke events, kidney protection, anti-inflammation, and immunomodulation. [Pharm Res 2022;39:1233-1248; N Engl J Med 2024;391:109-121; BMJ 2021;372:m4573] 

“Accordingly, GLP-1RAs may help alleviate the overall disease burden of obesity and diabetes, providing cardiometabolic and neurocognitive benefits that improve health and life expectancy,” they added.

The analysis included 60,860 adults with T2D and comorbid obesity, including 30,430 GLP-1RA users (mean age 57.9 years, 50.2 percent female, 55.6 percent White) and 30,430 propensity–score-matched users of other glucose-lowering drugs (mean age 58.0 years, 51.4 percent female, 56.1 percent White).

“Unlike prior cohort studies focusing solely on T2D or obesity, our large-scale analysis specifically targeted high-risk patients with both diabetes and obesity treated with the newer GLP-1RAs semaglutide and tirzepatide,” the investigators said. “[Overall, the present data] highlight the possible role of GLP-1RAs in mitigating neurodegenerative and cerebrovascular risks in this high-risk population.” [Alzheimers Dement 2024;20:8661-8672; Int Immunopharmacol 2024;143:113537]