A retrospective cohort study found that semaglutide and tirzepatide are linked with significantly lower risks of dementia and stroke, hinting at potential neuroprotective effects of GLP-1 therapies.
Novo Nordisk’s semaglutide and Eli Lilly’s tirzepatide—both leading GLP-1 agonists used for weight loss and diabetes—are associated with a lowered likelihood of developing neurodegenerative disorders such as dementia, according to a recent study.
The retrospective cohort study, published last week in JAMA Network Open, looked at electronic health record data of more than 60,800 adults 40 years and above with type 2 diabetes and obesity who had initiated treatment with semaglutide, tirzepatide or other antidiabetic drugs. Patients with prior neurodegenerative or cerebrovascular conditions were excluded from the analysis.
Over seven years of follow-up, patients treated with GLP-1 analogs were 37% less likely to develop dementia than counterparts on other antidiabetic medications. This effect was statistically significant.
Aside from dementia, the risks of ischemic stroke and all-cause mortality were likewise significantly reduced in patients treated with GLP-1s, with effect sizes of 19% and 30%, respectively. In contrast, GLP-1 therapies were not associated with altered risk of Parkinson’s disease, mild cognitive impairment and intracerebral hemorrhage versus other antidiabetic agents.
These findings carry the usual caveats of a cohort study, namely that it could carry “residual confounding from unmeasured factors,” according to the paper’s authors, such as the patients’ functional status and frailty. The database that the study drew from also does not have biomarker and genetic data or neuroimaging information, leaving a mechanistic blind spot for its results.
Still, these findings point to the “potential neuroprotective and cerebrovascular benefits” of GLP-1 drugs, according to the researchers, who added that future randomized trials in these patient populations are needed to “validate our findings and establish causality.”
Novo is already working toward that end. The Danish pharma is running the Phase III EVOKE and EVOKE Plus studies to test semaglutide in Alzheimer’s disease. Both studies have a primary completion date in September 2025. Novo has also previously tested its older-generation GLP-1 therapy liraglutide in a Phase IIb study and found that treated patients saw 18% slower cognitive decline than those on placebo.
For Lilly, the neuroprotective effects of tirzepatide could make the obesity drug a good complement to Kisunla, an anti-amyloid antibody approved in July 2024 for Alzheimer’s disease. The pharma is currently running the Phase III TRAILBLAZER ALZ-3 trial to test Kisunla in patients with preclinical disease.
In a July 22 note to investors, analysts at BMO Capital Markets said that the trial could read out sooner than expected, “potentially by the start of 4Q25.” Additionally, even an interim analysis could be sufficient to detect statistical significance on disease progression. In such a case, analysts added, data from TRAILBLAZER ALZ-3 “could illustrate the value of treating presymptomatic patients with beta-amyloid therapies.”
