Semaglutide attenuates a proteomics-based dementia risk signature in older adults with overweight or obesity and cardiovascular disease without diabetes: A post hoc analysis of the SELECT phase 3 trial.
Level 2 - randomized trial
Post hoc secondary analysis of an individual randomized controlled trial
PubMed 42571323 · doi:10.1002/dad2.70432
What was done
In a post hoc analysis of the SELECT phase 3 trial, researchers analyzed non-fasted serum samples collected at baseline and week 104 from 2,970 adults aged 65 years or older with overweight or obesity and established cardiovascular disease without diabetes. Participants had been randomized to weekly semaglutide 2.4 mg or placebo. Predicted 5-year and 20-year all-cause dementia risks were assessed using the Dementia SomaSignal Test (dSST), a validated 25-protein plasma proteomics risk model.
What was found
Semaglutide reduced the increases in predicted dementia risk compared with placebo. For 5-year risk, semaglutide showed a 2.5-fold smaller increase, corresponding to a 26.0% lower predicted event rate (odds ratio 0.74, 95% CI 0.65-0.85). For 20-year risk, semaglutide showed a 1.67-fold smaller increase, corresponding to an 8.8% lower predicted event rate (odds ratio 0.91, 95% CI 0.88-0.94). Semaglutide also decreased the odds of shifting into a higher dementia risk category by 36% (beta -0.44; P < 0.001).
Why it matters
This study provides evidence that GLP-1 receptor agonists can modify multi-pathway biological proteomic signatures associated with long-term neurodegenerative risk in older adults with overweight or obesity and cardiovascular disease.
Limits
The study was a post hoc analysis rather than a prespecified primary trial outcome. Findings are based on a surrogate 25-protein risk signature rather than incident clinical dementia diagnoses or cognitive testing. The cohort was restricted to individuals aged 65 and older with established cardiovascular disease and overweight or obesity without diabetes, limiting generalizability to broader populations.
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