Oral semaglutide did not significantly slow the progression of early Alzheimer’s disease over two years, according to a study published in The Lancet on Mar. 22. The findings come from two large phase 3 clinical trials that evaluated the drug's efficacy and safety in people with mild Alzheimer’s dementia or mild cognitive impairment.
The results are important because they address hopes raised by earlier observational studies and biomarker research suggesting that semaglutide, a glucagon-like peptide 1 receptor agonist (GLP-1RA), might offer neuroprotective benefits for patients with Alzheimer’s disease. Interventions at early stages of the disease are considered critical for delaying progression and reducing long-term disability.
The evoke and evoke+ trials enrolled participants aged 55–85 years with confirmed amyloid pathology across 566 sites in 40 countries. Patients received flexible doses of oral semaglutide or placebo for up to three years alongside standard care. The primary outcome measured was change in cognitive and functional decline using the Clinical Dementia Rating Sum of Boxes (CDR-SB) at week 104.
Researchers found no statistically meaningful improvement in cognitive or functional outcomes for those taking semaglutide compared to placebo. Secondary endpoints, including memory and daily functioning measures, also showed no significant differences between groups. As the primary endpoint was not met, further confirmatory statistical testing was not conducted.
Semaglutide's safety profile was consistent with previous studies involving other conditions such as type 2 diabetes and obesity. Common side effects included weight loss, reduced appetite, and gastrointestinal symptoms like nausea. Serious adverse events were similar between treatment and placebo groups. While some reductions in inflammatory biomarkers were observed among those taking semaglutide, these changes did not result in measurable clinical benefits.
The study concludes that oral semaglutide does not slow cognitive or functional decline in early-stage Alzheimer’s disease over a two-year period. Researchers suggest that future studies may explore whether GLP-1RAs could have preventive effects if used earlier or combined with other therapies.
