• Semaglutide provides a potential therapeutic avenue for aging-related neurodegenerative diseases, such as Alzheimer’s disease through enhanced brain glucose metabolism.
  • The comparable safety data presented by Novo Nordisk strengthens Semaglutide’s profile as a potential candidate in the early Alzheimer’s Disease market and provides the much-needed impetus as a treatment to slow the disease progression.

According to studies, having diabetes at the age of 55 increases the likelihood of acquiring dementia and Alzheimer’s disease due to an increased risk of brain artery damage. Semaglutide, a long-acting glucagon-like peptide-1 receptor agonist, mimics the naturally produced hormone glucagon-like peptide-1, and in preclinical animal studies has been shown to improve memory function, reduces phospho-tau accumulation, besides reducing neuroinflammation, which affects cognition and function.

Novo Nordisk presented findings from the phase III PIONEER, SUSTAIN, and STEP clinical studies at the American Academy of Neurology Annual Meeting (2024) in Denver, demonstrating the safety of semaglutide in individuals with type 2 diabetes (T2D) and overweight or obesity aged ≥55 years. This data supports and further validates the evaluation of semaglutide in an older population with early Alzheimer’s Disease in the Phase III EVOKE trials that aim to establish the efficacy of oral semaglutide in improving cognition and function. 

In the PIONEER (NCT02906930), SUSTAIN (NCT02207374; NCT02254291), and STEP (NCT03548935) clinical studies, which comprised 8595 participants aged 50 and older, semaglutide was administered orally once daily for PIONEER (3, 7, and 14 mg) and subcutaneously once-weekly in SUSTAIN and STEP ( 0.5 or 1 mg, and 2.4 mg, respectively). 

Overall, general adverse events (AEs) were 75.6%, 73.7%, and 91.9%, while, serious AEs were reported in 10.1%, 7.5%, and 12.4% of patients on semaglutide, in PIONEER, SUSTAIN, and STEP, respectively. In the semaglutide arms of PIONEER, SUSTAIN, and STEP, the percentages of individuals with adverse events that led to treatment discontinuation were 10.2%, 9.1%, and 7.7%. Gastrointestinal disorders were the most frequently reported AE, with nausea, diarrhea, constipation, and vomiting the most frequent gastrointestinal AEs. 

These findings corroborate Semaglutide’s favorable risk/benefit profile and offer a basis for evaluating the 4 mg dose of semaglutide in two phase III trials involving 1840 people with moderate cognitive impairment or mild dementia due to Alzheimer’s. EVOKE (NCT04777396) and EVOKE+ (NCT04777409) are randomized, double-blind, placebo-controlled trials enrolling persons aged 55-85 who are amyloid-positive, have mild cognitive impairment from Alzheimer’s, and have a Mini-Mental State Examination (MMSE) score of ≥22. For 156 weeks, participants were randomly assigned to receive either once-daily oral semaglutide 14 mg (titrated from 3 mg for the first four weeks to 7 mg for the next four weeks) or placebo plus standard of care. 

Alzheimer’s disease has been an area of increasing and extensive research over the past few decades, but progress in research and development is challenging due to the complexity and limited knowledge of the brain. The trial is underway and will provide the first insight into the potential of semaglutide, a T2D drug, which has up till now presented a compelling solution and increasing evidence of a potential therapeutic role for GLP-1, in the Alzheimer’s treatment landscape. Whether oral semaglutide will be able to secure its position in yet another lucrative market, only time will tell, as the drug may face fierce competition from various novel therapies entering the Alzheimer’s market over the next several years, but it “definitely has one talking.”