Novo Nordisk's semaglutide, known commercially as Ozempic and Wegovy, is under investigation for its potential to treat Alzheimer's disease, with Phase III trial results expected in September 2025. The EVOKE and EVOKE Plus trials are closely watched by researchers and clinicians alike, as they could signal a new direction in Alzheimer's treatment. These trials will evaluate the efficacy of oral semaglutide in slowing cognitive decline and other key markers of Alzheimer's progression.
The Diabetes-Alzheimer's Connection
The rationale behind using GLP-1 receptor agonists for Alzheimer's stems from observed links between insulin resistance, type 2 diabetes, and an increased risk of developing Alzheimer's. Some researchers have even proposed the term "type 3 diabetes" to describe Alzheimer's, highlighting the potential role of impaired insulin signaling in the brain. GLP-1s stimulate insulin secretion and regulate glucagon release, potentially improving insulin resistance in both the body and the brain.
Howard Fillit, co-founder and chief science officer at the Alzheimer’s Drug Discovery Foundation (ADDF), noted the increasing insulin resistance with aging, which can limit energy access for highly active neurons, leading to dysfunction and eventual cell death.
Emerging Evidence for GLP-1s in Alzheimer's
Recent studies have provided preliminary support for the potential of GLP-1 receptor agonists in Alzheimer's. A real-world study showed that patients with type 2 diabetes taking semaglutide had a 40% to 70% reduction in the risk of Alzheimer's disease diagnosis. Additionally, a Phase II trial of liraglutide, another GLP-1 drug, demonstrated a slower decline in cognitive function among patients on the drug compared to placebo.
Paul Edison, a professor of neuroscience at Imperial College London, led a study on liraglutide that found cognitive decline was 18% slower in the liraglutide group than in the placebo group over one year. Brain volume shrinkage was also reduced, suggesting a protective effect on the brain, similar to how statins protect the heart.
Challenges and Future Directions
Despite the promising signals, experts caution that more research is needed to confirm the benefits of GLP-1s in Alzheimer's. Key questions remain regarding the long-term safety and efficacy of these drugs for chronic use in an elderly population. Additionally, researchers are exploring novel GLP-1 therapies specifically designed to cross the blood-brain barrier more effectively.
Kariya Pharmaceuticals is developing KP405, a dual GLP-1/GIP receptor agonist, with modifications to enhance brain penetration and minimize peripheral side effects. Christian Hölcher, co-founder and chief scientific officer at Kariya, explained that standard GLP-1 drugs are designed to stay in the blood, which is beneficial for diabetes but limits their effectiveness in treating brain diseases like Alzheimer's.
While Eli Lilly has not yet announced clinical studies of tirzepatide in Alzheimer's, some experts believe it would be a logical next step, given the company's focus on neurology and neuroscience. The success of anti-amyloid antibodies like Leqembi and Kisunla has also raised the bar for new Alzheimer's therapies, requiring them to demonstrate significant clinical benefits.
Anticipated Trial Outcomes
The outcomes of Novo Nordisk's EVOKE and EVOKE Plus trials are eagerly awaited, as they could potentially reshape the Alzheimer's treatment landscape. If the trials demonstrate even a modest effect, it could shift the focus away from amyloid-based strategies and towards metabolic approaches to treating the disease.
