The darlings of the weight loss and diabetes spaces, GLP-1 receptor agonists have shown promise against Alzheimer’s in recent studies—with Phase III results expected next year from Novo Nordisk.
Data from two recent studies showed that Novo Nordisk’s GLP-1 drugs semaglutide (marketed as Ozempic and Wegovy) and liraglutide could help protect against Alzheimer’s disease or cognitive decline in Alzheimer’s, sparking hope that the trendy therapeutic class could offer a new weapon in medicine’s arsenal against the memory-robbing disorder.
The more recent paper, published in Alzheimer’s and Dementia in October, described a real-world study showing that patients with type 2 diabetes taking semaglutide had a 40% to 70% reduction in the risk of Alzheimer’s disease diagnosis. This followed results from a Phase II trial of liraglutide, Novo’s older GLP-1 (sold as Saxenda in obesity and Victoza in type 2 diabetes), demonstrating slower decline in cognitive function among patients on the drug compared with placebo. These data were announced at the Alzheimer’s Association International Conference in July.
“I think we are at the verge of a revolution,” said Christian Hölscher, co-founder and chief scientific officer at neurodegeneration-focused Kariya Pharmaceuticals, which is developing GLP-1 treatments.
Neuroscientist George Perry of the University of Texas at San Antonio was more cautious in his evaluation of the drug class for Alzheimer’s, speculating that if there is a role for GLP-1s in this space, it would be preventative, though he didn’t rule out the idea that GLP-1s could be disease-modifying. “I think there’s some evidence . . . that there’s really a profound metabolic change in the person during Alzheimer’s disease,” he said. If GLP-1s could reverse this, “that would be really exceptional, but I don’t think there’s any evidence for that.”
While preclinical studies have shown benefits of GLP-1 receptor agonists in targeting the core pathology of Alzheimer’s disease, data from clinical studies are limited, according to an article recently published in the Journal of Alzheimer’s Disease Reports. That’s set to change next year, however, when Novo is expecting readouts from two large Phase III trials, EVOKE and EVOKE Plus, testing semaglutide in patients with Alzheimer’s. Both trials are expected to be completed in September 2025.
“I’m confident that we will see some effects in the Novo Nordisk trials . . . because everything we’ve seen so far supports this concept,” Hölscher told BioSpace. “We know this is a worthwhile target and it definitely should be pursued.”
The Diabetes-Alzheimer’s Connection
The idea of using GLP-1s for Alzheimer’s isn’t out of left field, noted Graig Suvannevejh, senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas. There has always been an interest in whether drugs that are used for diabetes and targeting metabolic disease and endocrine disease pathways could have an impact on Alzheimer’s disease, he told BioSpace.
While there is much debate about what actually causes the disorder, Perry said there is an “intersection of diabetes and midlife obesity with Alzheimer’s disease.”
Indeed, several studies have suggested the connection between insulin resistance and Alzheimer’s. The hypothesis has even led to Alzheimer’s disease being dubbed “type 3 diabetes.” Multiple observational studies and meta-analyses have also linked type 2 diabetes to an increased risk of Alzheimer’s.
“There’s no doubt there’s increasing insulin resistance with aging across the whole body,” meaning that cells fail to take up glucose in response to the hormone, Howard Fillit, co-founder and chief science officer at the Alzheimer’s Drug Discovery Foundation (ADDF), previously told BioSpace. “When there’s sub-optimal glucose and highly active neurons have limited access to energy, they dysfunction and ultimately die on a chronic basis.”
If insulin resistance is indeed a contributor to Alzheimer’s, it stands to reason that GLP-1s, which work by stimulating insulin secretion and slowing glucagon release, could help to stave off the disease.
Growing Body of Evidence
While researchers await the results of Novo’s EVOKE and EVOKE Plus studies, the body of evidence for GLP-1s’ potential role in preventing and treating Alzheimer’s is growing.
Perry, who served as an advisor on the October study of semaglutide, urged caution in interpreting the results of the retrospective analysis but said that it “pinpoints the real, clear metabolic dimension to Alzheimer’s disease.”
The results from the Phase II liraglutide trial supported the same hypothesis. With 204 people at multiple sites in the UK randomized to receive placebo or Novo’s drug, the study found that cognitive function in the liraglutide cohort declined 18% slower than in the placebo arm over one year of treatment.
“The slower loss of brain volume suggests liraglutide protects the brain, much like statins protect the heart,” Paul Edison, an Imperial College London professor of science who led the study, said in a statement. While noting the need for further research, Edison said liraglutide may reduce brain inflammation, lower insulin resistance, improve nerve cell communication and limit the harm of amyloid-beta and tau.
Meanwhile, Kariya is developing KP405, a first-in-class, dual GLP-1/GIP receptor agonist, initially for Parkinson’s disease with plans for a study in Alzheimer’s. Hölscher previously told BioSpace that drugs like liraglutide and semaglutide have limitations when it comes to treating diseases of the brain. “They’re actually designed to stay in the blood, which is good for diabetes but bad for Alzheimer’s because a drug that stays in the blood doesn’t get into the brain.” The key, therefore, to applying GLP-1s to dementia is getting the drug where it’s needed.
Kariya has removed “add-ons” such as fatty acids that keep GLP-1s in the blood, allowing its drugs to enter the brain at a higher rate, Hölscher explained. The addition of a TAT sequence that is recognized by cell membrane receptors further enable the drug to reach the brain faster, according to Kariya.
Hölscher credited these modifications for helping KP405 to avoid certain side effects linked to GLP-1s in the Phase I Parkinson’s study. “The GLP-1s, the ones designed to treat diabetes, they can cause nausea and stomach upset and all kinds of side effects,” he said. Because KP405 doesn’t stay in the bloodstream, “the peripheral effects are very little.”
As for Novo’s top GLP-1 competitor Eli Lilly, while there are no studies of tirzepatide in Alzheimer’s listed on the ClinicalTrials.gov database, Suvannevejh said it would be a natural fit for a company “whose entire existence is focused on neurology and neuroscience and Alzheimer’s disease.” Lilly’s monoclonal antibody Kisunla was approved in July, becoming the third disease-modifying treatment for the condition and the second actively on the market.
Eli Lilly did not respond to BioSpace‘s request for comment.
Still To Prove
Despite the positive signs in certain studies, experts agree that GLP-1s still have a ways to go to prove their worth in Alzheimer’s.
Perry said the class will need to show that it can really make a difference in lowering the incidence of the disease—something that requires analyzing large populations in random, controlled trials with patients—but that’s easier said than done. “The cost and even the practicality of doing the trial really becomes difficult . . . because how do you follow a bunch of 60-year-old people that have really a low chance of transitioning to Alzheimer’s disease?”
Another potential hurdle is safety. “One of the things [GLP-1s] need to show is if they’re safe for chronic use,” Perry said. “To be effective for Alzheimer’s disease, at least the paradigm I would imagine is that people would take this drug continuously . . . therefore you have to worry about side effects.”
But Hölscher also expressed concern with anti-amyloid antibodies like Kisunla and Biogen/Eisai’s Leqembi. “The antibodies are too toxic, and the effect in patients is so small that it is unlikely that patients even notice a difference.”
He made a bold prediction regarding Novo’s EVOKE and EVOKE Plus studies: “If those trials show even a small effect, the amyloid strategy will be dead in the water.”
