From Glucose to Cognition: Where Repurposed Diabetes Drugs Stand in Alzheimer Disease

As World Diabetes Day is observed on November 14, a central question in Alzheimer disease (AD) research is whether drugs designed to control blood glucose can also alter the course of neurodegeneration. The largest test of that idea, Novo Nordisk's phase 3 EVOKE program of oral semaglutide, did not slow clinical decline, and attention has since shifted toward earlier intervention and combination approaches.

This feature traces how diabetes drugs became candidates for repurposing in AD, from the mechanistic and real-world evidence behind the hypothesis to the randomized trials that have tested it. It also looks at the studies still underway and what they are designed to answer.

A Hypothesis Built on Shared Biology

Much of the interest centers on glucagon-like peptide-1 receptor agonists (GLP-1RAs), the incretin-based class that includes liraglutide and semaglutide. In transgenic mouse models of AD, liraglutide improved memory and prevented synaptic loss while reducing β-amyloid and tau aggregation, neuroinflammation, and oxidative stress.¹ Investigators behind the semaglutide program framed their rationale around 2 early features of AD: glial activation and neurovascular dysfunction that can weaken the blood-brain barrier.²

Population data gave that preclinical work clinical weight. A 2022 analysis pooling 3 cardiovascular outcome trials in type 2 diabetes (T2D) found a lower dementia rate with GLP-1RAs than with placebo among 15,820 participants (HR, 0.47; 95% CI, 0.25-0.86).³

Later target trial emulations, which structure health record analyses to mimic a randomized trial, pointed the same way. Among more than 1 million patients with T2D, semaglutide was linked to a 40% to 70% lower risk of a first AD diagnosis compared with 7 other antidiabetic drugs.⁴ A 2025 study found comparable reductions in AD and related dementias with GLP-1RAs (HR, 0.67) and with sodium-glucose cotransporter-2 (SGLT2) inhibitors, a second glucose-lowering class (HR, 0.57).⁵

From Observation to Randomized Trials

The first randomized look in established disease came from ELAD (NCT01843075), a UK phase 2b trial of daily injectable liraglutide in 204 people with mild to moderate AD and no diabetes, published in December 2025. Over 52 weeks, liraglutide did not change the primary end point of cerebral glucose metabolism on FDG-PET (P = .14). It did show a nominal advantage in executive function (unadjusted P = .01), although global and functional measures, including the CDR-SB and ADCS-ADL, did not separate from placebo.¹

EVOKE and EVOKE+

EVOKE and EVOKE+ were built to answer the question at scale. The 2 phase 3, placebo-controlled trials (NCT04777396; NCT04777409) randomly assigned 3808 adults aged 55 to 85 years with amyloid-confirmed mild cognitive impairment (MCI) or mild dementia to once-daily oral semaglutide up to 14 mg or placebo across 566 sites in 40 countries. Topline results were presented at the 2025 Clinical Trials on Alzheimer's Disease (CTAD) conference, held December 1-4 in San Diego, California, and full data followed in The Lancet on March 19, 2026.^2,6

After 2 years, patients in both arms had declined at nearly the same pace. CDR-SB scores rose 2.3 points with semaglutide and 2.3 with placebo in EVOKE (difference, −0.08; 95% CI, −0.35 to 0.20), and 2.2 vs 2.1 points in EVOKE+ (difference, 0.10; 95% CI, −0.17 to 0.38).

The biomarker picture was less uniform. In a CSF substudy of 199 participants, semaglutide lowered markers of tau pathology, glial activation, and synaptic injury, including p-tau217, YKL-40, and neurogranin, by up to 10% relative to placebo, and plasma hsCRP declined in both trials.² Plasma p-tau levels, however, did not change.

The investigators offered several explanations. They cited a mean CSF semaglutide concentration of 0.08 nmol/L as evidence of limited central exposure, and noted that only 13.6% of participants had T2D, unlike the real-world cohorts that produced the original signal. They also raised earlier, presymptomatic treatment as a possibility the trials did not test. Discontinuations due to adverse events were about twice as common with semaglutide (roughly 17% vs 8%), and Novo Nordisk ended the planned 1-year extension.^2,6

What Is Still Being Tested

Other metabolic agents remain in the clinic. The National Institute on Aging-funded MAP trial (NCT04098666), a phase 2/3 study of the biguanide metformin, is comparing an extended-release formulation at up to 2000 mg daily with placebo over 18 months in overweight or obese adults with amnestic MCI and no diabetes. It reached primary completion in April 2026, with final completion expected in April 2027.⁷

Prevention is the other front. At the 2026 Alzheimer's Association International Conference (AAIC), held July 12-15 in London, the Alzheimer's Association launched PROTECT-Cog, a $100 million, 3-year global trial. The study will test whether adding a GLP-1RA or similar metabolism-targeting drug to the U.S. POINTER multidomain lifestyle program further lowers the risk of cognitive decline in at-risk older adults, moving the question from slowing established disease to preventing it.⁸

REFERENCES
1. Edison P, Femminella GD, Ritchie C, et al. Liraglutide in mild to moderate Alzheimer's disease: a phase 2b clinical trial. Nat Med. 2026;32(1):353-361. doi:10.1038/s41591-025-04106-7. https://pmc.ncbi.nlm.nih.gov/articles/PMC12823385/
2. Cummings JL, Atri A, Sano M, et al. Efficacy and safety of oral semaglutide 14 mg (flexible dose) in early-stage symptomatic Alzheimer's disease (evoke and evoke+): two phase 3, randomised, placebo-controlled trials. Lancet. 2026;407:2167-2179. doi:10.1016/S0140-6736(26)00459-9. https://pubmed.ncbi.nlm.nih.gov/41865758/
3. Nørgaard CH, Friedrich S, Hansen CT, et al. Treatment with glucagon-like peptide-1 receptor agonists and incidence of dementia: data from pooled double-blind randomized controlled trials and nationwide disease and prescription registers. Alzheimers Dement (N Y). 2022;8(1):e12268. doi:10.1002/trc2.12268
4. Wang W, Wang Q, Qi X, et al. Associations of semaglutide with first-time diagnosis of Alzheimer's disease in patients with type 2 diabetes: target trial emulation using nationwide real-world data in the US. Alzheimers Dement. Published online October 24, 2024. doi:10.1002/alz.14313. https://pubmed.ncbi.nlm.nih.gov/39445596/
5. Tang H, Donahoo WT, DeKosky ST, et al. GLP-1RA and SGLT2i medications for type 2 diabetes and Alzheimer disease and related dementias. JAMA Neurol. Published online April 7, 2025. doi:10.1001/jamaneurol.2025.0353. https://pubmed.ncbi.nlm.nih.gov/40193118/
6. Novo Nordisk. Evoke phase 3 trials did not demonstrate a statistically significant reduction in Alzheimer's disease progression. News release. November 24, 2025. https://www.novonordisk.com/news-and-media/news-and-ir-materials/news-details.html?id=916462
7. Metformin in Alzheimer's Dementia Prevention (MAP). ClinicalTrials.gov identifier: NCT04098666. Updated August 7, 2026. Accessed November 12, 2026. https://clinicaltrials.gov/study/NCT04098666
8. Alzheimer's Association launches "PROTECT-Cog" study to test U.S. POINTER lifestyle and GLP-1 or similar drug to cut risk of cognitive decline. News release. Alzheimer's Association. July 13, 2026. https://aaic.alz.org/releases-2026/new-study-protect-cog-glp-1-dementia.asp