1 dic. 2025
Clinical trial insights and biological rationale behind semaglutide’s investigation in early Alzheimer’s disease.
In recent developments, Novo Nordisk has announced the discontinuation of its Phase 3 trial exploring the use of Semaglutide for Alzheimer's disease. This decision has sparked interest and curiosity about the potential of this intriguing medication.
What’s the Buzz About Semaglutide?
You might recognize Semaglutide by its more famous brand name, OzempicTM, which has set the spotlight for its off-label weight loss effects among celebrities, even though it isn’t FDA-approved specifically for shedding pounds. Originally developed as a treatment for type 2 diabetes, Semaglutide is a synthetic, long-acting GLP-1 agonist (glucagon-like peptide-1) that first received FDA approval back in 2017.
Novo Nordisk presents a trio of GLP-1 medications tailored for those managing type 2 diabetes:
Ozempic: This is the once-weekly injection that many are talking about. You start with a dose of 0.25 mg each week, and after four weeks, you can bump it up to 0.5 mg. If needed, you can increase it further up to a maximum of 1 mg weekly.
Rybelsus: If you prefer tablets over injections, Rybelsus is your go-to; it’s taken daily and delivers the benefits of Semaglutide in an oral form.
Victoza: This option comes as an injection that you administer once a day, offering three incremental dose options: starting at 0.6 mg and escalating to 1.2 mg or 1.8 mg weekly.
So, how does Semaglutide work its magic?
GLP-1 is an incretin hormone that plays a critical role in insulin secretion, glycemic control, and even body weight regulation. Initially, the challenge was its short half-life, hindering its use as a treatment. However, through innovative biochemical engineering such as albumin binding and optimized fatty-acid linkers, scientists have extended the lifespan of these drug analogs while keeping their receptor effectiveness intact.
GLP-1 receptors are found in various organs, especially the pancreas and brain, and improve glycemic control, assist with weight loss, and boost cardiovascular health. While Liraglutide is already making waves in the obesity treatment arena, Semaglutide is actively being explored for obesity, NASH, and even potential oral delivery methods. These well-designed analogs represent a significant leap forward in managing type 2 diabetes and may open doors to broader therapeutic benefits in the future (Knudsen & Lau, 2019).
Why is it used in clinical trials to treat Alzheimer's disease?
In December 2020, Novo Nordisk made a groundbreaking announcement: they are advancing an oral medication known as semaglutide into phase 3a clinical trials aimed at early Alzheimer's disease (AD). This decision comes on the heels of mounting evidence from preclinical studies and real-world data, suggesting that GLP-1 therapies could significantly reduce the risk of dementia. The company is launching an ambitious program involving around 3,700 participants to explore whether taking semaglutide once daily can positively impact those living with early-stage Alzheimer’s.
So, why this interest in semaglutide? Well, Alzheimer’s disease is intricately linked to the brain’s ability to process glucose, and previous studies have shown that GLP-1 agonists like semaglutide may actually boost cognitive function in models of Alzheimer’s. The specifics of how this works, however, have remained somewhat enigmatic until recently.
In a study by Wang et al. published in 2023, researchers revealed that a protein called SIRT1 plays a pivotal role in linking GLP-1 receptor activation to glucose transport in the brain. Their results showed that semaglutide not only improved cognition in mice but also enhanced brain glucose metabolism, seen through increased glucose uptake in PET-CT scans and improved glycolysis in neuronal cells. Remarkably, this study also demonstrated that semaglutide could reduce Alzheimer’s pathology by lowering the burden of amyloid-beta plaques in the 3xTg mouse model. Another exciting finding indicated that semaglutide boosted levels of oxytocin (OXT) in both mouse brain tissue and human Alzheimer’s organoids, while also decreasing harmful markers associated with neuroinflammation.
Furthermore, a more recent analysis by Wang et al. in 2024 examined the real-world implications of semaglutide in clinical practice. Utilizing a comprehensive U.S. electronic health record database that spans 116 million patients, the study identified over a million adults with type 2 diabetes who hadn’t been previously diagnosed with Alzheimer’s. The results suggest that semaglutide might lower the risk of developing Alzheimer’s in individuals with type 2 diabetes. However, it’s important to approach these findings with caution. A critical commentary by Hsu & Lai in 2024 pointed out significant methodological limitations in the study that could affect its conclusions. They advocate for future research to gather detailed data on dosage and duration, consider lifestyle factors influencing Alzheimer’s risk, track HbA1c trajectory, and employ validated comorbidity indices. All these enhancements would help pave the way for more credible and clinically relevant outcomes.
Evoke3 and Evoke3+ clinical trials data
In an exciting advancement for Alzheimer’s research, the Evoke and Evoke+ trials are paving the way for potential new treatments. These innovative randomized, double-blind, placebo-controlled phase 3 trials are investigating the effectiveness, safety, and tolerability of once-daily oral semaglutide in individuals facing early-stage symptomatic Alzheimer’s disease (AD).
Around 1,840 participants, men and women aged 55 to 85 - this study specifically targets those with mild cognitive impairment or mild dementia linked to confirmed amyloid abnormalities in the brain. The trial structure includes an extensive 12-week screening phase, followed by a main treatment period lasting 104 weeks and a 52-week extension, which incorporates an 8-week dose escalation period.
The primary focus of the trial is on primary measure outcomes, including changes in the Clinical Dementia Rating–Sum of Boxes (CDR-SB) score, a critical tool for assessing cognitive function and daily living abilities. Moreover, several secondary outcome measures delve into various aspects of cognitive health, such as the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory for Mild Cognitive Impairment (ADCS-ADL-MCI), the Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI) scores, C-reactive protein levels, and the monitoring of treatment emergent adverse events (TEAEs), alongside the time to the first occurrence of major adverse cardiovascular events (MACE).
Interestingly, semaglutide is a double-edged sword in this context. While it has demonstrated notable effectiveness in managing blood sugar levels, promoting weight loss, and reducing cardiovascular risks associated with diabetes, it also holds promise as a therapeutic strategy for Alzheimer’s due to its anti-neuroinflammatory properties. However, caution is warranted, as semaglutide therapy comes with potential adverse effects, including acute pancreatitis, pulmonary aspiration risks, acute kidney injury, gallbladder complications, nonarteritic anterior ischemic optic neuropathy, and diabetic retinopathy.
Moreover, certain contraindications exist, such as a history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, alongside considerations for pregnant individuals. It’s also essential to be aware of possible drug interactions, particularly with other diabetes medications like metformin and various antipsychotics, which are linked to weight gain.
What’s Next?
As the story unfolds, it’s essential to stay informed about the latest research and developments in Alzheimer's treatment. While Semaglutide's journey in Alzheimer's research may be on hold, its impact on diabetes management and potential cognitive benefits cannot be ignored. Keep an eye on ongoing studies and announcements from Novo Nordisk and other researchers as we explore the future of this remarkable medication and its implications for Alzheimer's disease and beyond.
The world of pharmaceuticals is ever evolving, and who knows what breakthroughs lie ahead!
References -
Cummings, J. L., Atri, A., Feldman, H. H., Hansson, O., Sano, M., Knop, F. K., Johannsen, P., León, T., & Scheltens, P. (2025). evoke and evoke+: design of two large-scale, double-blind, placebo-controlled, phase 3 studies evaluating efficacy, safety, and tolerability of semaglutide in early-stage symptomatic Alzheimer’s disease. Alzheimer S Research & Therapy, 17(1), 14. https://doi.org/10.1186/s13195-024-01666-7
Knudsen, L. B., & Lau, J. (2019). The discovery and development of liraglutide and semaglutide. Frontiers in Endocrinology, 10, 155. https://doi.org/10.3389/fendo.2019.00155
News details. (2025, November 24). Novo Nordisk A/S: Evoke phase 3 trials did not demonstrate a statistically significant reduction in Alzheimer's disease progression. Novo Nordisk. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=916462
News details. (2020, December 16). Novo Nordisk to enter phase 3 development in Alzheimer’s disease with oral semaglutide. Novo Nordisk. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=39097
Pillarisetti, L., & Agrawal, D. K. (2025). Semaglutide: Double-edged Sword with Risks and Benefits. Archives of Internal Medicine Research, 8(1), 1–13. https://doi.org/10.26502/aimr.0189
Semaglutide does not treat Alzheimer’s. Could it prevent dementia? | ALZFORUM. (2025, December 16). https://www.alzforum.org/news/conference-coverage/semaglutide-does-not-treat-alzheimers-could-it-prevent-dementia
Study details | NCT04777396 | A research study investigating semaglutide in people with Early Alzheimer’s Disease (EVOKE) | ClinicalTrials.gov. (n.d.). https://clinicaltrials.gov/study/NCT04777396
Study details | NCT04777409 | A research study investigating semaglutide in people with Early Alzheimer’s Disease (EVOKE Plus) | ClinicalTrials.gov. (n.d.). https://www.clinicaltrials.gov/study/NCT04777409?cond=Alzheimer%20Disease&intr=semaglutide&rank=2