Semaglutide for Alzheimer's Disease

Not currently recruiting at 19 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Novo Nordisk A/S

Must be taking: Acetylcholinesterase inhibitors

Must not be taking: Systemic corticosteroids, immunosuppressants

Disqualifiers: Autoimmune diseases, CNS disease, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if semaglutide, a medication used for type 2 diabetes and excess weight, can aid in treating Alzheimer's disease by influencing the immune system and other body processes. Participants will receive either semaglutide or a placebo for 12 weeks, followed by semaglutide for an additional 52 weeks. The trial seeks participants with mild cognitive impairment or mild dementia due to Alzheimer's who are already on stable medication. Eligible participants need a study partner to assist with weekly injections. As a Phase 3 trial, this study represents the final step before potential FDA approval, offering participants a chance to contribute to groundbreaking research.

Do I need to stop my current medications for the trial?

The trial requires participants to be on a stable dose of acetylcholinesterase inhibitors for Alzheimer's disease for more than 90 days before starting. If you are taking systemic immunomodulating drugs, you must stop them 12 months before the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that semaglutide is generally safe for people. This medication, often used for type 2 diabetes and weight management, has been administered to many individuals with few serious side effects. In a large study involving over 60,000 patients, those using semaglutide had a lower risk of developing dementia-related conditions.

Some users of semaglutide have experienced mild side effects like nausea or an upset stomach, but these effects typically do not last long. As semaglutide undergoes final testing for Alzheimer's, it has already passed earlier safety checks. This suggests it is likely safe for most people, although further research is needed to confirm its safety specifically for Alzheimer's. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Alzheimer's disease?

Unlike the standard Alzheimer's treatments, which mainly focus on managing symptoms with medications like cholinesterase inhibitors and memantine, semaglutide offers a different approach. Originally used for diabetes, semaglutide is a GLP-1 receptor agonist that has shown potential in reducing inflammation and improving brain function. Researchers are excited because it targets underlying disease mechanisms, which could lead to not just symptom relief but also a slowing of disease progression. Additionally, its once-weekly subcutaneous administration is convenient and could improve adherence compared to daily oral medications.

What evidence suggests that semaglutide might be an effective treatment for Alzheimer's disease?

Research has shown that semaglutide can significantly reduce the risk of developing Alzheimer's disease. In earlier studies, individuals taking semaglutide had a 40% to 70% lower chance of developing Alzheimer's compared to those who did not take it. Another study found that semaglutide, commonly used for type 2 diabetes and weight loss, might also protect against Alzheimer's and other types of dementia. In this trial, participants will receive either semaglutide or a placebo during the study intervention period 1. These findings suggest that semaglutide could effectively lower the risk of Alzheimer's. ^{1 2 6 7}

Who Is on the Research Team?

Clinical Transparency (dept. 2834)

Principal Investigator

Novo Nordisk A/S

Are You a Good Fit for This Trial?

This trial is for men and women aged 55-75 with mild cognitive impairment or mild dementia due to Alzheimer's, confirmed by specific criteria. They must be on a stable dose of Alzheimer's medication for over 90 days and show amyloid presence in the brain. People with significant brain disease, autoimmune diseases, recent vaccinations, or use of immune-modifying drugs can't participate.

Inclusion Criteria

I am between 55 and 75 years old.

Clinical dementia rating (CDR) global score of 0.5 or 1 at screening (visit 1)

Mild cognitive impairment (MCI) or mild dementia of the Alzheimer's type according to the National Institute on Aging-Alzheimer's Association (NIA-AA) 2018 criteria

Exclusion Criteria

I haven't taken any immune system altering drugs in the last year.

I have not received any vaccines within 4 weeks before my first visit or won't until after visit 5.

I have an autoimmune disease like lupus or rheumatoid arthritis.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Period 1

Participants receive either semaglutide or placebo once-weekly subcutaneous injections for 12 weeks with dose escalation

12 weeks

Weekly visits for injections

Treatment Period 2

All participants receive semaglutide once-weekly subcutaneous injections for 52 weeks with dose escalation for those initially on placebo

52 weeks

Weekly visits for injections

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Placebo
• Semaglutide

Trial Overview The study tests Semaglutide's effects on the immune system and biological processes in Alzheimer's patients. Initially, participants are randomly given either Semaglutide or a placebo for 12 weeks; afterwards, all receive Semaglutide for 52 weeks. The medicine is administered weekly via an injection pen by a study partner.

How Is the Trial Designed?

Group I: Study intervention period 1 Experimental Treatment 2 Interventions

Participants will receive either semaglutide or placebo matched to semaglutide once-weekly subcutaneous (s.c.) injections for 12 weeks as an add on therapy to standard of care. Participants initially received 0.25 milligram (mg) once weekly and the dose was then escalated once in 4 weeks until the maintenance dose (1.0 mg) was reached: 0.25 mg (week 1 to week 4), 0.5 mg (week 5 to week 8), 1.0 mg (week 9 to week 12).

Group II: Study intervention period 2 Placebo Group 1 Intervention

All participants will receive 1.0 mg semaglutide s.c. injections once weekly for 52 weeks during study intervention period 2 as an add-on therapy to standard of care. Participants randomised to semaglutide s.c. 1.0 mg during study intervention period 1 remained on 1.0 mg target maintenance dose for 52 weeks from weeks 12-64. Participants initially randomised to placebo during study intervention period 1 will receive semaglutide s.c. in dose escalation fashion for 8 weeks (0.25 mg from weeks 12-16 and 0.5 mg from weeks 16-20) followed by a maintenance period from weeks 20-64 at dose 1.0 mg.

Who Is Running the Clinical Trial?

Novo Nordisk A/S

Lead Sponsor

Trials

1,578

Recruited

3,813,000+

Lars Fruergaard Jørgensen

Novo Nordisk A/S

Chief Executive Officer since 2017

MSc in Finance and Business Administration, Aarhus School of Business, Aarhus University, Denmark

Martin Holst Lange

Novo Nordisk A/S

Chief Medical Officer since 2021

MD from University of Copenhagen

Published Research Related to This Trial

In a phase 3 study involving 307 patients with relapsed and refractory multiple myeloma, the combination of isatuximab, pomalidomide, and dexamethasone significantly improved progression-free survival (11.5 months) compared to pomalidomide and dexamethasone alone (6.5 months).

The most common side effects included infusion reactions and upper respiratory infections, with a low incidence of treatment-related deaths, indicating that isatuximab is a relatively safe and effective treatment option for patients who have not responded to other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Attal, M., Richardson, PG., Rajkumar, SV., et al.[2020]

In a pooled analysis of phase 3a trials involving patients with type 2 diabetes, semaglutide demonstrated significant reductions in HbA1c and body weight, with greater efficacy observed in patients with higher baseline HbA1c levels.

The safety profile of semaglutide was consistent with other GLP-1 receptor agonists, primarily featuring gastrointestinal side effects, indicating it is a safe option for a wide range of patients with varying diabetes characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of baseline characteristics and beta-cell function on the efficacy and safety of subcutaneous once-weekly semaglutide: A patient-level, pooled analysis of the SUSTAIN 1-5 trials. Aroda, VR., Capehorn, MS., Chaykin, L., et al.[2022]

In two phase III trials involving 2764 participants with overweight or obesity, semaglutide 2.4 mg once weekly significantly improved cardiometabolic risk factors, including reductions in waist circumference, blood pressure, and fasting glucose compared to placebo.

The benefits of semaglutide were not sustained after stopping the treatment, indicating that ongoing administration may be necessary to maintain improvements in health outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Semaglutide improves cardiometabolic risk factors in adults with overweight or obesity: STEP 1 and 4 exploratory analyses. Kosiborod, MN., Bhatta, M., Davies, M., et al.[2023]

Semaglutide has shown potential protective effects against Alzheimer's disease by enhancing autophagy and inhibiting apoptosis in SH-SY5Y cells treated with Aβ25-35, a model for Alzheimer's.

The study found that semaglutide increased levels of autophagy-related proteins (like LC3II and Beclin-1) and decreased apoptosis-related proteins (like Bax), suggesting a mechanism through which it may help protect against neurodegeneration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Semaglutide-mediated protection against Aβ correlated with enhancement of autophagy and inhibition of apotosis. Chang, YF., Zhang, D., Hu, WM., et al.[2021]

Oral semaglutide significantly reduces HbA1c levels and body weight in patients with type 2 diabetes, showing greater efficacy than placebo and other antidiabetic agents in a review of 11 randomized controlled trials involving 9890 patients.

While oral semaglutide is effective in managing blood glucose and weight, it is associated with increased gastrointestinal side effects like nausea and vomiting, although it has a favorable safety profile regarding severe hypoglycemia and cardiovascular events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral semaglutide for type 2 diabetes: A systematic review and meta-analysis. Avgerinos, I., Michailidis, T., Liakos, A., et al.[2021]

In a study involving 2117 participants treated with semaglutide 2.4 mg for 68 weeks, gastrointestinal adverse events (AEs) like nausea and diarrhea were more common than in the placebo group, but these AEs were mostly mild and transient, with only 4.3% of participants discontinuing treatment due to them.

Weight loss with semaglutide was significant and similar in participants with and without GI AEs, indicating that the weight loss effects of semaglutide are largely independent of these gastrointestinal side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gastrointestinal tolerability of once-weekly semaglutide 2.4 mg in adults with overweight or obesity, and the relationship between gastrointestinal adverse events and weight loss. Wharton, S., Calanna, S., Davies, M., et al.[2022]

Subcutaneous daratumumab, a monoclonal antibody for multiple myeloma, has been shown to be non-inferior to the traditional intravenous formulation, providing similar efficacy with the added benefits of reduced infusion times and lower rates of infusion-related reactions.

Clinical trials, including PAVO, COLUMBA, and PLEIADES, support the use of subcutaneous daratumumab in both newly diagnosed and relapsed refractory myeloma patients, indicating it may improve patient quality of life and decrease healthcare resource use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An evaluation of subcutaneous daratumumab for the treatment of multiple myeloma. Paul, B., Atrash, S., Bhutani, M., et al.[2021]

Daratumumab significantly improves overall survival (OS) compared to pomalidomide plus low-dose dexamethasone in patients with heavily pretreated multiple myeloma, with hazard ratios indicating a strong treatment benefit (0.56 and 0.51 for two different studies).

The survival advantage of daratumumab is even more pronounced in patients who have not previously been treated with pomalidomide, suggesting it may be particularly effective in this subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative Efficacy of Daratumumab Monotherapy and Pomalidomide Plus Low-Dose Dexamethasone in the Treatment of Multiple Myeloma: A Matching Adjusted Indirect Comparison. Van Sanden, S., Ito, T., Diels, J., et al.[2019]

The combination of daratumumab, pomalidomide, and low-dose dexamethasone is shown to be a safe and effective treatment for relapsed/refractory multiple myeloma, with significant immune system enhancements observed in patients.

Treatment led to increased activation and proliferation of T cells, particularly CD8+ T cells, while also reducing certain immune cell types, suggesting a mechanism for improved immune-mediated tumor destruction without increasing exhausted T-cell phenotypes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunomodulation in Pomalidomide, Dexamethasone, and Daratumumab-Treated Patients with Relapsed/Refractory Multiple Myeloma. Pierceall, WE., Amatangelo, MD., Bahlis, NJ., et al.[2021]

Citations

1. alz-journals.onlinelibrary.wiley.com alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.14313

Associations of semaglutide with first‐time diagnosis of ... Semaglutide was associated with significantly reduced risk for first-time AD diagnosis, most strongly compared with insulin.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12262134/

Associations of semaglutide with Alzheimer's disease-related ... In a recent real-world emulation trial in T2D patients, we showed that semaglutide was associated with a significant 40%-70% reduction in AD ...

3. alzinfo.org alzinfo.org/articles/treatment/weight-loss-drugs-may-protect-against-alzheimers/

Weight Loss Drugs May Protect Against Alzheimer's Popular weight loss drugs like Ozempic and Wegovy may cut the risk of Alzheimer's disease and other forms of dementia, a large new analysis found.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12056300/

A pooled analysis of semaglutide in adults aged ≥ 65 years Participants aged ≥ 65 years receiving semaglutide had an estimated weight loss of 3.8% at week 52 compared to 0.1% with placebo. DISCUSSION.

5. alz.org alz.org/blog/2025/glp-1s-and-alzheimer-s-what-you-need-to-know

GLP-1s and Alzheimer's: What You Need to Know If the data are positive, the drug's manufacturer, Novo Nordisk, may apply for regulatory approval to market semaglutide for Alzheimer's disease ...

6. brightfocus.org brightfocus.org/resource/how-glp-1s-could-transform-alzheimers-treatment/

How GLP-1s Could Transform Alzheimer's Treatment The studies began in 2021 and are designed to provide definitive answers about whether semaglutide can slow cognitive decline and reduce brain ...

7. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2836412

Neurodegeneration and Stroke After Semaglutide and ... Findings In this cohort study of 60 860 patients, those treated with semaglutide or tirzepatide had significantly lower risks of dementia, ...