Oral semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist widely used for the treatment of type 2 diabetes and obesity, failed to demonstrate a clinical benefit in slowing cognitive decline among patients with early Alzheimer’s disease (AD), according to topline results from two large phase 3 trials announced by Novo Nordisk.

The findings come from the EVOKE and EVOKE+ studies, which evaluated whether long-term treatment with oral semaglutide could modify disease progression in individuals with mild cognitive impairment or mild dementia caused by Alzheimer’s disease.

Background: Why Semaglutide Was Studied in Alzheimer’s Disease

Interest in GLP-1 receptor agonists as potential treatments for neurodegenerative diseases has grown in recent years. Preclinical studies and observational data suggested that these drugs may reduce neuroinflammation, improve insulin signaling in the brain, and potentially protect neurons from degeneration.

Because Alzheimer’s disease is increasingly recognized as having metabolic and inflammatory components, semaglutide emerged as a promising candidate for disease modification beyond its established metabolic benefits.

Study Design and Patient Population

The EVOKE and EVOKE+ trials were large, global, randomized, double-blind, placebo-controlled phase 3 studies. Together, they enrolled 3,808 adults aged 55 to 85 years with:

• Mild cognitive impairment due to Alzheimer’s disease, or

• Mild Alzheimer’s dementia

All participants had confirmed amyloid positivity, ensuring that enrolled patients met biological criteria for Alzheimer’s pathology.

Participants were randomly assigned to receive either:

• Once-daily oral semaglutide 14 mg, or

• Matching placebo

Treatment was administered for a total of 156 weeks, consisting of a 104-week main treatment period followed by a 52-week extension, in addition to standard background care for Alzheimer’s disease.

Primary and Secondary Endpoints

The primary endpoints of the trials focused on slowing cognitive and functional decline, as measured by standardized clinical assessment tools commonly used in Alzheimer’s research.

Secondary endpoints included measures of daily functioning, global clinical status, safety, and tolerability.

Topline Results: Primary Endpoints Not Met

According to Novo Nordisk’s announcement, neither EVOKE nor EVOKE+ met their primary endpoints. Patients receiving oral semaglutide did not show a statistically significant slowing of cognitive decline compared with those receiving placebo over the treatment period.

As a result, the trials did not provide evidence that semaglutide can modify disease progression in early Alzheimer’s disease.

Safety and Tolerability

Despite the lack of efficacy, semaglutide was generally well tolerated in the Alzheimer’s population. The safety profile observed in EVOKE and EVOKE+ was consistent with the known effects of GLP-1 receptor agonists.

Common adverse events included:

• Gastrointestinal symptoms such as nausea and vomiting

• Decreased appetite

• Weight loss

No new major safety concerns specific to the Alzheimer’s population were reported in the topline analysis.

Implications for Alzheimer’s Drug Development

The failure of semaglutide to demonstrate cognitive benefit underscores the ongoing challenges in developing effective treatments for Alzheimer’s disease. While metabolic and anti-inflammatory pathways remain areas of active investigation, these results suggest that targeting GLP-1 signaling alone may not be sufficient to alter disease progression once cognitive symptoms are present.

The findings also highlight the importance of large, long-term, biomarker-confirmed trials in accurately evaluating potential disease-modifying therapies.

What This Means for Patients and Clinicians

For clinicians, the results indicate that semaglutide should not be used with the expectation of slowing cognitive decline in early Alzheimer’s disease. Its use should remain limited to approved indications such as diabetes and weight management.

For patients and caregivers, the results are disappointing but provide clarity, helping to avoid off-label use that may not deliver meaningful cognitive benefits.

Next Steps

Novo Nordisk has stated that full trial data will be presented at upcoming scientific meetings and submitted for peer-reviewed publication. Further analyses may explore whether specific subgroups derived any benefit, although the overall primary outcomes were negative.

Meanwhile, research into Alzheimer’s disease continues to focus on amyloid-targeting therapies, tau-directed treatments, neuroinflammation, and combination approaches that may offer greater potential for slowing disease progression.

Conclusion

The phase 3 EVOKE and EVOKE+ trials demonstrate that oral semaglutide does not slow cognitive decline in patients with early Alzheimer’s disease, despite strong theoretical rationale and encouraging preclinical data. While the drug remains an important therapy for metabolic disorders, its role in Alzheimer’s disease appears limited based on current evidence.

The results reinforce the complexity of Alzheimer’s pathology and the urgent need for continued innovation in the search for effective disease-modifying treatments.