GLP-1 Receptor Agonists Investigated in People with Alzheimer Disease

Liraglutide Treatment Shows Slowed Decline in Executive Function and Slowed Loss of Select Brain Volumes in Alzheimer Disease

Once-daily treatment with Saxenda (liraglutide; Novo Nordisk, Plainsboro, NJ), a glucagon-like peptide-1 receptor agonist (GLP-1RA), over 12 months in people with early Alzheimer disease (AD) was not shown to significantly affect cerebral glucose metabolism but was shown to slow decline in executive function and reduce loss of select brain volumes. These findings from a phase 2b, placebo-controlled clinical trial (NCT01843075), published in Nature Medicine, suggest that GLP-1RA treatment over a prolonged period may positively influence cognition in people with AD, and may be associated with a neuroprotective effect. However, the study authors noted that further, larger studies are needed to confirm the data from these exploratory outcomes.

The Evaluating Liraglutide in Alzheimer’s Disease (ELAD) study took place across 24 sites in the United Kingdom and included 204 individuals who did not have diabetes. Study participants were randomized 1:1 to receive treatment with Saxenda as a subcutaneous injection up to 1.8 mg daily (n=102) or placebo (n=102) for a period of 52 weeks. The primary end point of the study was change in cerebral glucose metabolic rate in cortical regions of the brain. Secondary outcomes included cognitive and functional assessments (Alzheimer’s Disease Assessment Scale–Executive domain [ADAS-Exec], Clinical Dementia Rating–Sum of Boxes [CDR-SoB], and Alzheimer’s Disease Cooperative Study–Activities of Daily Living [ADCS-ADL]), as well as measurement of microglial activation, MRI changes, cerebrospinal fluid (CSF) biomarkers, and adverse events (AEs).

Key results from the trial include the following:

• There was no significant difference in cerebral glucose metabolism between those treated with Saxenda and those who received placebo (adjusted difference -0.17; 95% CI, -0.39 to 0.06; P=.14)
• Executive function (ADAS-Exec) scores declined less in the Saxenda-treated group vs the placebo group (z-score difference, 0.15; 95% CI, 0.03 to 0.28; P=.01).
• There were no significant differences in z-scores for CDR-SoB or ADCS-ADL between the Saxenda- and placebo-treated participants.
• Exploratory MRI analyses showed smaller reductions in total gray matter volume (7274 mm³; 95% CI, 2704.05 to 11,844.8; P=.002) and temporal lobe volume (696 mm³; 95% CI, 184.37 to 1208.12; P<.001) for those who received Saxenda vs placebo.
• Serious adverse events occurred in 6.9% of participants in the Saxenda group vs 17.6% in the placebo group.

Source: Edison P, Femminella GD, Ritchie C, et al. Liraglutide in mild to moderate Alzheimer’s disease: a phase 2b clinical trial. Nat Med (2025). doi:10.1038/s41591-025-04106-7.

Semaglutide Treatment in People with Early Symptomatic Alzheimer Disease Does not Show Significantly Reduced Clinical Progression

Treatment with another GLP-1RA, Ozempic (semaglutide; Novo Nordisk, Plainsboro, NJ), was not shown to significantly slow clinical progression in individuals with mild cognitive impairment (MCI) or mild dementia due to AD.

In results from the phase 3 EVOKE (NCT04777396) and EVOKE+ (NCT04777409) studies presented at the 18th annual Clinical Trials on Alzheimer’s Disease (CTAD) conference, which included a cumulative total of 3808 participants, there were no significant differences in the primary end point of CDR-SoB over 104 weeks, nor any key secondary measures (ADCS–ADL-MCI or time to dementia progression) in those treated with Ozempic vs placebo. Exploratory analyses showed nominal reductions in several CSF biomarkers (eg, p-tau181, total tau, YKL-40), but no cognitive or functional benefit was observed. Safety and tolerability were consistent with prior studies of Ozempic treatment, with gastrointestinal events being most common.

According to an announcement from Novo Nordisk, the development of Ozempic for the treatment of people with AD has been discontinued following publication of results from the EVOKE and EVOKE+ trials.

Source: Cummings J, Johannsen P, Atri A, et al. EVOKE and EVOKE+: Two phase 3 randomised placebo-controlled trials of semaglutide in participants with early-stage Alzheimer’s disease (NCT04777396 and NCT04777409). Presented at: 18th annual Clinical Trials on Alzheimer’s Disease Conference; December 1-4, 2025; San Diego, California.

Novo Nordisk. Company Announcement: Novo Nordisk A/S: Evoke phase 3 trials did not demonstrate a statistically significant reduction in Alzheimer’s disease progression. Press Releases. Published 24 November, 2025. Accessed 9 December, 2025. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=916462