Trial Results Suggest Older GLP-1 Drug May Slow Cognitive Decline in Alzheimer Patients

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The results of a Phase IIb clinical trial suggest that the glucagon-like peptide-1 (GLP-1) drug liraglutide (Novo Nordisk) may slow cognitive decline associated with Alzheimer disease (AD) by protecting against shrinkage in areas of the brain controlling memory, learning, language, and decision-making.1 Findings of the ELAD trial, presented at the Alzheimer's Association International Conference 2024, show liraglutide may protect against mild AD and lower cognitive decline by as much as 18% following one year of treatment compared to placebo.

"The slower loss of brain volume suggests liraglutide protects the brain, much like statins protect the heart," said trial lead Paul Edison, MD, PhD, professor of science from Imperial College London, in a press release. "While further research is needed, liraglutide may work through various mechanisms, such as reducing inflammation in the brain, lowering insulin resistance and the toxic effects of Alzheimer's biomarkers amyloid-beta and tau, and improving how the brain's nerve cells communicate."1

Liraglutide is currently indicated to treat diabetes under the brand name Victoza and to treat obesity under the brand name Saxenda. The GLP-1 receptor agonist class acts by mimicking the natural hormone GLP released after eating. Prior research conducted in animals indicate the drug class may also have neuroprotective effects by lowering early forms of amyloid, normalizing glucose processing in the brain, and improving memory and learning.1

A study published by Nature Metabolism in August 2023 found that liraglutide helped normalize sensory-associated learning and restored brain circuit function in patients with obesity and diminished insulin sensitivity.2

“We show here that basic behaviors such as associative learning depend not only on external environmental conditions but also on the body's metabolic state,” study author Marc Tittgemeyer, PhD, of the Max Planck Institute for Metabolism Research, said in a press release. “So, whether someone has overweight or not, also determines how the brain learns to associate sensory signals and what motivation is generated.”3

The randomized, double-blind, placebo-controlled ELAD trial enrolled 204 patients with mild AD across 24 clinics in the United Kingdom. Each patient was administered a daily subcutaneous injection of liraglutide for one year, with 102 patients administered up to 1.8 mg of liraglutide to compare with 102 patients administered a placebo. Prior to the study, all patients received an MRI to analyze brain structure and volumes, glucose metabolism PET scans, and detailed memory testing. The exams were subsequently repeated at the end of the study with regular safety visits.

The trial did not achieve the primary endpoint of change in cerebral glucose metabolic rate in the cortical regions of the brain. Liraglutide did achieve the secondary endpoint of change in scores for clinical and cognitive measures, as well as a statistically significant benefit in the exploratory endpoint of brain volume.

An MRI showed that patients in the liraglutide cohort experienced approximately 50% less volume loss in several areas of the brain, including frontal, temporal, parietal, and total gray matter, which impact memory, language, and decision-making. Cognitive testing conducted prior to treatment and again at weeks 24 and 52 showed that patients administered liraglutide experienced an 18% reduction in cognitive function decline over one year compared to the placebo cohort. Patients completing 52 weeks of treatment (treatment n=79, placebo n=87) experienced a statistically significant slowing in cognitive decline (p<0.01).

In terms of safety, the most frequently reported adverse events (AEs) were gastrointestinal in nature, such as nausea, comprising 25.5% of all AEs in the liraglutide cohort. Further, 25 serious AEs were reported in 18 patients in the placebo cohort and seven patients in the liraglutide cohort. Investigators stated that the most serious AEs were unlikely to be related to liraglutide.

"We are in an era of unprecedented promise, with new treatments in various stages of development that slow or may possibly prevent cognitive decline due to Alzheimer's disease," Maria C. Carrillo, PhD, Alzheimer's Association chief science officer and medical affairs lead, said in a press release. "This research provides hope that more options for changing the course of the disease are on the horizon.

"Repurposing drugs already approved for other conditions has the advantage of providing data and experience from previous research and practical use—so we already know a lot about real-world effectiveness in other diseases and side effects.”1

References

1. GLP-1 DRUG LIRAGLUTIDE MAY PROTECT AGAINST DEMENTIA. News release. Alzheimer's Association. July 30, 2024. Accessed July 30, 2024. https://prnmedia.prnewswire.com/news-releases/glp-1-drug-liraglutide-may-protect-against-dementia-302209255.html

2. Hanssen R, Rigoux L, Kuzmanovic B, Iglesias S, et al. Liraglutide restores impaired associative learning in individuals with obesity. Nat Metab. 2023;10.1038/s42255-023-00859-y. doi:10.1038/s42255-023-00859-y

3. Anti-obesity drug improves associative learning in people with obesity. News release. Science Daily. August 17, 2023. Accessed July 30, 2024. https://www.sciencedaily.com/releases/2023/08/230817163920.htm