Liraglutide (a glucagon-like peptide-1, GLP-1) appears to slow cognitive decline by protecting the brain, according to Phase 2b clinical trial data reported at the Alzheimer’s Association International Conference (AAIC) 2024, in Philadelphia and online.
Previous research in animal models of Alzheimer’s disease suggests these drugs may have neuroprotective effects, reduce early forms of amyloid, normalise the brain’s processing of glucose, and improve memory and learning. This new research suggests liraglutide may protect the brains of people with mild Alzheimer’s disease and reduce cognitive decline by as much as 18% after one year of treatment compared to placebo, by slowing the shrinking of the parts of the brain that are vital for memory, learning, language and decision-making.
“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,” said Dr Maria C Carrillo, Alzheimer’s Association chief science officer and medical affairs lead. “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.”
The Alzheimer’s Association Part the Cloud research grants program has invested more than $82 million to advance 68 clinical trials targeting a variety of compounds, including repurposed drugs, addressing known and potential new aspects of the disease.
The randomised, double-blind, placebo-controlled Evaluating the Effects of the Novel GLP-1 Analogue Liraglutide in Alzheimer’s Disease (ELAD) trial led by Professor Paul Edison, professor of science from Imperial College London, included 204 patients with mild Alzheimer’s disease seen at 24 clinics throughout the United Kingdom. Each received a daily subcutaneous injection for one year: half (102) received up to 1.8mg of liraglutide and half (102) received a placebo.
Before the study began, all patients had magnetic resonance imaging (MRI) to evaluate brain structure and volumes, glucose metabolism PET scans and detailed memory testing. These were repeated at the end of the study with regular safety visits.
The study’s primary endpoint was change in the cerebral glucose metabolic rate in the cortical regions of the brain (hippocampus, medial temporal lobe and posterior cingulate), which was not met. However, the secondary endpoint of change in scores for clinical and cognitive measures and the exploratory endpoint of brain volume showed statistically significant benefit.
“The slower loss of brain volume suggests liraglutide protects the brain, much like statins protect the heart,” said Edison. “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.”
Edison added that those in the study who received liraglutide had nearly 50% less volume loss in several areas of the brain, including frontal, temporal, parietal and total grey matter, as measured by MRI. These areas are responsible for a variety of critical functions that often are affected by Alzheimer’s disease, including memory, language and decision-making.
Researchers also conducted cognitive testing in the patients before treatment and at 24 and 52 weeks. Although the study was not powered to assess cognitive changes, researchers found that patients who received liraglutide had an 18% slower decline in cognitive function in a year compared to those who got the placebo.
Cognitive function was calculated as a composite score of 18 different tests of memory, comprehension, language and spatial orientation (ADAS EXEC z score). For those in the study who completed 52 weeks of treatment (treatment n=79, placebo n=87), those taking the drug saw a statistically significant slowing of cognitive decline (p<0.01).
Gastrointestinal problems such as nausea were the most common side effects, which totalled 25.5% of all adverse events in the liraglutide group. Twenty-five serious side effects occurred in 18 participants (17.6%) in the placebo arm and seven participants (6.9%) in the treatment arm. Most serious side effects were considered unlikely to be related to the study treatment, Edison added.
Well-positioned to test this further are current late-stage clinical trials of GLP-1 analogues, several of which are ongoing. For example, EVOKE Plus is a 3-year clinical trial of semaglutide in more than 1,800 people with early Alzheimer's disease.
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