Promising New Data Support GLP-1s for Dementia Prevention

A new study supports the potential to repurpose glucagon-like peptide 1 (GLP-1) receptor agonists, used to treat type 2 diabetes and obesity, for dementia prevention. 

In the phase 2b ELAD clinical trial, adults with early-stage Alzheimer’s disease (AD) taking the GLP-1 receptor agonist liraglutide exhibited slower decline in memory and thinking and experienced less brain atrophy over 12 months compared with placebo.

“The slower loss of brain volume suggests liraglutide protects the brain, much like statins protect the heart,” study chief Paul Edison, MD, PhD, with Imperial College London, London, United Kingdom, said in a statement.

“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 said.

He presented the study results on July 30 at the Alzheimer’s Association International Conference 2024.

Brain Benefits

Liraglutide has previously demonstrated promising neuroprotective effects in animal models of AD and epidemiologic studies. 

In the ELAD trial, 204 patients with mild to moderate AD were randomly allocated (1:1) to a daily subcutaneous injection of up to 1.8 mg of liraglutide or placebo for 12 months; 80 patients in the liraglutide group and 89 in the placebo group completed the study. 

Brain MRI was performed at baseline and at 12 months, along with neuropsychometric evaluation and 18F-fludeoxyglucose PET. 

The study’s primary endpoint — change in the cerebral glucose metabolic rate in the cortical regions of the brain (hippocampus, medial temporal lobe, and posterior cingulate) — was not met. 

However, patients taking liraglutide experienced a significant slowing of cognitive decline, compared with placebo group (P = .01), which was a key secondary outcome, calculated as a composite score of 18 different tests of memory, comprehension, language, and spatial orientation. 

Although the study was not powered to assess cognitive changes, adults taking liraglutide had an 18% slower decline in cognitive function over 12 months compared with those on placebo, Edison reported. 

In addition, patients treated with liraglutide had nearly 50% less volume loss in several areas of the brain involved in memory, language, and decision-making, including frontal, temporal, parietal, and total gray matter, as measured by MRI. 

Liraglutide daily subcutaneous injections were safe and well tolerated in patients with AD, Edison reported. There were 25 serious side effects — 18 in the placebo group and seven in the liraglutide group, — and most were considered unlikely to be related to the study treatment. There were no deaths. 

Promising, Preliminary

This study shows a positive effect of liraglutide on the brain in terms of “slowing down of brain atrophy and slowing down the rate of cognitive decline,” said Howard Fillit, MD, founding executive director of the Alzheimer’s Drug Discovery Foundation, who wasn’t involved in the study.

Heather Snyder, PhD, vice-president of medical and scientific relations at the Alzheimer’s Association, said it’s “interesting” to see slowing of brain volume loss and some cognitive benefit “especially as the study was not powered necessarily to see some of those changes. 

The fact that they did see these changes in this small study provides a window into what may happen, but we certainly need larger phase 3 studies,” she told Medscape Medical News.

In a statement from the UK nonprofit Science Media Centre, Tara Spires-Jones, PhD, president of the British Neuroscience Association and group leader at the UK Dementia Research Institute, called the data “promising.”

“There are clear links from strong data in the field between vascular risk factors including diabetes and obesity being associated with increased risk of dementia. The GLP-1 drug should help reduce these risk factors as well as potentially directly protecting brain cells,” Spires-Jones said. 

However, she said “more research in bigger trials is needed to confirm whether this type of treatment will be effective in people with Alzheimer’s disease.”

Stephen Evans, MSc, emeritus professor, London School of Hygiene and Tropical Medicine, London, United Kingdom, noted that the repurposing of drugs is “an important avenue of research but there is a lot of uncertainty here.”

He cautioned that the “50% brain volume change may not translate to important cognitive effects, and reporting only on those who completed the full 52 weeks of treatment could bring bias into the results. It sounds like it is worth pursuing a larger trial, but these results cannot demonstrate that liraglutide can protect against dementia.”

The ongoing phase 3 EVOKE trial is investigating the effects of the GLP-1 receptor agonist semaglutide in early AD.

Funding for the study was provided by Alzheimer’s Society UK, Alzheimer’s Drug Discovery Foundation, Novo Nordisk AS, John and Lucille Van Geest Foundation, and the National Institute for Health and Care Research Biomedical Research Centre. Edison, Fillit, Snyder, Evans, Spires-Jones had no relevant conflicts of interest.