Older GLP-1 drug shows glimmer of benefit in Alzheimer's

It's possible that Alzheimer's disease could be added to the lengthening list of health conditions that can be improved by treatment with GLP-1 receptor agonists.

The phase 2 ELAD study of Novo Nordisk's once-daily injectable GLP-1 agonist liraglutide in people with early-stage Alzheimer's has shown that the drug was able to reduce shrinking in the areas of the brain that control memory, learning, language, and decision-making by nearly 50% compared to placebo.

Moreover, subjects taking liraglutide saw an 18% slower cognitive decline after a year's treatment compared to the control group, according to data presented at the Alzheimer's Association International Conference (AAIC) today.

Liraglutide is on the market as Victoza for diabetes and Saxenda for obesity. It has been largely superseded, however, by Novo Nordisk's semaglutide-based therapies, Ozempic for diabetes and Wegovy for obesity – which can be dosed by injection once a week.

Novo Nordisk is already running the EVOKE and EVOKE Plus trials of an oral formulation of semaglutide – sold as Rybelsus for diabetes – in around 3,700 people with early-stage Alzheimer's, with results expected in 2025.

At the very least, the positive ELAD result raises hopes of a positive outcome in that larger study. It comes after a large-scale observational study published earlier this month that suggested people who used Ozempic for diabetes had a lower risk of cognitive problems in the first year of use.

The main endpoint of ELAD – which enrolled 204 patients in the UK with mild-to-moderate Alzheimer's disease – was change in the cerebral glucose metabolic rate in the cortical regions of the brain, which was not met, but the improvements in brain volume and cognitive function were statistically significant.

The 50% slower reduction in brain volume affected the frontal, temporal, parietal, and total grey matter areas, measured using MRI, while the cognitive improvement was assessed using the ADAS EXEC z scale. It should be noted that the trial wasn't statistically powered to detect cognitive changes, so the latter result is exploratory.

"The slower loss of brain volume suggests liraglutide protects the brain, much like statins protect the heart," said lead investigator Professor Paul Edison of Imperial College London.

"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," he suggested.

The data, while preliminary, was hailed by Dr Sheona Scales, director of research at Alzheimer's Research UK, who said: "Developing drugs for diseases like Alzheimer's is costly and can take many years. Being able to repurpose drugs already licensed for other health conditions could help accelerate progress and open up new avenues to prevent or treat dementia-causing diseases."

Prof Stephen Evans, emeritus professor of the London School of Hygiene and Tropical Medicine, sounded a note of caution, however, saying that the repurposing of drugs is an important avenue of research, but that "there is a lot of uncertainty" there.

He added: "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."