番茄社区

PHILADELPHIA -- A GLP-1 receptor agonist may have the ability to protect cognition in people with mild Alzheimer's dementia, data from the phase IIb ELAD trial suggested.

Liraglutide (Saxenda, Victoza) showed benefit on one of three secondary outcomes that measured cognition, reported Paul Edison, MD, PhD, of Imperial College London, at the Alzheimer's Association International Conference.

On the ADAS-Exec z-score -- a cognitive outcome that combined the Alzheimer's Disease Assessment Scale-Cognitive subscale and the executive domain portions of the Neuropsychological Test Battery -- participants who completed 52 weeks of liraglutide treatment had a statistically significant slowing of cognitive decline (P=0.01), Edison said.

The trial was not powered to detect cognitive changes, Edison pointed out, and liraglutide showed no effect on two other cognitive measures. It also failed on the study's primary outcome of cerebral glucose uptake compared with placebo.

However, the liraglutide group had less loss in temporal lobe volume and total gray matter volume than the placebo group (P<0.001). Voxel-based morphometry analysis showed the liraglutide group also had a slower reduction in whole cortical gray matter, frontal, temporal, and parietal lobe volume.

"What we have demonstrated is that there's a hint it can improve cognition," Edison told 番茄社区. The slower loss of brain volume suggests that liraglutide -- and perhaps other GLP-1 drugs -- might protect the brain, he added.

"These drugs are made for diabetes and now are being used for weight loss," Edison said. "But the same class of drug, which can get into the brain much better than existing drugs, could be made specifically for Alzheimer's disease."

The study offers hope that more options for treating Alzheimer's disease may be on the horizon, noted Maria Carrillo, PhD, chief science officer of the Alzheimer's Association.

"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," Carrillo said.

"We know that aging is the leading risk factor for Alzheimer's, but the disease is not a normal part of aging," noted Howard Fillit, MD, of the Alzheimer's Drug Discovery Foundation in New York City.

"Metabolic dysfunction is one of the various pathways linked to the underlying disease biology, and both diabetes and metabolic dysfunction are significant risk factors for Alzheimer's," he told 番茄社区.

"The brain uses around 20% of the body's energy supply and this mechanism breaks down as we age, leading many scientists to hypothesize GLP-1 agonists may help maintain the brain's glucose metabolic rate," Fillit continued. "If successful, these drugs have the potential to promote neuroprotection and reduce the likelihood of comorbidities, thus slowing - or potentially preventing - cognitive decline."

ELAD is one of several trials looking at whether GLP-1 drugs can benefit neurodegenerative diseases. In two phase III studies -- and -- the effects of the GLP-1 receptor agonist semaglutide (Ozempic, Wegovy) are being evaluated in early Alzheimer's.

Another trial is assessing whether semaglutide can change in people with or without diabetes who are amyloid-positive and have no or mild cognitive impairment. The GLP-1 receptor agonist lixisenatide (Adlyxin) also has been studied in Parkinson's.

In , GLP-1 receptor agonists have reduced neuroinflammation, tau, and amyloid, and have increased synaptic function. "These drugs have multiple mechanisms; they don't just work on one mechanism," Edison noted.

"I think it's primarily their influence on decreasing insulin resistance and improving neuronal function," he suggested. "Then comes reducing tau formation and neuroinflammation."

enrolled 204 diabetes-free participants in the U.K. with mild Alzheimer's dementia for a 12-month course of daily liraglutide 1.8 mg or placebo. PET, MRI, and cognitive tests were conducted at baseline and after 12 months of treatment. The study was completed in 2020.

Gastrointestinal problems like nausea were the most common adverse events in the liraglutide group. Serious adverse events were considered not likely to be related to treatment.

The study highlights the possible role of GLP-1 agonists in Alzheimer's disease, Edison observed.

"We need to demonstrate in a larger phase III study that the cognitive benefit comes through, but there's definitely great potential," he said.

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