GLP may slow brain volume decline and loss in Alzheimer's disease.

A new clinical trial showed promising safety and efficacy of liraglutide in the treatment of Alzheimer's disease.

Alzheimer's disease affects 24 million people worldwide, with one in three adults over the age of 85 living with the disease.Although Alzheimer's dementia is the most common form, there is still no cure.

Approved treatments that can slow the progression of the disease, namely Donanemab, provided by Eli Lilly, and Lecanemab, provided by Eisai.Both antibody treatments work by targeting and removing amyloid plaques from the brain, which are associated with the onset and progression of the disease.However, Alzheimer's disease is a complex disease with multiple mechanisms of pathogenesis, and there is a distinct lack of therapies targeting non-amyloid pathways.

Glucagon-like peptides (GLP) may be a solution to this problem.A new phase IIb clinical trial (NCT01843075) involving more than 200 patients, published in Nature Medicine, found that liraglutide may slow disease progression.

Push the line

The rate of progression of Alzheimer's disease varies greatly from person to person, with patients living anywhere from three to 20 years after diagnosis.Although there are currently no drugs on the market that can stop the disease, most focus on a simple goal - shopping time.

As Alzheimer's progresses from mild to severe disease, patients can go from memory loss and minor personality changes to completely losing the ability to speak.The disease can lead to patients needing help with daily activities, including eating, dressing and going to the toilet.A recent longitudinal study has shown that quality of life (QoL) declines rapidly across all aspects of Alzheimer's as the disease progresses.

Liraglutide is a GLP-1 agonist that was originally developed to treat type 2 diabetes by stimulating insulin production and reducing the amount of glucose produced by the body.Like other GLP-1 agonists, it is now also prescribed for weight loss.

New treatments for Alzheimer's disease, such as liraglutide, can slow the progression of the disease, allowing patients to maintain a better quality of life for longer.To study the effects of liraglutide, researchers at Imperial College London (England) began a 12-month, double-blind, controlled trial comparing the drug with a placebo control in patients with mild to moderate Alzheimer's disease.

To assess changes in brain structure, the researchers assessed tissue volumes observed in magnetic resonance imaging (MRI) and performed voxel-based morphometry analysis (VBM).

In MRI observations, the group treated with liraglutide experienced less tissue shrinkage in the temporal lobe, parietal lobe, frontoparietal area, and total volume of gray matter compared to the placebo group.When using the VBM analysis, Alzheimer patients treated with liraglutide showed statistically significantly slower decreases in frontal, parietal and temporal lobe, healthy cortical gray matter and white matter volumes.

Liraglutide-treated patients had significantly reduced progression of brain atrophy, although both the treatment and placebo groups lost cerebral volume.

"Liraglutide works in different ways," Paul Edison, corresponding author, told BioProcess Insider."Tau, neuroinflammation, microglial activation, astrocyte activation, insulin resistance and possibly amyloid".

The patient's cognitive function was then assessed using the ADAS-cog clinical instrument, a series of tasks that assessed and scored on the domains of language memory and praxis (motor planning ability, for example, raising hands when introduced).The cognitive decline assessed was slower in patients treated with liraglutide compared with administration.

"The ADAS-Exec is a composite of 18 tests, and they are calculated using the Z-score for the individual tests," Addison added."This reduces the natural variability associated with conventional tests used in Alzheimer's disease."

All that glitters is not gold.

Although these results sound promising, But many parameters of brain volume and maintenance of cognitive function were not met.

First, the primary outcome of the study assigned by the researchers was that the change in the rate of glucose metabolism in the brain was not statistically significant between the treatment and control groups.As seen in patients with Alzheimer's disease, the rate of brain glucose metabolism is reduced in cases of dementia or loss of cognitive function.

Although researchers noted encouraging results and slower cognitive decline in the treatment group using the ADAS-cog, when using two other scoring systems to measure Alzheimer's disease progression—Clinical Dementia Assessment and Activities of Daily Living)—the difference was not significant.

All three scores are widely used in health care settings to assess the progress and ongoing care needs of patients with Alzheimer's disease.However, a meta-analysis of 34 studies found that the ADAS-cog is more sensitive than clinical dementia score in assessing treatment outcomes.

"Liraglutide works by affecting the whole brain, so we showed a beneficial effect in a large area," Edison explained."Small areas such as the hippocampus and entorhinal cortex may have been damaged and become atrophic in these patients."

In addition, whole-brain positron emission tomography (PET) scans, considered more sensitive to molecular and metabolic changes in the brain, showed no significant differences between treatment and control groups. In fact, patients treated with liraglutide had worse results when assessed by PET scans, indicating greater loss of metabolic activity compared to controls, although this did not reach statistically significant levels.

Despite the mixed results, liragluit-treated patients in the treatment group showed significant improvements in brain atrophy in multiple regions compared to the food control that is achieved by a mechanism not only focused on reducing amyloid plaque.

In addition, liraglutide was well tolerated in Alzheimer's disease cohorts without diabetes mellitus and was shown to have a good safety profile.Adverse events were more frequent in the placebo group, with gastrointestinal-related adverse events reported in the treatment group being consistent with the GLP side effect profile.

The researchers say the 12-month study period may not be long enough to confirm liraglutide's long-term neuroprotective effects.It may be that there were no statistically significant differences in brain glucose metabolic rate despite the strong initial study (NCT01469351) and previous data.However, preliminary studies did not show statistically significant differences in brain glucose metabolism.

At the moment, it appears that liraglutide and other GLPs may have therapeutic effects on Alzheimer's patients, but the extent of its long-term effects and the underlying biological mechanisms are unknown.With a good and well-tolerated safety profile as well as greater effects on preserving brain mass and cognition, liraglutide deserves further investigation.

"We are now trying to see the mechanism by which GLP has beneficial effects and the possibility of conducting larger studies," said Edison."To advance liraglutide, we need larger phase III studies to demonstrate clinical efficacy."