GLP-1 Agonist Liraglutide Shows Protective Effects on Alzheimer Disease in Phase 2 Trial

Paul Edison, MD, PhD

Newly reported research from a phase 2b study showed that treatment with liraglutide (Novo Nordisk), a glucagon-like peptide 1 (GLP-1) receptor agonist, has neuroprotective effects against Alzheimer disease (AD) dementia. Presented at the 2024 Alzheimer’s Association International Conference (AAIC), held July 28-August 1 in Philadelphia, Pennsylvania, these findings highlight the potential of GLP-1 analogues in the treatment of AD.

The study, a multicenter, randomized, double-blind, placebo-controlled trial, featured 204 patients with AD from 7 cohorts in the UK who were treated with either liraglutide or placebo as a daily subcutaneous injection for 12 months. At the conclusion of the treatment period, results on MRI showed a slower decline of temporal lobe volume and total grey matter volume in liraglutide-treated patients relative to those on placebo.

Although the primary end point of change in the cerebral glucose metabolic rate in the cortical regions of the brain was not met, the study revealed changes on secondary end points of clinical and cognitive measures and statistically significant benefits on brain volume. Overall, those on active treatment had an 18% slower decline in cognitive function at 1 year compared with placebo. Of note, the trial was not powered to assess cognitive changes.

"The slower loss of brain volume suggests liraglutide protects the brain, much like statins protect the heart,” lead investigator Paul Edison, MD, PhD, professor of science at Imperial College London, said in a statement.¹ "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."

In recent years, there has been growth from a research standpoint on GLP-1 agonists, notably known for treating diabetes mellitus (DM), and their potential impact on AD. Liraglutide, approved for type 2 DM, is also used to reduce the risk of life-threatening events, including heart attack and stroke, in adults with type 2 DM and established heart or blood vessel disease. It may be also used together with a reduced-calorie diet and proper excise to help patients with obesity lose weight.

READ MORE: Processed Red Meat Intake Linked to Increased Dementia Risk and Cognitive Decline

Among those who completed 52 weeks of treatment (liraglutide: n = 79; placebo: n = 87), patients on liraglutide showed a statistically significant slowing of cognitive decline on the Alzheimer’s Disease Assessment EXEC z score, which captures several aspects of memory, comprehension, language, and spatial orientation. Voxel-based morphometry (VMB) analysis revealed a slowed reduction in whole cortical grey matter, frontal, temporal, and parietal lobe volume in those treated with liraglutide vs placebo. Slower reductions observed in treated patients were associated with attenuated decline in cognitive function.

In terms of safety, gastrointestinal issues, found in 25.5% of treated patients, were the most common adverse events (AEs) of liraglutide. Notably, fewer patients on liraglutide (6.9%) experienced serious AEs in comparison with placebo (17.6%). Most serious AEs were considered unlikely to be related to study treatment.

Maria Carillo, PhD

"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 disease,” Maria Carillo, PhD, chief science officer and medical affairs lead at the Alzheimer’s Association, said in a statement.¹ "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."

Novo Nordisk is currently funding 2 international phase 3 studies to assessed semaglutide, another GLP-1 receptor agonist, in patients with early AD. Dubbed evoke (NCT04777396) and evoke+ (NCT04777409), each trial is expected to include 1840 amyloid-positive participants (aged 55-85 years) with mild cognitive impairment due to AD or mild AD dementia. Participants will be randomized 1:1 to either oral semaglutide 14 mg daily, escalated via 3- and 7-mg doses over 8 weeks, or placebo, for 156 weeks. Both trials, which use change in Clinical Dementia Rating-Sum of Boxes score as the primary end point, are expected to have data read out in 2025.²

During AAIC 2024, Edison sat down to discuss the data, including the primary cognitive and neuroimaging outcomes observed among patients with AD treated with liraglutide. In the video below, he also talked about how the findings of this study might influence future research or development of GLP-1 analogs for neurological conditions.

Click here for more coverage of AAIC 2024.

REFERENCES
1. GLP-1 drug liraglutide may protect against dementia. Alzheimer’s Association. July 30, 2024. Accessed July 31, 2024. https://aaic.alz.org/downloads2024/AAIC-2024-GLP-1-Ph2-trial.pdf
2. Atri A, Feldman HH, Honore JB, et al. evoke and evoke+: design of two large-scale, double-blind, placebo-controlled, phase 3 studies evaluating the neuroprotective effects of semaglutide in early Alzheimer’s disease. Presented at: AAIC 2022; ABSTRACT P3-004