09 Aug 2024

Among the hundreds of studies presented at this year’s Alzheimer’s Association International Conference, held July 27 to August 1 in Philadelphia, one of the few that made a splash in the news was not news at all. Perhaps spurred by a press release, media outlets reported that tantalizing results from a small trial suggested that the GLP-1 agonist liraglutide might shield the brain from dementia. The results were featured by Reuters, The Guardian, STAT News, USA Today, Forbes, CNN, and various national news channels.

Alas, the findings shown in Philadelphia were the same ones shared at the Clinical Trials for Alzheimer’s Disease conference back in 2020, after the trial had concluded in 2019. This information is available both at clinicaltrials.gov and, in chronologically narrated form, in Alzforum’s online therapeutics database. The same findings were also presented at AAIC in 2021, but were never published in a peer-reviewed journal.

Importantly, results from this Phase 2b trial, which compared liraglutide to placebo among 204 people with mild AD who did not have diabetes, were nothing much to write home about.

“This was a negative study,” said Paul Aisen of the University of Southern California in San Diego. Aisen added that the secondary and exploratory measures presented at AAIC did not look particularly encouraging.

Glucagon-like peptide analogues form the class of drugs including Ozempic, Mounjaro, and others, which are experiencing soaring use for the treatment of diabetes and to help people lose weight.

As shown (again) by Paul Edison of Imperial College London at this year’s conference, the trial missed its primary endpoint of curbing decline in brain glucose metabolism as gauged by FDG-PET scans, over the yearlong trial period. Both the press release and Edison’s subsequent talk focused largely on some of the trial’s secondary and exploratory outcomes.

Here, too, the findings fell flat. According to the published trial protocol, clinical secondary outcome measures included change on the ADAS-Cog-Exec z score—which contains the ADAS-Cog and the executive function portion of the neuropsychological test battery—as well as the Clinical Dementia Rating Scale Sum of Boxes and the AD Cooperative Study—Activities of Daily Living (Femminella et al., 2019). In Philadelphia, Edison reported that on the ADAS-Cog-Exec, participants on liraglutide declined less precipitously over the 12-month trial relative to those on placebo, and that, at p<0.01, the effect was statistically significant.

However, cognitive trajectories of the treatment and placebo groups largely overlapped, as did the error bars. Any difference between the groups was small, at best. Edison declined permission for Alzforum to include the plots in this news story.

In his Philadelphia talk, Edison designated the CDR-SB and ADCS-ADL as exploratory outcomes. He noted that the study was not powered to detect a benefit on these measures, and didn’t find one.

For MRI, Edison reported data from exploratory endpoints. They were based on 83 participants on liraglutide and 75 on placebo who underwent MRI scans at baseline, 24, and 52 weeks. He said participants on liraglutide lost significantly less gray matter across the brain, as well as independently in the temporal, parietal, and frontoparietal lobes. No meaningful difference between the groups was apparent in the plots presented. Edison told the audience the effects were statistically significant. Again, the curves he showed were close together and their error bars largely overlapped.

Edison reported that the drug curbed gray matter atrophy by 50 percent—a statistic then widely reported in the news. What was it based on? Participants in the placebo group lost a total of 13,500 voxels, or 1mm³ cubes, of cortical gray matter throughout the trial, while those taking liraglutide lost about half as many. To put those losses in perspective, both groups started the trial with some 555,500 voxels, meaning placebo and treatment groups lost roughly 2.4 and 1.2 percent of their cortical gray matter, respectively.

Other secondary and exploratory measures, including change in microglial activation as gauged by TSPO-PET, and changes in amyloid- and tau-PET, were part of the trial, but Edison reported no results for those.

Lon Schneider of the University of Southern California in Los Angeles noted that not only were the effect sizes of the presented exploratory outcomes too small to be meaningful, but the p values of such exploratory measures calculated by the investigators have no value, particularly when in the context of other primary, secondary, and exploratory outcome measures that were negative.

“In short, these findings do not demonstrate clinical benefit on these outcomes,” he said.

According to an Alzheimer’s Association spokesman, the authors have submitted their trial to Alzheimer’s & Dementia for review.

While this trial was negative, other trials of GLP-1 agonists in AD are ongoing. One evaluates liraglutide’s successor semaglutide, which Novo Nordisk markets as Ozempic for Type 2 diabetes and Wegovy for weight loss. The company is running two Phase 3 trials in people with MCI or mild AD. Both are fully enrolled and expected to finish in 2026. Other trials test Lixisenatide and Exenatide.

At an AAIC session on GLP-1 analogues in neurodegenerative disease, speakers elaborated on the concept and possible underlying mechanisms. Additional talks suggest GLP-1 manufacturers are exploring how to expand their drugs into these indications.

A recent review reported no evidence thus far of effects on core Alzheimer’s biomarkers or cognition, but possible metabolic or neuroprotective effects (Liang et al., 2024).—Jessica Shugart

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References

Therapeutics Citations

1. Liraglutide
2. Semaglutide
3. Lixisenatide
4. Exenatide

Paper Citations

1. Femminella GD, Frangou E, Love SB, Busza G, Holmes C, Ritchie C, Lawrence R, McFarlane B, Tadros G, Ridha BH, Bannister C, Walker Z, Archer H, Coulthard E, Underwood BR, Prasanna A, Koranteng P, Karim S, Junaid K, McGuinness B, Nilforooshan R, Macharouthu A, Donaldson A, Thacker S, Russell G, Malik N, Mate V, Knight L, Kshemendran S, Harrison J, Brooks DJ, Passmore AP, Ballard C, Edison P. Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer's disease: study protocol for a randomised controlled trial (ELAD study). Trials. 2019 Apr 3;20(1):191. PubMed. Correction.
2. Liang Y, Doré V, Rowe CC, Krishnadas N. Clinical Evidence for GLP-1 Receptor Agonists in Alzheimer's Disease: A Systematic Review. J Alzheimers Dis Rep. 2024;8(1):777-789. Epub 2024 May 7 PubMed.

External Citations

1. press release
2. clinicaltrials.gov
3. AAIC

Further Reading

No Available Further Reading