Liraglutide in mild to moderate Alzheimer's disease: a phase 2b clinical trial.

Liraglutide, a glucagon-like peptide 1 (GLP-1) agonist and antidiabetic drug, has shown neuroprotective effects in animal models. In this study, we aimed to evaluate the safety and efficacy of liraglutide in mild to moderate Alzheimer's disease syndrome. 'Evaluating liraglutide in Alzheimer's disease' (ELAD) is a multicenter, randomized, double-blind, placebo-controlled phase 2b trial in 204 participants with mild to moderate Alzheimer's disease syndrome with no diabetes. Participants received daily injections of liraglutide or placebo for 52 weeks. They underwent fluorodeoxyglucose positron emission tomography, magnetic resonance imaging and detailed neuropsychometric evaluations. The primary outcome was a change in cerebral glucose metabolic rate. Secondary outcomes were safety and tolerability and cognitive changes. The primary outcome showed no significant differences in cerebral glucose metabolism (difference = -0.17; 95% confidence interval: -0.39 to 0.06; P = 0.14) between the two groups. The secondary outcome-score on the Alzheimer's Disease Assessment Scale-Executive domain (ADAS-Exec)-performed better in liraglutide-treated patients compared to placebo (0.15; 95% confidence interval: 0.03-0.28; unadjusted P = 0.01). No significant differences were observed in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) (-0.58; 95% confidence interval: -3.13 to 1.97; unadjusted P = 0.65) or Clinical Dementia Rating-Sum of Boxes (CDR-SoB) (-0.06; 95% confidence interval: -0.57 to 0.44; unadjusted P = 0.81) scores. Liraglutide was generally safe and well tolerated in non-diabetic patients with Alzheimer's disease. ClinicalTrials.gov identifier: NCT01843075 .

Description

Acknowledgements: We thank all the staff at the Imperial College Clinical Imaging Facility, including A. Busza, S. H. McDevitt, R. Punjani, V. Vaja, N. Patel and P. Vicente, for performing all MRI and PET scanning during the trial. We thank all the participants and carers for their generous participation in the study. Funding for the conduct of the trial was provided by the Alzheimer’s Society (WNCN-P36891 and WNCN-P71735, P.E., C.B., A.P.P., D.J.B., C.H. and C.R.); the Alzheimer’s Drug Discovery Foundation (WNCN-P40813 and WNCN-P62411, P.E., C.B. and D.J.B.); the Van Geest Foundation + King’s College NIHR Biomedical Research Centre (WNCN-P47705, P.E.); the NIHR Imperial Biomedical Research Centre; and Novo Nordisk A/S (WNCN-P43336, P.E.). The funding sources had no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the manuscript for publication. We would like to thank the Exeter BRC for supporting the role of C.B. in the study. We would like to thank all the funders for their generous funding to make this study happen.

Keywords

Humans, Liraglutide, Alzheimer Disease, Male, Female, Aged, Double-Blind Method, Positron-Emission Tomography, Magnetic Resonance Imaging, Treatment Outcome, Middle Aged, Glucose, Cognition, Aged, 80 and over, Glucagon-Like Peptide 1, Brain

Journal Title

Nat Med

Journal ISSN

1078-8956
1546-170X

Volume Title

32

Publisher

Springer Nature

Publisher DOI

https://doi.org/10.1038/s41591-025-04106-7

Rights and licensing

Except where otherwised noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/

Sponsorship

Alzheimer’s Drug Discovery Foundation (ADDF) (WNCN-P40813)

Collections

Jisc Publications Router