GLP-1, GIP, and Glucagon Receptor Agonism at the Obesity–Neurodegeneration Interface: A Narrative Review
4 affiliations
- 1Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, 16 Universitatii Str., 700115 Iasi, Romania.
- 2Department of Preventive Medicine and Interdisciplinarity, "Grigore T. Popa" University of Medicine and Pharmacy, Universitatii Str. 16, 700115 Iasi, Romania.
- 3"Prof. Dr. Nicolae Oblu" Emergency Clinic Hospital, 700309 Iasi, Romania.
- 42nd Internal Medicine Department, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania.
Abstract
Glucagon-like peptide-1 receptor agonism has attracted interest in neurodegeneration because of its effects on metabolic and inflammatory pathways implicated in neuronal dysfunction. This narrative review examines the molecular rationale and neurological evidence for selective glucagon-like peptide-1 receptor agonists, dual agonists additionally targeting the glucose-dependent insulinotropic polypeptide receptor, and triple agonists also engaging the glucagon receptor. English-language literature retrieved from PubMed, Scopus, and Web of Science was synthesized according to study design and neurological relevance. Preclinical findings indicate modulation of insulin signaling, synaptic function, mitochondrial homeostasis, and neuroinflammation, but responses vary across compounds and experimental models. In Alzheimer’s disease, liraglutide did not meet its primary trial endpoint, and semaglutide did not slow clinical progression. Parkinson’s disease trials have yielded mixed results without establishing disease modification. Observational associations with reduced dementia risk remain susceptible to confounding. Neurological evidence for tirzepatide and retatrutide remains predominantly observational or preclinical. Greater metabolic efficacy does not establish neuroprotection, while nutritional vulnerability may constrain therapeutic applicability. Dedicated randomized trials integrating clinical outcomes with pharmacological exposure, target engagement, and metabolic mediation are required to distinguish systemic effects from direct neural actions and determine whether these therapies can prevent cognitive decline or modify established neurodegenerative disease.
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BibTeX
@article{popa2026glp1,
title = {{GLP-1, GIP, and Glucagon Receptor Agonism at the Obesity–Neurodegeneration Interface: A Narrative Review}},
author = {Elena Popa and Andrei Emilian Popa and Vladimir Poroch and Thomas Gabriel Schreiner and Ana Maria Slanina and Mihaela Poroch and Alexandru Matei Hatneanu and Monica Iuliana Ungureanu and Antoneta Dacia Petroaie and Agnes Iacinta Bacusca and Elena Adorata Coman},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = sep,
doi = {10.3390/ijms27198738},
url = {https://www.mdpi.com/1422-0067/27/19/8738},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - GLP-1, GIP, and Glucagon Receptor Agonism at the Obesity–Neurodegeneration Interface: A Narrative Review
AU - Elena Popa
AU - Andrei Emilian Popa
AU - Vladimir Poroch
AU - Thomas Gabriel Schreiner
AU - Ana Maria Slanina
AU - Mihaela Poroch
AU - Alexandru Matei Hatneanu
AU - Monica Iuliana Ungureanu
AU - Antoneta Dacia Petroaie
AU - Agnes Iacinta Bacusca
AU - Elena Adorata Coman
PY - 2026
DA - 2026/09/30
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27198738
UR - https://www.mdpi.com/1422-0067/27/19/8738
AB - Glucagon-like peptide-1 receptor agonism has attracted interest in neurodegeneration because of its effects on metabolic and inflammatory pathways implicated in neuronal dysfunction. This narrative review examines the molecular rationale and neurological evidence for selective glucagon-like peptide-1 receptor agonists, dual agonists additionally targeting the glucose-dependent insulinotropic polypeptide receptor, and triple agonists also engaging the glucagon receptor. English-language literature retrieved from PubMed, Scopus, and Web of Science was synthesized according to study design and neurological relevance. Preclinical findings indicate modulation of insulin signaling, synaptic function, mitochondrial homeostasis, and neuroinflammation, but responses vary across compounds and experimental models. In Alzheimer’s disease, liraglutide did not meet its primary trial endpoint, and semaglutide did not slow clinical progression. Parkinson’s disease trials have yielded mixed results without establishing disease modification. Observational associations with reduced dementia risk remain susceptible to confounding. Neurological evidence for tirzepatide and retatrutide remains predominantly observational or preclinical. Greater metabolic efficacy does not establish neuroprotection, while nutritional vulnerability may constrain therapeutic applicability. Dedicated randomized trials integrating clinical outcomes with pharmacological exposure, target engagement, and metabolic mediation are required to distinguish systemic effects from direct neural actions and determine whether these therapies can prevent cognitive decline or modify established neurodegenerative disease.
SN - 1422-0067
ER -