A feasibility study of the combination of intranasal insulin with oral semaglutide for cognition in older adults with metabolic syndrome at high dementia risk- Study rationale and design

Tal Davidy*, Iscka Yore, Tali Cukierman-Yaffe, Ramit Ravona-Springer, Abigail Livny, Orit H. Lesman-Segev, Yossi Azuri, Owen Carmichael, Dimitrios Kapogiannis, Henrik Zetterberg, Hung Mo Lin, Mary Sano, Michal Schnaider Beeri

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Introduction: We present the rationale and design of a double-blind placebo-controlled feasibility trial combining intranasal insulin (INI) with semaglutide, a GLP-1 receptor agonist, to improve cognition in older adults with metabolic syndrome (MetS) and mild cognitive impairment (MCI). Since both INI and dulaglutide have beneficial effects on the cerebrovascular disease (CVD), we anticipate that improved CVD will underlie the hypothesized cognitive benefits. Methods: This 12-months trial will include 80 older adults aged > 60 with MetS and MCI, randomized to 4 groups: INI/oral semaglutide, intranasal placebo/oral semaglutide, INI/oral placebo, and intranasal placebo/oral placebo. Feasibility of combining INI with semaglutide will be tested by examining the ease of use of INI (20IU, twice/day) with semaglutide (14 once daily), adherence, and safety profile are the efficacy of combination therapy on global cognition and neurobiological markers: cerebral blood flow, cerebral glucose utilization, white matter hyperintensities, Alzheimer's related blood biomarkers and expression of insulin signaling proteins measured in brain-derived exosomes. Efficacy will be assessed for the intent-to-treat sample. Discussion: This feasibility study is anticipated to provide the basis for a multi-center large-scale randomized clinical trial (RCT) of the cognitive benefits of the combination of INI with semaglutide in individuals enriched for CVD and at high dementia risk.

Original languageEnglish
Article number111898
JournalMechanisms of Ageing and Development
Volume218
DOIs
StatePublished - Apr 2024

Funding

FundersFunder number
Gerald and Daphna Cramer Foundation Fund
Alzheimer's AssociationPTC-22–972151
Alzheimer's Association

    Keywords

    • Cerebral blood flow
    • Cognition
    • Dulaglutide
    • Intranasal insulin
    • Metabolic syndrome
    • Mild cognitive impairment

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