A single dose of exenatide had no effect on blood flow velocity in the middle cerebral artery in elderly healthy volunteers: Randomized, placebo-controlled, double-blind clinical trial

Joakim Ölmestig; Ida R Marlet; Tina Vilsbøll; Jørgen Rungby; Egill Rostrup; Kate L Lambertsen; Christina Kruuse

doi:10.3389/fnagi.2022.899389

A single dose of exenatide had no effect on blood flow velocity in the middle cerebral artery in elderly healthy volunteers: Randomized, placebo-controlled, double-blind clinical trial

Front Aging Neurosci. 2022 Jul 25:14:899389. doi: 10.3389/fnagi.2022.899389. eCollection 2022.

Authors

Joakim Ölmestig^{1

2}, Ida R Marlet¹, Tina Vilsbøll^{2

3}, Jørgen Rungby^{2

4}, Egill Rostrup⁵, Kate L Lambertsen^{6

7

8}, Christina Kruuse^{1

2}

Affiliations

¹ Neurovascular Research Unit, Department of Neurology, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark.
² Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
³ Steno Diabetes Center Copenhagen, Copenhagen, Denmark.
⁴ Department of Endocrinology, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark.
⁵ Center for Neuropsychiatric Schizophrenia Research, Copenhagen University Hospital - Mental Health Center Glostrup, Copenhagen, Denmark.
⁶ Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
⁷ Department of Neurology, Odense University Hospital, Odense, Denmark.
⁸ BRIDGE - Brain Research-Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.

Abstract

Background and aims: Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RA) are widely used for the treatment of type 2 diabetes, and recent studies indicate that they may be cardio- and neuroprotective. The safety and effect of a single dose of exenatide, a short-acting GLP-1RA, on cerebral and peripheral arterial function remain unknown.

Methods: In this randomized, double-blind pilot trial, we assigned elderly healthy volunteers without diabetes and no previous history of stroke to receive a single dose of subcutaneous exenatide (5 μg) or placebo. Primary outcome was immediate changes over time in blood flow velocity of the middle cerebral arteries (V_MCA) assessed by repeated transcranial Doppler measurements. Secondary outcomes were changes in peripheral arterial function with finger plethysmography, ankle-brachial index (ABI), and inflammatory- and endothelial-specific biomarkers.

Results: Healthy volunteers (13 women and 17 men) were included: (mean ± standard deviation) age: 62 ± 8 years; body weight: 79.6 ± 12.7 kg; V_MCA: 65.3 ± 10.7 cm/s; fasting plasma glucose: 5.5 ± 0.5 mmol/L; HbA1c: 33.9 ± 4.1 mmol/mol (5.3 ± 0.38%). No differences between exenatide and placebo group were seen regarding V_MCA (p = 0.058), systolic ABI (p = 0.71), plethysmography (p = 0.45), tumor necrosis factor (p = 0.33), interleukin-6 (p = 0.11), interleukin-1β (p = 0.34), vascular cell adhesion molecule 1 (p = 0.73), intercellular adhesion molecule 1 (p = 0.74), or E-selectin (p = 0.31). No severe adverse events were observed.

Conclusion: A single dose of exenatide did not change cerebral blood flow velocity or peripheral vessel function in elderly healthy volunteers. The medication was safe to use in persons without diabetes allowing us to investigate this drug further in search of the neuroprotective mechanisms.

Clinical trial registration: https://clinicaltrials.gov, Identifier NCT02838589.

Keywords: cerebral blood flow; clinical trial; exenatide; glucagon-like peptide 1; healthy volunteers.

Associated data

ClinicalTrials.gov/NCT02838589

Grants and funding

Salary for IM and medical expenses were funded from scholarships from Aase og Ejnar Danielsens Fund (no grant number), Grosserer L. F. Foght’s Fund (no grant number), and AP Møller Foundation for the Advancement of Medical Sciences (no grant number). JÖ was funded from a scholarship from the University of Copenhagen. CK was funded by Borregaard Stipend, Novo Nordisk Foundation, grant number: NNF18OC0031840.