Heart rate acceleration with GLP-1 receptor agonists in type 2 diabetes patients: an acute and 12-week randomised, double-blind, placebo-controlled trial
Open accessAbstract
Objective: To examine mechanisms underlying resting heart rate (RHR) increments of GLP-1 receptor agonists in type 2 diabetes patients. Design: Acute and 12-week randomised, placebo-controlled, double-blind, single-centre, parallel-group trial. Methods: In total, 57 type 2 diabetes patients (mean ± s.d. age: 62.8 ± 6.9 years; BMI: 31.8 ± 4.1 kg/m 2; HbA1c: 7.3 ± 0.6%), treated with metformin and/or sulfonylureas, were included between July 2013 and August 2015. In the acute study, the GLP-1 receptor agonist exenatide (n = 29) or placebo (saline 0.9%; n = 28) was infused intravenously. Subsequently, patients were again randomised to receive the GLP-1 receptor agonist liraglutide (n = 19) or matching placebo (n = 17) for 12 weeks. RHR and blood pressure (BP) were measured by oscillometric technique, systemic haemodynamics by finger photoplethysmography, sympathetic nervous system (SNS) activity by heart rate variability and arterial stiffness by applanation tonometry. This trial was registered at ClinicalTrials.gov (Nbib1744236). Results: Exenatide-infusion increased RHR (mean ± s.e.m. +7.5 ± 0.9 BPM, P < 0.001), and systolic and diastolic BP (both P < 0.05), compared with placebo. Vascular resistance increased during exenatide-infusion, whereas stroke volume and arterial stiffness decreased (P < 0.05). SNS activity and cardiac output were unaffected. Twelve-week treatment with liraglutide increased RHR (+6.6 ± 2.1 BPM), while reducing systolic BP (−12.6 ± 4.7 mmHg) and stroke volume (all P < 0.01). Cardiac output, vascular resistance, arterial stiffness and SNS activity remained unchanged (all P > 0.05). Conclusions: RHR acceleration with acute and 12-week GLP-1 receptor agonist treatment in type 2 diabetes patients is not explained by changes in SNS activity, and our data argue against vasodilation. In line with pre-clinical data, direct sino-atrial stimulation may be involved.
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Several clinical mechanistic trials provided conflicting evidence on GLP-1RA-induced heart rate increase.
“Several clinical mechanistic trials provided conflicting evidence while aiming to understand the GLP-1RA-induced heart rate-increase.”
From Safety of Semaglutide (2021) · cites this paper as [106]
Some studies found systemic vasodilation (with likely consequent reflex tachycardia), while others failed to show this.
“Some studies found systemic vasodilation (with likely consequent reflex tachycardia), while others failed to show this”
From Safety of Semaglutide (2021) · cites this paper as [106]
Discrepant findings are available for activation of the cardiac sympathetic nervous system.
“Similarly, discrepant findings are available for activation of the (cardiac) sympathetic nervous system”
From Safety of Semaglutide (2021) · cites this paper as [106]
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Smits, M. M., & Van Raalte, D. H. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.645563 · Cited by 332 · see citing works
Self-citationCornell, S. (2020) · Journal of Clinical Pharmacy and Therapeutics · doi:10.1111/jcpt.13230 · Cited by 156 · see citing works
Heuvelman, V. D., Van Raalte, D. H., & Smits, M. M. (2020) · Cardiovascular Research · doi:10.1093/cvr/cvz323 · Cited by 106 · see citing works
Self-citationGlucagon-Like Peptide-1 (GLP-1) in the Integration of Neural and Endocrine Responses to Stress
Diz-Chaves, Y., Herrera-Pérez, S., González-Matías, L. C., Lamas, J. A., & Mallo, F. (2020) · Nutrients · doi:10.3390/nu12113304 · Cited by 84 · see citing works
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- Authors
- Smits, M. M., Tonneijck, L., Muskiet, M. H. A., Hoekstra, T., Kramer, M. H. H., Diamant, M., & van Raalte, D. H.
- Affiliations
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Amsterdam Public Health (NL)
- 1Department of Internal MedicineDiabetes Center, VU University Medical Center, Amsterdam, The Netherlands
- Corresponding author
- Smits, Mark M
- Venue
- European Journal of Endocrinology
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-01
- Volume
- 176
- Issue
- 1
- Pages
- 77-86
- ISSN
- 0804-4643 (ISSN-L)
- 1479-683X
- OpenAlex
- W2536045672
- Cited by
- 54
- References
- 7
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 8 · 2023: 4 · 2022: 4 · 2021: 4 · 2020: 8 · 2019: 6 · 2018: 5 · 2017: 4
- FWCI
- 5.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Journal of Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Pure Amsterdam UMC (acceptedVersion, other-oa)
- VU Research Portal (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Keywords
- GLP-1 receptor agonists, resting heart rate, type 2 diabetes, exenatide, liraglutide, blood pressure, arterial stiffness, vascular resistance, stroke volume, cardiac output, sympathetic activity, hemodynamics
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Liraglutide, Exenatide, Aged, Blood Glucose, Blood Pressure, Diabetes Mellitus, Type 2, Double-Blind Method, Female, Heart Rate, Humans, Hypoglycemic Agents, Male, Metformin, Middle Aged, Peptides, Sulfonylurea Compounds, Venoms, Treatment Outcome
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