Exenatide acutely increases heart rate in parallel with augmented sympathetic nervous system activation in healthy overweight males
Open accessAbstract
Aim: Clinical use of glucagon‐like peptide‐1 receptor agonists (GLP‐1RA) is consistently associated with heart rate (HR) acceleration in type 2 diabetes patients. We explored the mechanisms underlying this potential safety concern. Methods: Ten healthy overweight males (aged 20–27 years) were examined in an open label, crossover study. Automated oscillometric blood pressure measurements and finger photoplethysmography were performed throughout intravenous administration of placebo (saline 0.9%), exenatide (targeting therapeutic concentrations) and a combination of exenatide and the nitric oxide synthase inhibitor L‐N G‐monomethyl arginine (L‐NMMA). Sympathetic nervous system (SNS) activity was measured by heart rate variability and rate‐pressure product. Results: Exenatide increased HR by a mean maximum of 6.8 (95% CI 1.7, 11.9) beats min–1 (P < 0.05), systolic blood pressure (SBP) by 9.8 (95% CI 3.5, 16.1) mmHg (P < 0.01) and markers of SNS activity (P < 0.05). No changes in total peripheral resistance were observed. Increases in HR, SBP and sympathetic activity were preserved during concomitant L‐NMMA infusion. Conclusions: Our data argue against exenatide‐induced reflex tachycardia as a response to vasodilation and rather suggest the involvement of SNS activation in humans.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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 [107]
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 [107]
Cites
A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management
Pi-Sunyer, X., Astrup, A., Fujioka, K., Greenway, F., Halpern, A., Krempf, M., Lau, D. C. W., le Roux, C. W., Violante Ortiz, R., Jensen, C. B., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1411892 · Cited by 2,724 · see citing works
Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome
Pfeffer, M. A., Claggett, B., Diaz, R., Dickstein, K., Gerstein, H. C., Køber, L. V., Lawson, F. C., Ping, L., Wei, X., Lewis, E. F., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1509225 · Cited by 2,409 · see citing works
GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus
Meier, J. J. (2012) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2012.140 · Cited by 1,311 · see citing works
Pyke, C., Heller, R. S., Kirk, R. K., Ørskov, C., Reedtz-Runge, S., Kaastrup, P., Hvelplund, A., Bardram, L., Calatayud, D., & Knudsen, L. B. (2014) · Endocrinology · doi:10.1210/en.2013-1934 · Cited by 876 · see citing works
Yamamoto, H., Lee, C. E., Marcus, J. N., Williams, T. D., Overton, J. M., Lopez, M. E., Hollenberg, A. N., Baggio, L., Saper, C. B., Drucker, D. J., et al. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0215595 · Cited by 429 · see citing works
Fehse, F., Trautmann, M., Holst, J. J., Halseth, A. E., Nanayakkara, N., Nielsen, L. L., Fineman, M. S., Kim, D. D., & Nauck, M. A. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-1093 · Cited by 297 · see citing works
Robinson, L. E., Holt, T. A., Rees, K., Randeva, H. S., & O'Hare, J. P. (2013) · BMJ Open · doi:10.1136/bmjopen-2012-001986 · Cited by 296 · see citing works
Bharucha, A. E., Charkoudian, N., Andrews, C. N., Camilleri, M., Sletten, D., Zinsmeister, A. R., & Low, P. A. (2008) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00153.2008 · Cited by 98 · see citing works
Direct cardiovascular effects of glucagon like peptide-1
Sheikh, A. (2013) · Diabetology & Metabolic Syndrome · doi:10.1186/1758-5996-5-47 · Cited by 45 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Nauck, M. A., Meier, J. J., Cavender, M. A., Abd El Aziz, M., & Drucker, D. J. (2017) · Circulation · doi:10.1161/circulationaha.117.028136 · Cited by 582 · see citing works
Smits, M. M., & Van Raalte, D. H. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.645563 · Cited by 332 · see citing works
Self-citationKhan, M. S., Fonarow, G. C., McGuire, D. K., Hernandez, A. F., Vaduganathan, M., Rosenstock, J., Handelsman, Y., Verma, S., Anker, S. D., McMurray, J. J. V., et al. (2020) · Circulation · doi:10.1161/circulationaha.120.045888 · Cited by 139 · 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
Janssen, L. G. M., Nahon, K. J., Bracké, K. F. M., van den Broek, D., Smit, R., Sardjoe Mishre, A. S. D., Koorneef, L. L., Martinez-Tellez, B., Burakiewicz, J., Kan, H. E., et al. (2020) · Metabolism · doi:10.1016/j.metabol.2020.154167 · Cited by 54 · see citing works
Cardiovascular Effects of Glucagon-Like Peptide-1 Receptor Agonists
Kang, Y. M., & Jung, C. H. (2016) · Endocrinology and Metabolism · doi:10.3803/enm.2016.31.2.258 · Cited by 51 · see citing works
Cacciatori, V., Zoppini, G., Bellavere, F., Rigolon, R., Thomaseth, K., Pichiri, I., Trombetta, M., Dauriz, M., De Santi, F., Targher, G., et al. (2018) · Journal of the Endocrine Society · doi:10.1210/js.2017-00300 · Cited by 18 · see citing works
- Authors
- Smits, M. M., Muskiet, M. H. A., Tonneijck, L., Hoekstra, T., Kramer, M. H. H., Diamant, M., & van Raalte, D. H.
- Affiliations
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Amsterdam Public Health (NL)
- Diabetes Center, Department of Internal Medicine VU University Medical Center Amsterdam
- Corresponding author
- Smits, Mark M.
- Venue
- British Journal of Clinical Pharmacology
- Publisher
- Wiley
- Published
- 2016-01-25
- Volume
- 81
- Issue
- 4
- Pages
- 613-620
- ISSN
- 0306-5251 (ISSN-L)
- 1365-2125
- PMC
- PMC4799913
- OpenAlex
- W2176491627
- Cited by
- 60
- References
- 9
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 2 · 2023: 2 · 2022: 5 · 2021: 5 · 2020: 4 · 2019: 8 · 2018: 9 · 2017: 8 · 2016: 8
- FWCI
- 7.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Clinical Pharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- VU Research Portal (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (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 › Heart Rate Variability and Autonomic Control
- Keywords
- exenatide, heart rate, sympathetic activation, GLP-1 receptor agonists, reflex tachycardia, nitric oxide synthase inhibition, L-NMMA, systolic blood pressure, systemic vascular resistance, heart rate variability, rate-pressure product, drug safety
- MeSH terms
- Exenatide, Adult, Blood Glucose, Heart Rate, Humans, Lipids, Male, Peptides, Sympathetic Nervous System, Vascular Resistance, Venoms, Body Mass Index, Cross-Over Studies, Overweight, Glucagon-Like Peptide 1, Young Adult, Healthy Volunteers
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
