Mark M Smits1, Lennart Tonneijck2, Marcel H A Muskiet2, Trynke Hoekstra3, Mark H H Kramer2, Michaela Diamant2, Daniël H van Raalte2. 1. Department of Internal MedicineDiabetes Center, VU University Medical Center, Amsterdam, The Netherlands mm.smits1@vumc.nl. 2. Department of Internal MedicineDiabetes Center, VU University Medical Center, Amsterdam, The Netherlands. 3. Department of Health Sciences and the EMGO Institute for Health and Care ResearchVU University, Amsterdam, The Netherlands and Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
Abstract
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/m2; 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.
RCT Entities:
OBJECTIVE: To examine mechanisms underlying resting heart rate (RHR) increments of GLP-1 receptor agonists in type 2 diabetespatients. DESIGN: Acute and 12-week randomised, placebo-controlled, double-blind, single-centre, parallel-group trial. METHODS: In total, 57 type 2 diabetespatients (mean ± s.d. age: 62.8 ± 6.9 years; BMI: 31.8 ± 4.1 kg/m2; 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 diabetespatients 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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