Effects of GLP-1 Receptor Agonists on Heart Rate and the Autonomic Nervous System Using Holter Electrocardiography and Power Spectrum Analysis of Heart Rate Variability

Nakatani, Yuki; Kawabe, Atsuhiko; Matsumura, Mihoko; Aso, Yoshimasa; Yasu, Takanori; Banba, Nobuyuki; Nakamoto, Takaaki

doi:10.2337/dc15-1437

Cited by 55 publications

(69 citation statements)

References 4 publications

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“…Although we did not observe effects on total vasomotion, exenatide acutely increased activity in the neurogenic domain, which reflects an increase in microcirculatory sympathetic nervous system (SNS) activity. 29 This is in line with previous findings, in which GLP-1 receptor agonists were shown to stimulate SNS activity, measured by heart rate variability, 30,31 or plasma catecholamine levels. 32 Although increased SNS activity is commonly associated with vasoconstriction, several studies have demonstrated that for the microcirculation, SNS activity might be associated with improved perfusion and consequently glucose uptake.…”

Section: Discussionsupporting

confidence: 91%

GLP-1–Based Therapies Have No Microvascular Effects in Type 2 Diabetes Mellitus

Smits

Tonneijck

Muskiet

et al. 2016

ATVB

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Objective— To assess the effects of glucagon-like peptide (GLP)-1–based therapies (ie, GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors) on microvascular function in patients with type 2 diabetes mellitus. Approach and Results— We studied 57 patients with type 2 diabetes mellitus (mean±SD age: 62.8±6.9 years; body mass index: 31.8±4.1 kg/m 2 ; HbA 1c [glycated hemoglobin] 7.3±0.6%) in an acute and 12-week randomized, placebo-controlled, double-blind trial conducted at the Diabetes Center of the VU University Medical Center. In the acute study, the GLP-1 receptor agonist exenatide (therapeutic concentrations) or placebo (saline 0.9%) was administered intravenously. During the 12-week study, patients received the GLP-1 receptor agonist liraglutide (1.8 mg daily), the dipeptidyl peptidase-4 inhibitor sitagliptin (100 mg daily), or matching placebos. Capillary perfusion was assessed by nailfold skin capillary videomicroscopy and vasomotion by laser Doppler fluxmetry, in the fasting state and after a high-fat mixed meal. In neither study, treatment affected fasting or postprandial capillary perfusion compared with placebo ( P >0.05). In the fasting state, acute exenatide infusion increased neurogenic vasomotion domain power, while reducing myogenic domain power (both P <0.05). After the meal, exenatide increased endothelial domain power ( P <0.05). In the 12-week study, no effects on vasomotion were observed. Conclusions— Despite modest changes in vasomotion, suggestive of sympathetic nervous system activation and improved endothelial function, acute exenatide infusion does not affect skin capillary perfusion in type 2 diabetes mellitus. Twelve-week treatment with liraglutide or sitagliptin has no effect on capillary perfusion or vasomotion in these patients. Our data suggest that the effects of GLP-1–based therapies on glucose are not mediated through microvascular responses.

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Section: Discussionsupporting

confidence: 91%

GLP-1–Based Therapies Have No Microvascular Effects in Type 2 Diabetes Mellitus

Smits

Tonneijck

Muskiet

et al. 2016

ATVB

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“…There is currently insufficient evidence to assess the arrhythmogenic potential of intermittent versus sustained GLP-1R agonism in diabetic subjects with various subtypes of pre-existing CVD. GLP-1 may increase HR through enhanced sympathetic nervous system activation, reduced parasympathetic tone, or direct engagement of GLP-1Rs in the sinoatrial node (Griffioen et al, 2011;Nakatani et al, 2016;Yamamoto et al, 2002). Nevertheless, there are little data elucidating the extent to which these or other mechanisms account for increases in HR in humans exposed to sustained GLP-1R agonism.…”

Section: Endothelial Function Blood Pressure Blood Flow and Hrmentioning

confidence: 99%

The Cardiovascular Biology of Glucagon-like Peptide-1

2016

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Glucagon-like peptide-1, produced predominantly in enteroendocrine cells, controls glucose metabolism and energy homeostasis through regulation of islet hormone secretion, gastrointestinal motility, and food intake, enabling development of GLP-1 receptor (GLP-1R) agonists for the treatment of diabetes and obesity. GLP-1 also acts on the immune system to suppress inflammation, and GLP-1R signaling in multiple tissues impacts cardiovascular function in health and disease. Here we review how GLP-1 and clinically approved GLP-1R agonists engage mechanisms that influence the risk of developing cardiovascular disease. We discuss how GLP-1R agonists modify inflammation, cardiovascular physiology, and pathophysiology in normal and diabetic animals through direct and indirect mechanisms and review human studies illustrating mechanisms linking GLP-1R signaling to modification of the cardiovascular complications of diabetes. The risks and benefits of GLP-1R agonists are updated in light of recent data suggesting that GLP-1R agonists favorably modify outcomes in diabetic subjects at high risk for cardiovascular events.

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“…Priority for inclusion in this manuscript was awarded to studies that measured HR over a full 24-h period by serial ECG monitoring or those using ambulatory blood pressure measurements including serial or continuous HR detection. Two trials fulfilling these criteria directly compared the short-acting GLP-1 RA lixisenatide with the long-acting GLP-1 RA liraglutide [17, 18]. Moreover, relevant data from product monographs were also reviewed.…”

Section: Data Searchmentioning

confidence: 99%

“…The effects on HR for the short-acting RA lixisenatide vs. the long-acting GLP-1 agent liraglutide were analyzed in two independent head-to-head comparison studies [17, 18]. In the first trial, lixisenatide 20 µg QD (n = 46) and liraglutide 1.2 (n = 44) and 1.8 mg QD (n = 46) were compared following 8 weeks’ treatment in 142 subjects with T2DM not adequately controlled with insulin glargine with or without metformin [17].…”

Section: Comparison Of Short- Vs Long-acting Glp-1 Ras On Hr: Lixisementioning

confidence: 99%

“…A second head-to-head comparison trial between lixisenatide and liraglutide was performed in 60 subjects with T2DM [18]. In this study, a 24-h Holter ECG recording was performed at baseline, after the maximum daily dose for each drug (lixisenatide 20 µg, liraglutide 0.9 mg) had been administered for at least 1 week following completion of the up-titration period.…”

Section: Comparison Of Short- Vs Long-acting Glp-1 Ras On Hr: Lixisementioning

confidence: 99%

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Differential effects of glucagon-like peptide-1 receptor agonists on heart rate

Lorenz

Lawson

Owens

et al. 2017

Cardiovasc Diabetol

111

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While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are known to increase heart rate (HR), it is insufficiently recognized that the extent varies greatly between the various agonists and is affected by the assessment methods employed. Here we review published data from 24-h time-averaged HR monitoring in healthy individuals and subjects with type 2 diabetes mellitus (T2DM) treated with either short-acting GLP-1 RAs, lixisenatide or exenatide, or long-acting GLP-1 RAs, exenatide LAR, liraglutide, albiglutide, or dulaglutide (N = 1112; active-treatment arms). HR effects observed in two independent head-to-head trials of lixisenatide and liraglutide (N = 202; active-treatment arms) are also reviewed. Short-acting GLP-1 RAs, exenatide and lixisenatide, are associated with a transient (1–12 h) mean placebo- and baseline-adjusted 24-h HR increase of 1–3 beats per minute (bpm). Conversely, long-acting GLP-1 RAs are associated with more pronounced increases in mean 24-h HR; the highest seen with liraglutide and albiglutide at 6–10 bpm compared with dulaglutide and exenatide LAR at 3–4 bpm. For both liraglutide and dulaglutide, HR increases were recorded during both the day and at night. In two head-to-head comparisons, a small, transient mean increase in HR from baseline was observed with lixisenatide; liraglutide induced a substantially greater increase that remained significantly elevated over 24 h. The underlying mechanism for increased HR remains to be elucidated; however, it could be related to a direct effect at the sinus node and/or stimulation of the sympathetic nervous system, with this effect related to the duration of action of the respective GLP-1 RAs. In conclusion, this review indicates that the effects on HR differ within the class of GLP-1 RAs: short-acting GLP-1 RAs are associated with a modest and transient HR increase before returning to baseline levels, while some long-acting GLP-1 RAs are associated with a more pronounced and sustained increase during the day and night. Findings from recently completed trials indicate that a GLP-1 RA-induced increase in HR, regardless of magnitude, does not present an increased cardiovascular risk for subjects with T2DM, although a pronounced increase in HR may be associated with adverse clinical outcomes in those with advanced heart failure.

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Effects of GLP-1 Receptor Agonists on Heart Rate and the Autonomic Nervous System Using Holter Electrocardiography and Power Spectrum Analysis of Heart Rate Variability

Cited by 55 publications

References 4 publications

GLP-1–Based Therapies Have No Microvascular Effects in Type 2 Diabetes Mellitus

GLP-1–Based Therapies Have No Microvascular Effects in Type 2 Diabetes Mellitus

The Cardiovascular Biology of Glucagon-like Peptide-1

Differential effects of glucagon-like peptide-1 receptor agonists on heart rate

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