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Diabetes Therapy
Published in: Diabetes Therapy 2/2018

Open Access 01-04-2018 | Original Research

Changes in Heart Rate Associated with Exenatide Once Weekly: Pooled Analysis of Clinical Data in Patients with Type 2 Diabetes

Authors: Steven P. Marso, Elise Hardy, Jenny Han, Hui Wang, Robert J. Chilton

Published in: Diabetes Therapy | Issue 2/2018

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Abstract

Introduction

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycemia in patients with type 2 diabetes, but heart rate increases have been observed.

Methods

A pooled post hoc analysis of 11 randomized clinical trials (N = 4595) of 10–30 weeks’ duration from the exenatide once-weekly (QW) development program evaluated heart rate with exenatide QW (intervention group) and exenatide twice daily (BID), liraglutide, and non-GLP-1RAs (insulin, metformin, pioglitazone, and sitagliptin) (comparison groups). The time course and size of heart rate changes from baseline and the relationship of heart rate change with baseline heart rate were studied. A multivariate analysis (9 studies; N = 3903) examined associations between patient characteristics or treatments and heart rate increases.

Results

Mean baseline heart rate ± standard deviation was 75.0 ± 8.5 beats per minute (bpm) with exenatide QW (n = 2096), 75.8 ± 8.7 bpm with exenatide BID (n = 606), 75.2 ± 8.9 bpm with liraglutide (n = 450), and 74.5 ± 8.6 bpm with non-GLP-1RAs (n = 1443). Least-squares mean ± standard error changes from baseline to final heart rate were + 2.7 ± 0.2, + 1.0 ± 0.3, and + 3.0 ± 0.4 bpm with exenatide QW, exenatide BID, and liraglutide, respectively, and − 0.8 ± 0.2 bpm with non-GLP-1RAs. The size and direction of heart rate changes in individual patients varied within each treatment group at all time points. At posttreatment follow-up, heart rate reverted to the baseline level after GLP-1RA discontinuation. Heart rate changes correlated negatively with baseline heart rate for all therapies (r = − 0.3 to − 0.4). Baseline heart rate was the strongest predictor of increased heart rate.

Conclusions

Small increases in heart rate were associated with exenatide QW, exenatide BID, and liraglutide treatments but reverted to baseline after discontinuation. Increases were more likely in patients with a low baseline heart rate. The clinical relevance of these heart rate increases is unknown but will be clarified by several ongoing and recently completed cardiovascular outcome studies.
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Literature
1.
2.
Kolterman OG, Buse JB, Fineman MS, et al. Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab. 2003;88:3082–9.CrossRefPubMed
3.
Drucker DJ, Buse JB, Taylor K, et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet. 2008;372:1240–50.CrossRefPubMed
4.
Bergenstal RM, Wysham C, Macconell L, et al. Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet. 2010;376:431–9.CrossRefPubMed
5.
Bunck MC, Diamant M, Eliasson B, et al. Exenatide affects circulating cardiovascular risk biomarkers independently of changes in body composition. Diabetes Care. 2010;33:1734–7.CrossRefPubMedPubMedCentral
6.
Buse JB, Sesti G, Schmidt WE, et al. Switching to once-daily liraglutide from twice-daily exenatide further improves glycemic control in patients with type 2 diabetes using oral agents. Diabetes Care. 2010;33:1300–3.CrossRefPubMedPubMedCentral
7.
Garber A, Henry RR, Ratner R, Hale P, Chang CT, Bode B. Liraglutide, a once-daily human glucagon-like peptide 1 analogue, provides sustained improvements in glycaemic control and weight for 2 years as monotherapy compared with glimepiride in patients with type 2 diabetes. Diabetes Obes Metab. 2011;13:348–56.CrossRefPubMedPubMedCentral
8.
Ji L, Onishi Y, Ahn CW, et al. Efficacy and safety of exenatide once-weekly vs exenatide twice-daily in Asian patients with type 2 diabetes mellitus. J Diabetes Investig. 2013;4:53–61.CrossRefPubMed
9.
Darpo B, Sager P, MacConell L, et al. Exenatide at therapeutic and supratherapeutic concentrations does not prolong the QTc interval in healthy subjects. Br J Clin Pharmacol. 2013;75:979–89.CrossRefPubMed
10.
Gill A, Hoogwerf BJ, Burger J, et al. Effect of exenatide on heart rate and blood pressure in subjects with type 2 diabetes mellitus: a double-blind, placebo-controlled, randomized pilot study. Cardiovasc Diabetol. 2010;9:6.CrossRefPubMedPubMedCentral
11.
Cooney MT, Vartiainen E, Laatikainen T, Juolevi A, Dudina A, Graham IM. Elevated resting heart rate is an independent risk factor for cardiovascular disease in healthy men and women. Am Heart J. 2010;159(612–9):e3.
12.
Smits MM, Muskiet MH. Exenatide increases heart rate by augmenting sympathetic nervous activity in healthy overweight men. Presented at the 75th Scientific Sessions of the American Diabetes Association (ADA); June 5–9, 2015; Boston, MA, USA.
13.
14.
15.
Blevins T, Pullman J, Malloy J, et al. DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. J Clin Endocrinol Metab. 2011;96:1301–10.CrossRefPubMed
16.
Buse JB, Nauck M, Forst T, et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet. 2013;381:117–24.CrossRefPubMed
17.
Davies M, Heller S, Sreenan S, et al. Once-weekly exenatide versus once- or twice-daily insulin detemir: randomized, open-label, clinical trial of efficacy and safety in patients with type 2 diabetes treated with metformin alone or in combination with sulfonylureas. Diabetes Care. 2013;36:1368–76.CrossRefPubMedPubMedCentral
18.
Diamant M, Van Gaal L, Stranks S, et al. Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial. Lancet. 2010;375:2234–43.CrossRefPubMed
19.
Inagaki N, Atsumi Y, Oura T, Saito H, Imaoka T. Efficacy and safety profile of exenatide once weekly compared with insulin once daily in Japanese patients with type 2 diabetes treated with oral antidiabetes drug(s): results from a 26-week, randomized, open-label, parallel-group, multicenter, noninferiority study. Clin Ther. 2012;34(9):1892–908.e1. doi: https://​doi.​org/​10.​1016/​j.​clinthera.​2012.​07.​007.
20.
Iwamoto K, Nasu R, Yamamura A, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of exenatide once weekly in Japanese patients with type 2 diabetes. Endocr J. 2009;56:951–62.CrossRefPubMed
21.
Kim D, MacConell L, Zhuang D, et al. Effects of once-weekly dosing of a long-acting release formulation of exenatide on glucose control and body weight in subjects with type 2 diabetes. Diabetes Care. 2007;30:1487–93.CrossRefPubMed
22.
Russell-Jones D, Cuddihy RM, Hanefeld M, et al. Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): a 26-week double-blind study. Diabetes Care. 2012;35:252–8.CrossRefPubMedPubMedCentral
23.
McAlister FA, Wiebe N, Ezekowitz JA, Leung AA, Armstrong PW. Meta-analysis: beta-blocker dose, heart rate reduction, and death in patients with heart failure. Ann Intern Med. 2009;150:784–94.CrossRefPubMed
24.
Sun F, Wu S, Guo S, et al. Impact of GLP-1 receptor agonists on blood pressure, heart rate and hypertension among patients with type 2 diabetes: a systematic review and network meta-analysis. Diabetes Res Clin Pract. 2015;110:26–37.CrossRefPubMed
25.
26.
Smits MM, Muskiet MH, Tonneijck L, et al. Exenatide acutely increases heart rate in parallel with augmented sympathetic nervous system activation in healthy overweight males. Br J Clin Pharmacol. 2016;81:613–20.CrossRefPubMedPubMedCentral
27.
Valensi P, Chiheb S, Fysekidis M. Insulin- and glucagon-like peptide-1-induced changes in heart rate and vagosympathetic activity: why they matter. Diabetologia. 2013;56:1196–200.CrossRefPubMed
28.
Pyke C, Heller RS, Kirk RK, et al. GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology. 2014;155:1280–90.CrossRefPubMed
29.
Nakatani Y, Kawabe A, Matsumura M, et al. 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. Diabetes Care. 2016;39:e22–3.PubMed
30.
Lorenz M, Owens D, Raccah D, et al. Differential effects of GLP-1 receptor agonists on 24-hour averaged heart rate in healthy volunteers and patients with type 2 diabetes. In: Presented at the European Association for the Study of Diabetes (EASD) 2015 Annual Meeting; September 14–18, 2015; Stockholm, Sweden.
31.
Madsbad S, Kielgast U, Asmar M, Deacon CF, Torekov SS, Holst JJ. An overview of once-weekly glucagon-like peptide-1 receptor agonists—available efficacy and safety data and perspectives for the future. Diabetes Obes Metab. 2011;13:394–407.CrossRefPubMed
32.
Palatini P, Parati G. Persistently elevated heart rate accelerates the progression of arterial stiffness. J Hypertens. 2010;28:653–6.CrossRefPubMed
33.
Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834–44.CrossRefPubMed
34.
Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373:2247–57.CrossRefPubMed
35.
Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377:1228–39.CrossRefPubMed
36.
Metadata
Title
Changes in Heart Rate Associated with Exenatide Once Weekly: Pooled Analysis of Clinical Data in Patients with Type 2 Diabetes
Authors
Steven P. Marso
Elise Hardy
Jenny Han
Hui Wang
Robert J. Chilton
Publication date
01-04-2018
Publisher
Springer Healthcare
Published in
Diabetes Therapy / Issue 2/2018
Print ISSN: 1869-6953
Electronic ISSN: 1869-6961
DOI
https://doi.org/10.1007/s13300-018-0370-z

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