High resting heart rate increases the risk of cardiovascular morbidity and mortality in the general population, as well as in those with hypertension, and in those with type 2 diabetes. Drugs that increase the heart rate may adversely affect cardiovascular health
Population studies have shown that there is a relationship between high resting heart rate and increased risk of cardiovascular events and mortality. This has also been obvious in most studies in patients with hypertension - findings summarized in a report from a Consensus Meeting of the European Society of Hypertension in 2005.1 This report was updated in 2016 in a statement from the Second Consensus Conference, which concluded that heart rate measurement should be included in the routine assessment of the hypertensive patient.2 A similar view was reported from a group reviewing publications from the Asia Pacific region.3
An analysis of prospective studies in patients with hypertension found that night-time heart rate measured by ambulatory recordings was a better predictor of mortality than elevated heart rate in the clinic.4 The analysis included 7602 hypertensive patients with ambulatory blood pressure (BP) and heart rate recordings from 6 prospective studies in Italy, Japan and Australia. They defined tachycardia as an office heart rate >85 beats/minute or a night-time heart rate >76 beats/minute (these represented the upper quintiles). Patients with elevated heart rate in the clinic but normal night-time heart rate were considered to have white-coat tachycardia whereas those with normal clinic heart rate but increased night-time heart rate were classified as having masked tachycardia and those with elevated heart rate in both clinic and night-time recordings had sustained tachycardia.
White-coat tachycardia was not a significant predictor of increased major adverse cardiovascular events (MACEs) or all-cause mortality, whereas increased risk of MACE was seen with both masked tachycardia [hazard ratio (HR), 95% confidence interval (CI); 1.40, 1.11–1.77] and sustained tachycardia (1.86, 1.44–2.40) (Figure 1). In adjusted models, masked tachycardia was the only significant heart rate predictor of excess mortality with a HR of 1.62 (1.14–2.29) or in multivariable parsimonious Cox models 1.68 (1.18–2.41). These findings would support making additional measurements of ambulatory or out of office heart rate to define the risk of tachycardia more clearly.
Drugs that increase heart rate may also have adverse effects on cardiovascular morbidity and mortality. Sibutramine was used as a weight-reducing agent but its action was partly through increased sympathetic activity associated with an increase in plasma noradrenaline levels and increases in heart rate and BP.5 In the Sibutramine Cardiovascular Outcomes (SCOUT) trial, when following the 6-week, single-blind, lead-in period with sibutramine and participation in a weight-management program, the overweight or obese subjects randomized to sibutramine treatment had a higher heart rate ranging from 2.2 to 3.7 beats/min compared with the placebo group over the next 5 years.6 The increase in heart rate with sibutramine was associated with an attenuated fall in BP compared with the placebo-treated group and with sibutramine there were significant increases in the rates of nonfatal myocardial infarction and nonfatal stroke, but not cardiovascular or all-cause mortality.6 Following the SCOUT trial, sibutramine was withdrawn from the market.
More recently, increases in heart rate have been seen with the longer acting glucagon-like peptide-1 receptor agonists (GLP‑1RAs), such as liraglutide, used in the management of type two diabetes mellitus (T2DM) and obesity.7 Overall, the GLP‑1RAs are well tolerated with little risk of hypoglycaemia but some increase in gastrointestinal adverse events.8 In the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial in patients with T2DM, treatment with liraglutide significantly reduced the primary composite outcome of death from cardiovascular causes and nonfatal myocardial infarction or stroke by 22%.9 The mean differences between the liraglutide group and the placebo group throughout the trial were a small reduction in HbA1c of 0.40%, reduction of body weight of 2.3 kg, reduction in systolic BP of 1.2 mmHg, reduction in diastolic BP of 0.6 mmHg but an increase in heart rate of 3.0 beats/minute.
Similar effects on heart rate were reported in the study of liraglutide in those with obesity, the Satiety and Clinical Adiposity – Liraglutide Evidence in Nondiabetic and Diabetic Individuals (SCALE) Obesity and Prediabetes trial where the mean increase in resting pulse with liraglutide compared with placebo was 2.4 beats/min (95% CI 1.9–3.0 beats/min).10 In the studies of liraglutide for obesity, improvements in BP and plasma lipids have been largely driven by liraglutide-induced weight loss,11 but small increases in heart rate were still seen. Some studies reported no change in the average heart rate with liraglutide treatment in patients with T2DM over a period of two years, but this might suggest that heart rate increased in some patients but decreased in others.12
The mechanism for the increase in heart rate with GLP-1RAs has been investigated. Studies in rats showed that centrally and peripherally administered GLP-1RAs produced dose-dependent increases in BP and heart rate by increasing central sympathetic outflow.13 Continuous subcutaneous infusion of natural GLP-1 did not increase BP and heart rate in patients with T2DM,14 but the more potent degradation-resistant long-acting GLP-1 analogues are likely to have different effects to the natural incretin hormone. A recent small 12-week crossover study in patients with newly diagnosed T2DM and stable coronary artery disease found increased daytime and nighttime heart rate and reduced heart rate variability with liraglutide compared with placebo suggesting that liraglutide may affect sympathovagal balance.15 Studies in mice suggested that central GLP-1 receptor stimulation diminishes parasympathetic modulation of the heart thereby increasing heart rate.16
As well as the association between increased resting heart rate and mortality in the general population and in patients with hypertension there is also evidence of an association in patients with T2DM. In 11,140 patients who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study, a higher resting heart rate was associated with a significantly increased risk of all-cause mortality (fully adjusted HR 1.15 per 10 beat/minute [95% CI 1.08, 1.21], P<0.001), cardiovascular death and major cardiovascular outcomes without adjustment and after adjusting for age, sex and multiple covariates.17
Whether the increase in heart rate with GLP‑1RAs represents a harmful effect is not known but if so, it was overcome by the beneficial effects with liraglutide in the LEADER trial and more recently with semaglutide in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN 6).18 However, treatment with the short acting GLP-1RA lixisenatide in patients with T2DM and a recent acute coronary syndrome had more modest effects on HbA1c, body weight, systolic BP and heart rate in the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial and there was no significant benefit on cardiovascular outcomes.19 The increase in heart rate with liraglutide and other longer acting GLP‑1RAs may be attenuated by the loss in weight which also results in beneficial effects on BP, lipids and body fat distribution. Each of these effects may vary in different individuals, so it would be important to look at the overall pattern of cardiovascular risk factors including heart rate and not assume that every patient is going to benefit from the treatment.
Furthermore, GLP‑1RAs were predicted to have direct beneficial effects on the heart, but in the LEADER and SUSTAIN 6 trials there were no significant reductions in hospitalizations for heart failure with the GLP‑1RA treatments.9,18 Likewise, in a study of patients recently hospitalized with established heart failure and reduced left ventricular ejection fraction, treatment with liraglutide had no significant benefit on primary or secondary outcomes.20 It is salutary to consider whether the effects of GLP‑1RAs on sympathovagal balance with a tendency to increase heart rate may offset some of their beneficial effects and it is important to monitor the changes in all cardiovascular risks including heart rate in individual patients to facilitate an overall assessment of the benefits and risks.
Figure 1: Unadjusted rates of major adverse cardiovascular events (%) in hypertensive patients based on elevated heart rate in clinic and night-time ambulatory recordings
Adapted from: Palatini P, et al. J Hypertens 2017;35:487-492.
For explanations see text.
1. Palatini P, Benetos A, Grassi G, et al. Identification and management of the hypertensive patient with elevated heart rate: statement of a European Society of Hypertension Consensus Meeting. J Hypertens. 2006;24:603-610. http://www.ncbi.nlm.nih.gov/pubmed/16531784
2. Palatini P, Rosei EA, Casiglia E, et al. Management of the hypertensive patient with elevated heart rate: Statement of the Second Consensus Conference endorsed by the European Society of Hypertension. J Hypertens. 2016;34:813-821. http://www.ncbi.nlm.nih.gov/pubmed/26982382
6. James WP, Caterson ID, Coutinho W, et al. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med. 2010;363:905-917. http://www.ncbi.nlm.nih.gov/pubmed/20818901
11. Bays H, Pi-Sunyer X, Hemmingsson JU, et al. Liraglutide 3.0 mg for weight management: weight-loss dependent and independent effects. Curr Med Res Opin. 2017;33:225-229. http://www.ncbi.nlm.nih.gov/pubmed/27817208
12. Rondinelli M, Rossi A, Gandolfi A, et al. Use of liraglutide in the real world and impact at 36 months on metabolic control, weight, lipid profile, blood pressure, heart rate, and renal function. Clin Ther. 2017;39:159-169. http://www.ncbi.nlm.nih.gov/pubmed/27939305
13. Yamamoto H, Lee CE, Marcus JN, et al. Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons. J Clin Invest. 2002;110:43-52. http://www.ncbi.nlm.nih.gov/pubmed/12093887
14. Toft-Nielsen MB, Madsbad S, Holst JJ. Continuous subcutaneous infusion of glucagon-like peptide 1 lowers plasma glucose and reduces appetite in type 2 diabetic patients. Diabetes Care. 1999;22:1137-1143. http://www.ncbi.nlm.nih.gov/pubmed/10388979
15. Kumarathurai P, Anholm C, Larsen BS, et al. Effects of liraglutide on heart rate and heart rate variability: A randomized, double-blind, placebo-controlled crossover study. Diabetes Care. 2017;40:117-124. http://www.ncbi.nlm.nih.gov/pubmed/27797930
16. Griffioen KJ, Wan R, Okun E, et al. GLP-1 receptor stimulation depresses heart rate variability and inhibits neurotransmission to cardiac vagal neurons. Cardiovasc Res. 2011;89:72-78. http://www.ncbi.nlm.nih.gov/pubmed/20736238
17. Hillis GS, Woodward M, Rodgers A, et al. Resting heart rate and the risk of death and cardiovascular complications in patients with type 2 diabetes mellitus. Diabetologia. 2012;55:1283-1290. http://www.ncbi.nlm.nih.gov/pubmed/22286552
20. Margulies KB, Hernandez AF, Redfield MM, et al. Effects of liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction: A randomized clinical trial. JAMA. 2016;316:500-508. http://dx.doi.org/10.1001/jama.2016.10260