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

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are indicated with diet and exercise for the improvement of glycemic control in adults with type 2 diabetes mellitus (T2DM), many of whom are taking background oral glucose-lowering medications such as metformin and sulfonylureas. Exenatide was the first-in-class GLP-1RA and is available worldwide in twice-daily (BID) and once-weekly (QW) formulations for administration via subcutaneous injection. The slow pharmacokinetics and inherent titration of the extended-release formulation achieves minimal effective concentrations in 2 weeks and steady-state concentrations in 6–7 weeks, compared with the intermittent exposure of exenatide achieved with BID dosing. Liraglutide is a GLP-1RA that is available as a once-daily (QD) subcutaneous injection, and maximum concentrations are achieved 8–12 h postdose [1].

GLP-1RAs reduce glucose levels by multiple mechanisms, including glucose-dependent stimulation of insulin secretion, suppression of glucagon, and slowing of gastric emptying [2]. In randomized controlled studies, exenatide BID and QW have also been associated with improvements in cardiovascular risk factors, including body weight, blood pressure, lipids, and endothelial function [3‐8]. In addition, exenatide has been shown to not prolong the QTc interval at supratherapeutic concentrations [9, 10]. Liraglutide QD has also been associated with improved body weight, systolic blood pressure, and triglycerides [6, 11, 12] and a reduced risk of cardiovascular events [13].

The use of GLP-1RAs is associated with increases in heart rate [14]. The aim of this post hoc analysis was to examine the relationship of heart rate changes over time, to explore the relationship of heart rate changes with baseline heart rate, and to identify patient characteristics associated with changes in heart rate in the exenatide QW development program.

This analysis showed that, although heart rate measures were highly variable, small, reversible heart rate increases were rapidly observed among patients treated with exenatide QW, exenatide BID, and liraglutide compared with non-GLP-1RA therapies. Changes in heart rate varied markedly between patients within each treatment group. Not all patients experienced increases in heart rate, and some patients in each treatment group had no change or a reduction in heart rate from baseline at each time point. Heart rate changes were negatively correlated with baseline heart rate, regardless of treatment, with observed increases being greater in patients with a low heart rate at baseline and smaller in patients with a high heart rate at baseline, suggesting the phenomenon of regression to the mean. The mean heart rate over time remained within a normal range (< 80 bpm) among patients treated with GLP-1RAs.

Because β-blockers are known to reduce heart rate [23], changes in heart rate with GLP-1RA therapy were examined in patient subgroups according to baseline β-blocker use. Increases in heart rate were seen among patients who were treated with GLP-1RAs in both those taking β-blockers at baseline and β-blocker-naïve patients, whereas the heart rate remained stable in those receiving non-GLP-1RA treatments in both β-blocker subgroups. Increases in heart rate among GLP-1RA-treated patients were greater for those taking β-blockers at baseline than for β-blocker-naïve patients; however, these results are confounded by differences in patient characteristics. Baseline characteristics were not balanced across the β-blocker subgroups and because the β-blocker population was determined based on baseline β-blocker use, treatment effects on heart rate could potentially be confounded by new concomitant β-blocker use or changes in dosage during the study treatment period.

The mechanism by which GLP-1RAs increase heart rate among patients with diabetes has yet to be established [24]. However, proposed mechanisms include vagal depression, sympathetic activation [25, 26], increased levels of endogenous insulin [24, 27], and stimulation of glucagon-like peptide-1 receptors in myocytes in the sinoatrial node [28]. Recent studies in healthy volunteers and patients with T2DM have suggested that GLP-1RAs may increase the heart rate through a direct stimulatory effect on the sinoatrial node [25, 29], and the differential effects of GLP-1RAs on heart rate appear to be the result of differences in molecular structure as well as duration of action [25].

Increased heart rate appears to be dependent on the GLP-1RA dose, with an associated heart rate increase of 2–3 bpm observed in a meta-analysis of randomized controlled trials of exenatide and liraglutide [14].

Doses of liraglutide QD and exenatide QW are active throughout the day or longer, and in our analysis they were associated with greater mean heart rate increases than exenatide BID. The onset of heart rate changes appeared to be more rapid with liraglutide than with exenatide QW.

Reviews and analyses on the effect of GLP-1RAs on heart rate have also found differences between long- and short-acting formulations. One meta-analysis found that exenatide QW and liraglutide, but not exenatide BID, were associated with increases in heart rate in comparison to placebo [24]. A review that investigated the effects of GLP-1RAs on 24-h heart rate and stratified these GLP-1RAs by formulation found that long-acting formulations could induce a 24-h time-averaged mean heart rate increase of 3–10 bpm, while the short-acting formulations resulted in a transient (10–12-h) increase in heart rate of 8–10 bpm [25]. These results are consistent with an earlier analysis showing that short-acting GLP-1RAs (exenatide BID and lixisenatide QD) were associated with smaller, more transient increases in heart rate than the longer-acting GLP-1RAs exenatide QW, liraglutide, and albiglutide; while the increase in heart rate with dulaglutide was small, it persisted at nighttime [30]. These differences in heart rate increases between individual GLP-1RAs may be due to pharmacokinetic differences between short- and long-acting formulations [31].

The cardiovascular safety of T2DM therapies is of central importance because patients with T2DM are at increased risk of cardiovascular disease. The risk of cardiovascular events has been shown to increase with heart rate in epidemiological studies, although higher heart rate was not usually associated with drug therapy in these populations and the data were not stratified by baseline heart rate. Furthermore, patients with higher heart rate may have underlying health conditions, giving rise to potential selection bias in these epidemiological studies. An increase in the resting heart rate of 15 bpm has been found to be associated with an increased risk of cardiovascular disease mortality [11]. Increased heart rate could accelerate the progression to arterial wall stiffness and atherosclerosis [32]. However, the clinical importance of increased heart rate varies with a patient’s clinical circumstances.

Ongoing and recently completed cardiovascular safety outcome trials will help resolve questions surrounding the clinical implications of heart rate increases with GLP-1RA therapy. To date, published results from cardiovascular outcome trials have demonstrated that GLP-1RA treatment was either noninferior or superior to comparators in reducing cardiovascular end-point events in different patient populations with T2DM. The available data thus far do not indicate that GLP-1RA treatment, despite the associated increases in heart rate, is associated with an increased risk of cardiovascular events. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial (NCT01179048), an international placebo-controlled study, evaluated the effect of liraglutide compared with placebo, added on to standard care, on cardiovascular events in 9340 patients with T2DM and high cardiovascular risk [13]. After a median follow-up of 3.8 years, liraglutide-treated patients had a significant reduction in the primary composite outcome of the first occurrence of cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke (13.0 vs. 14.9% for placebo; P < 0.01 for superiority). The Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6; NCT01720446) evaluated semaglutide or placebo, given in addition to standard care, in 3297 patients with T2DM and high cardiovascular risk [33]. After 104 weeks, semaglutide demonstrated noninferiority to placebo for the primary composite end point of the first occurrence of cardiovascular death, nonfatal MI, or nonfatal stroke (6.6 vs. 8.9%; P < 0.001 for noninferiority; P = 0.02 for superiority). The incidence of nonfatal stroke (1.6 vs. 2.7%; P = 0.04), but not cardiovascular death or nonfatal MI, was significantly lower with semaglutide than with placebo. Lixisenatide was compared with placebo among patients with T2DM who recently experienced an acute coronary event in the phase 3b Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial (NCT01147250) [34]. Lixisenatide demonstrated noninferiority to placebo for the primary outcome, time to the first occurrence of major adverse cardiovascular events, defined as cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina (hazard ratio [HR] 1.02; 95% confidence interval [CI] 0.89–1.17). No increased risk of heart failure (HR 0.96; 95% CI 0.75–1.23) or death (HR 0.94; 95% CI 0.78–1.13) was observed with lixisenatide. There was a mean increase in heart rate of + 0.4 bpm with lixisenatide versus placebo (P = 0.01).

Results from the Exenatide Study of Cardiovascular Event Lowering (EXSCEL; NCT01144338), a placebo-controlled phase 4 trial examining exenatide QW for effects on cardiovascular outcomes in 14,752 patients with T2DM, of whom more than 70% had prior cardiovascular disease, showed no increase in cardiovascular events compared to placebo [35]. Assessment of the primary outcome of this study, the time to the first confirmed cardiovascular event in the primary composite cardiovascular end point (cardiovascular death, nonfatal MI, or nonfatal stroke), over a median follow-up of 3.2 years indicated that exenatide QW was noninferior to placebo for safety (P < 0.001) but not superior to placebo for efficacy (P = 0.06) [35]. An LS mean increase in heart rate of + 2.51 bpm was observed with exenatide QW versus placebo during the study period (P < 0.001).

A meta-analysis of the LEADER, SUSTAIN-6, ELIXA, and EXSCEL trials found that GLP-1RAs significantly reduced the risk of the composite end point of cardiovascular death, nonfatal MI, or nonfatal stroke (P = 0.033), in addition to reducing cardiovascular mortality (P < 0.007) and all-cause mortality (P < 0.002) [36]. The effect of GLP-1RA therapy on cardiovascular outcomes will also be assessed in the Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) trial (NCT01394952), which will compare the time to the first occurrence of cardiovascular death, nonfatal MI, or nonfatal stroke with dulaglutide versus placebo over an average follow-up of approximately 6.5 years. Results from this study are expected in 2018.

The limitations of the current analysis include its post hoc nature and the relatively short duration of the included studies. Limitations of the data are that heart rate measurements were part of clinical procedures for collecting vital signs for clinical trials and were therefore not a standardized procedure, as would occur in a clinical study focused on heart rate data. The collection of heart rate data also varied among studies because of different study schedules, resulting in variations in patient numbers for each time point. Because heart rate was measured during clinic visits, it was not possible to examine changes outside these visits or the general variability in heart rate within individual patients. Another limitation is the considerably larger number of patients included in the exenatide QW group compared with the other treatment groups after pooling studies and treatments. This imbalance may limit the interpretation of results, although data were reported for the individual GLP-1RAs to avoid the potential impact of this imbalance on results for the pooled GLP-1RAs. Limitations associated with the multivariate analysis include lack of adjustment for multiplicity and the use of postbaseline factors, such as change in body weight. Nevertheless, this was justified by the post hoc nature of the multivariate analysis and the difficulty of distinguishing the direct effect of study medication on heart rate change and the indirect effect of study medication on body weight change and subsequently heart rate change. Although only the potential effect of background treatment with metformin plus a sulfonylurea was investigated in the analysis, this was the most frequently used background therapy combination. Patients receiving background therapy with metformin plus a sulfonylurea were likely to have been older and to have had a longer duration and greater severity of diabetes than patients on monotherapy background treatments. Because of these limitations, the multivariate analysis to identify potential risk factors for increased heart rate should be considered hypothesis-generating and to require validation.

This analysis showed that treatment with GLP-1RAs was associated with an increase in heart rate among patients with T2DM, although the heart rate remained within normal ranges. Baseline heart rate was the strongest predictor of heart rate changes; however, further studies are required to confirm the results from this multivariate analysis. While the clinical relevance of increases in heart rate with GLP-1RA therapy is unclear, the results from GLP-1RA cardiovascular outcome trials to date do not indicate that increased heart rate is associated with an increased rate of cardiovascular events.