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Liraglutide Increases Heart Rate in T2DM

Study also finds reduced heart rate variability (HRV) in overweight patients with newly diagnosed type 2 diabetes (T2D) and stable coronary artery disease (CAD).

Reduced heart rate variability (HRV) and increased heart rate (HR) have been associated with cardiovascular mortality. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) increase HR, and studies have suggested that they may reduce HRV. We examined the effect of the GLP-1 RA liraglutide on HRV and diurnal variation of HR in overweight patients with newly diagnosed type 2 diabetes (T2D) and stable coronary artery disease (CAD).

Preman Kumarathurai, M.D., from the Copenhagen University Hospital of Bispebjerg in Denmark, and colleagues administered liraglutide or placebo to a therapy of metformin. As a measure of HRV, the standard deviation of beat-to-beat (SDNN) intervals was assessed by 24-hour Holter monitoring. The authors also assessed diurnal HRV and sympathovagal balance analyzed by root mean square of successive differences (RMSSD) in NN intervals and high frequency (HF) and low-frequency (LF) power.

Liraglutide or placebo was administrated to a backbone therapy of metformin in this double-blind, placebo-controlled 12 + 12–week crossover study. SD of beat-to-beat (NN) intervals (SDNN) was assessed by 24-h Holter monitoring as a measure of HRV. Diurnal HR variation and sympathovagal balance analyzed by root mean square of successive differences (RMSSD) in NN intervals and high-frequency (HF) and low-frequency (LF) power were assessed.

What they found was that, compared with placebo, liraglutide decreased SDNN in 27 subjects; decreased RMSSD; and increased the mean, daytime, and nighttime HR. After adjustment for metabolic and HR changes, the decrease in SDNN remained significant. Liraglutide also correlated with a reduction in HF power, without affecting the LF/HF ratio.

“In overweight patients with CAD and newly diagnosed T2D, liraglutide increased HR and reduced HRV despite significant weight loss and improvement in metabolic parameters,” the authors write.

They found that when compared with placebo, liraglutide decreased SDNN in 27 subjects (−33.9 ms; P < 0.001, paired analysis); decreased RMSSD (−0.3 log-ms; P = 0.025); and increased the mean HR (8.1 beats/min; P = 0.003), daytime HR (5.7; P = 0.083), and nighttime HR (6.3; P = 0.026). In a multivariable regression analysis, the decrease in SDNN remained significant after adjustment for metabolic and HR changes. Liraglutide reduced HF power (−0.7 log-ms2; P = 0.026) without any change in LF/HF ratio.

We demonstrated that 12 weeks of liraglutide treatment induced a significant increase in HR and reduction in long-term HRV in patients with newly diagnosed T2D and stable CAD. We show that the reduction in HRV was not mediated by the increased HR observed after liraglutide therapy. To our knowledge, this randomized placebo-controlled study is the first to assess the effects of a GLP-1 RA on long-term HRV in a clinical setting. The chronotropic effect of liraglutide may be mediated through the GLP-1 receptor on the sinoatrial node and influence the measures of HRV. However, the multivariable regression analysis revealed no significant association between changes in mean NN and SDNN.

Furthermore, the association between liraglutide treatment and SDNN reduction was still significant after adjustment for mean NN. These findings suggest that the impaired HRV may be due to a direct influence on sympathovagal balance.

The time domain parameter RMSSD decreased significantly during liraglutide treatment. Of note, this decrease was mainly during nighttime hours, where vagal activity is considered dominant. The correlation analyses showed a relatively large R2 value for RMSSD and HF power, thus confirming the close association between these two parameters. A significant decrease during nighttime hours was also evident for SDNN-index.

This hypothesis is supported by findings from previous studies. In a randomized study in 30 patients with T2D, liraglutide induced an increase in HR in conjunction with an increase in the LF/HF ratio during several time points of the day. Furthermore, in a small study of seven patients with T2D, 24 weeks of liraglutide treatment increased HR, decreased SDNN, and decreased LF and HF power, and the authors concluded that this may be due to an inhibiting effect on vagal activity. Short-term infusion of exenatide in overweight, healthy participants revealed an increase in HR and a concomitant increase in LF/HF ratio, thus in accordance with a relative increase in sympathetic activity. Finally, an experimental study in mice showed an inhibitory effect of GLP-1 on vagal activity because both short- and long-term central administration of the GLP-1 RA exendin-4 increased HR-reduced HF and LF powers and inhibited neurotransmission to vagal neurons.

From the results they concluded that, in overweight patients with CAD and newly diagnosed T2D, liraglutide increased HR and reduced HRV despite significant weight loss and improvement in metabolic parameters. The increase in nightly heart rate in conjunction with a decrease in parameters of parasympathetic activity suggests that liraglutide may affect sympathovagal balance.

Practice Pearls:

  • Reduced heart rate variability (HRV) and increased heart rate (HR) have been associated with cardiovascular mortality.
  • In overweight patients with CAD and newly diagnosed T2D, liraglutide increased HR and reduced HRV despite significant weight loss and improvement in metabolic parameters.
  • The results suggests that liraglutide may affect sympathovagal balance.

Published online Oct. 19 in Diabetes Care.