Does empagliflozin modulate the autonomic nervous system among individuals with type 2 diabetes and coronary artery disease? The EMPA-HEART CardioLink-6 Holter analysis

Vinay Garg; Subodh Verma; Kim A Connelly; Andrew T Yan; Aditya Sikand; Ankit Garg; Paul Dorian; Fei Zuo; Lawrence A Leiter; Bernard Zinman; Peter Jüni; Atul Verma; Hwee Teoh; Adrian Quan; C David Mazer; Andrew C T Ha

doi:10.1016/j.metop.2020.100039

Does empagliflozin modulate the autonomic nervous system among individuals with type 2 diabetes and coronary artery disease? The EMPA-HEART CardioLink-6 Holter analysis

Metabol Open. 2020 Jun 21:7:100039. doi: 10.1016/j.metop.2020.100039. eCollection 2020 Sep.

Authors

Vinay Garg^{1

2

3}, Subodh Verma^{1

3

4}, Kim A Connelly^{2

5

6}, Andrew T Yan^{2

5}, Aditya Sikand¹, Ankit Garg², Paul Dorian^{2

3

5}, Fei Zuo⁷, Lawrence A Leiter^{2

8

9}, Bernard Zinman^{2

10}, Peter Jüni^{2

7

11}, Atul Verma¹², Hwee Teoh^{1

8}, Adrian Quan¹, C David Mazer^{6

13

14}, Andrew C T Ha^{2

15}

Affiliations

¹ Division of Cardiac Surgery, Li Ka Shing Knowledge Institute of St Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada.
² Department of Medicine, University of Toronto, Toronto, ON, Canada.
³ Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
⁴ Department of Surgery, University of Toronto, Toronto, ON, Canada.
⁵ Division of Cardiology, Li Ka Shing Knowledge Institute of St Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada.
⁶ Department of Physiology, University of Toronto, Toronto, ON, Canada.
⁷ Applied Health Research Centre, Li Ka Shing Knowledge Institute of St Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada.
⁸ Division of Endocrinology and Metabolism, Li Ka Shing Knowledge Institute of St Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada.
⁹ Department of Nutritional Sciences, University of Toronto, Toronto, ON, Canada.
¹⁰ Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
¹¹ Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada.
¹² Department of Cardiology, Southlake Regional Health Centre, University of Toronto, Newmarket, ON, Canada.
¹³ Department of Anesthesia, Li Ka Shing Knowledge Institute of St Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada.
¹⁴ Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, ON, Canada.
¹⁵ Peter Munk Cardiac Center, Toronto General Hospital, University Health Network, Toronto, ON, Canada.

Abstract

Context: We examined if empagliflozin was associated with modulation of cardiac autonomic tone among subjects with type 2 diabetes and stable coronary artery disease (CAD) relative to placebo.

Methods: Using ambulatory 24-h Holter electrocardiographic data prospectively collected from a randomized trial, we compared changes in heart rate variability (HRV) parameters between empagliflozin- and placebo-assigned subjects over a follow-up period of 6 months. Measured HRV domains included: standard deviation (SD) of NN intervals (SDNN), SD of average NN intervals per 5-min (SDANN), root mean square of successive RR interval differences (RMSSD), % successive NN intervals differing >50 ms (ms) (pNN50), low frequency (LF), high frequency (HF) and the LF/HF ratio (LF:HF). Differences in HRV parameters between the 2 groups were compared with analysis of covariance (ANCOVA). Statistical measures of significance were reported as adjusted differences between the 2 groups and their corresponding 95% confidence intervals.

Results: Sixty-six subjects completed 24-h Holter monitoring at baseline and 6-months. Over 6 months, the change in HRV was similar between subjects treated with empagliflozin vs. placebo for the following parameters: RMSSD -1.2 ms (-6.0 to 3.6 ms); pNN50 0.5% (-2.6 to 3.6%); VLF -907.8 ms² (-2388.8 to 573.1 ms²); LF -341 ms² (-878.7 to 196.7 ms²); HF -33.8 ms² (-111.1 to 43.5 ms²); LF:HF -0.1 (-0.4 to 0.2). Subjects who received placebo experienced an increase in SDNN 18.6 ms (2.8-34.3 ms) and SDANN 20.2 ms (3.2-37.3 ms) relative to those treated with empagliflozin.

Conclusion: Compared to placebo, empagliflozin did not result in changes in autonomic tone among individuals with type 2 diabetes and stable coronary artery disease.