Open Access Highly Accessed Original investigation

The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus

David ZI Cherney1*, Bruce A Perkins2, Nima Soleymanlou3, Ronnie Har1, Nora Fagan4, Odd Erik Johansen5, Hans-Juergen Woerle5, Maximilian von Eynatten4 and Uli C Broedl5

Author Affiliations

1 Division of Nephrology, University Health Network, University of Toronto, Toronto General Hospital, 585 University Ave, Toronto 8N-845, M5G 2N2, Ontario, Canada

2 Division of Endocrinology, University Health Network, University of Toronto, Toronto, Canada

3 Boehringer Ingelheim Canada Ltd./Ltée, Burlington, Canada

4 Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA

5 Boehringer Ingelheim Pharma GmbH & Co.KG, Ingelheim, Germany

For all author emails, please log on.

Cardiovascular Diabetology 2014, 13:28  doi:10.1186/1475-2840-13-28

Published: 29 January 2014

Abstract

Background

Individuals with type 1 diabetes mellitus are at high risk for the development of hypertension, contributing to cardiovascular complications. Hyperglycaemia-mediated neurohormonal activation increases arterial stiffness, and is an important contributing factor for hypertension. Since the sodium glucose cotransport-2 (SGLT2) inhibitor empagliflozin lowers blood pressure and HbA1c in type 1 diabetes mellitus, we hypothesized that this agent would also reduce arterial stiffness and markers of sympathetic nervous system activity.

Methods

Blood pressure, arterial stiffness, heart rate variability (HRV) and circulating adrenergic mediators were measured during clamped euglycaemia (blood glucose 4–6 mmol/L) and hyperglycaemia (blood glucose 9–11 mmol/L) in 40 normotensive type 1 diabetes mellitus patients. Studies were repeated after 8 weeks of empagliflozin (25 mg once daily).

Results

In response to empagliflozin during clamped euglycaemia, systolic blood pressure (111 ± 9 to 109 ± 9 mmHg, p = 0.02) and augmentation indices at the radial (-52% ± 16 to -57% ± 17, p = 0.0001), carotid (+1.3 ± 1 7.0 to -5.7 ± 17.0%, p < 0.0001) and aortic positions (+0.1 ± 13.4 to -6.2 ± 14.3%, p < 0.0001) declined. Similar effects on arterial stiffness were observed during clamped hyperglycaemia without changing blood pressure under this condition. Carotid-radial pulse wave velocity decreased significantly under both glycemic conditions (p ≤ 0.0001), while declines in carotid-femoral pulse wave velocity were only significant during clamped hyperglycaemia (5.7 ± 1.1 to 5.2 ± 0.9 m/s, p = 0.0017). HRV, plasma noradrenalin and adrenaline remained unchanged under both clamped euglycemic and hyperglycemic conditions.

Conclusions

Empagliflozin is associated with a decline in arterial stiffness in young type 1 diabetes mellitus subjects. The underlying mechanisms may relate to pleiotropic actions of SGLT2 inhibition, including glucose lowering, antihypertensive and weight reduction effects.

Trial registration

Clinical trial registration: NCT01392560

Keywords:
Diabetes mellitus; Systemic blood pressure; SGLT2 inhibition; Empagliflozin; Hyperglycaemia; Arterial stiffness; Heart rate variability