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

David Zi Cherney, Bruce A Perkins, Nima Soleymanlou, Ronnie Har, Nora Fagan, Odd Erik Johansen, Hans-Juergen Woerle, Maximilian von Eynatten, Uli C Broedl, David Zi Cherney, Bruce A Perkins, Nima Soleymanlou, Ronnie Har, Nora Fagan, Odd Erik Johansen, Hans-Juergen Woerle, Maximilian von Eynatten, Uli C Broedl

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.

Clinical trial registration: NCT01392560.

Figures

Figure 1
Figure 1
Physiological mechanisms implicated in arterial stiffness lowering effects with sodium glucose cotransport-2 inhibition.
Figure 2
Figure 2
The effect of empagliflozin on carotid (A) and aortic (B) augmentation indices during clamped euglycaemia and hyperglycaemia in patients with type 1 diabetes. *p < 0.0001 compared to baseline parameter under the same glycemic condition.

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