Dataset Information

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

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.

SUBMITTER: Cherney DZ

PROVIDER: S-EPMC3915232 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Publications

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

Cherney David Zi DZ Perkins Bruce A BA Soleymanlou Nima N Har Ronnie R Fagan Nora N Johansen Odd Erik OE Woerle Hans-Juergen HJ von Eynatten Maximilian M Broedl Uli C UC

Cardiovascular diabetology 20140129

<h4>Background</h4>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 a ...[more]

PMID: 24475922

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Project description:BackgroundEmpagliflozin has been shown to reduce cardiovascular mortality, but the underlying pathogenetic mechanisms are poorly understood. It was previously demonstrated that empagliflozin improved arterial stiffness.MethodsOur analysis comprising 58 patients with type 2 diabetes mellitus identifies factors triggering the improvement of arterial stiffness. All patients participated in an investigator-initiated, prospective, double-blind, randomized, placebo-controlled, interventional clinical trial ( http://www.ClinicalTrials.gov : NCT02471963, registered 15th June 2015, retrospectively registered) and received either 6-weeks treatment with 25 mg empagliflozin orally once daily or placebo (crossover). Central systolic pressure and central pulse pressure were recorded by the SphygmoCor System (AtCor Medical). Now, we investigated the impact of parameters of glucose metabolism, volume status, sympathetic activation, lipids, uric acid, blood pressure and inflammation on vascular parameters of arterial stiffness using multivariate regression analysis.ResultsAs previously reported, therapy with empagliflozin improved arterial stiffness as indicated by reduced central systolic blood pressure (113.6 ± 12.1 vs 118.6 ± 12.9 mmHg, p < 0.001), central pulse pressure (39.1 ± 10.2 vs 41.9 ± 10.7 mmHg, p = 0.027) forward (27.1 ± 5.69 vs 28.7 ± 6.23 mmHg, p = 0.031) as well as reflected wave amplitude (18.9 ± 5.98 vs 20.3 ± 5.97 mmHg, p = 0.045) compared to placebo. The multivariate regression analysis included age, sex and change between empagliflozin and placebo therapy of the following parameters: HbA1c, copeptin, hematocrit, heart rate, LDL-cholesterol, uric acid, systolic 24-h ambulatory blood pressure and high sensitive CRP (hsCRP). Besides the influence of age (beta = - 0.259, p = 0.054), sex (beta = 0.292, p = 0.040) and change in systolic 24-h ambulatory blood pressure (beta = 0.364, p = 0.019), the change of hsCRP (beta = 0.305, p = 0.033) emerged as a significant determinant of the empagliflozin induced reduction in arterial stiffness (placebo corrected). When replacing HbA1c with fasting plasma glucose in the multivariate regression analysis, a similar effect of the change in hsCRP (beta = 0.347, p = 0.017) on arterial stiffness parameters was found.ConclusionBesides age and sex, change in systolic 24-h ambulatory blood pressure and change in hsCRP were determinants of the empagliflozin induced improvement of vascular parameters of arterial stiffness, whereas parameters of change in glucose metabolism and volume status had no significant influence. Our analysis suggests that empagliflozin exerts, at least to some extent, its beneficial vascular effects via anti-inflammatory mechanisms. Trial registration http://www.ClinicalTrials.gov : NCT02471963, registered 15th June 2015, retrospectively registered.

Project description:ObjectiveCardiac autonomic neuropathy (CAN) is an independent risk factor for cardiovascular mortality and also is associated with a high risk of lethal arrhythmias and sudden death in people with type 1 or 2 diabetes. Heart rate variability (HRV) is an index of cardiac autonomic function. To investigate the relationship between HRV and arterial stiffness evaluated by the cardio-ankle vascular index (CAVI), a relatively new marker for arterial stiffness and a predictor of cardiovascular disease, in patients with type 2 diabetes.Materials and methodsWe studied consecutive 313 patients with type 2 diabetes in a cross-sectional design. HRV was estimated by the coefficient of variation of 100 R-R intervals (CVR-R) at rest and during deep breathing (DB). The difference in CVR-R was defined as CVR-R during DB minus CVR-R at rest. Arterial stiffness was evaluated by CAVI, which is independent of blood pressure (BP). A CAVI greater than or equal to 9.0 was defined as significant arterial stiffening.ResultsLinear regression analysis showed that CAVI correlated positively with age, duration of diabetes, urinary albumin creatinine ratio (UACR), CVR-R during DB, and the difference in CVR-R and negatively with body mass index (BMI), estimated glomerular filtration rate, and sensory nerve conduction velocity and action potential of the sural nerve. Multivariate analysis found that age, BMI, systolic blood pressure, UACR, and CVR-R during DB were independently associated with arterial stiffness determined by CAVI. The CVR-R at rest and during deep breathing was significantly lower in the patients with arterial stiffness than in those without it.ConclusionLow HRV estimated by CVR-R during DB is closely associated with arterial stiffness measured by CAVI in people with type 2 diabetes, suggesting that arterial stiffness associated with CAN may be an independent risk factor for cardiovascular disease in people with type 2 diabetes.Supplementary informationThe online version contains supplementary material available at 10.1007/s13340-022-00604-y.

Dataset Information

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

Background

Methods

Results

Conclusions

Trial registration

Clinical trial registration

Publications

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

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