The Effects of Empagliflozin on Arterial Wall Characteristics
The Effects of Empagliflozin on Arterial Wall Characteristics
Introduction: Diabetes mellitus is characterized by impaired arterial function and high
 incidence of cardiovascular events. Metformin and most recent antidiabetic groups of drugs,
 SGLT2 inhibitors, were in previous studies shown to reduce cardiovascular events. Until now,
 direct effect of empagliflozin on arterial function and its comparison to metformin was not
 studied yet.

 Aim: The aim of the present study is to explore and compare potential direct effects of
 empagliflozin and metformin on arterial functional and structural arterial wall
 characteristics in patients with type 1 diabetes mellitus.

 Methods: Patients with type 1 diabetes mellitus are randomized into four groups: 1)
 empagliflozin (25 mg daily), 2) metformin (2000 mg daily), 3) combination (empagliflozin 25
 mg daily and metformin 2000 mg daily) and 4) control (placebo). At inclusion and after 12
 weeks treatment, arterial function is assessed: endothelial function (brachial artery
 flow-mediated dilation (FMD), reactive hyperemia index (RHI)) and arterial stiffness (carotid
 pulse wave velocity (PWV), carotid-femoral PWV (cfPWV) and common carotid artery stiffness
 (β-stiffness)).
Introduction: Diabetes mellitus is characterized by impaired arterial function and high
 incidence of cardiovascular events. Metformin and most recent antidiabetic groups of drugs,
 SGLT2 inhibitors, were in previous studies shown to reduce cardiovascular events. Until now,
 direct effect of empagliflozin on arterial function and its comparison to metformin was not
 studied yet.

 Aim: The aim of the present study is to explore and compare potential direct effects of
 empagliflozin and metformin on arterial functional and structural arterial wall
 characteristics in patients with type 1 diabetes mellitus.

 Methods: Patients with type 1 diabetes mellitus are randomized into four groups: 1)
 empagliflozin (25 mg daily), 2) metformin (2000 mg daily), 3) combination (empagliflozin 25
 mg daily and metformin 2000 mg daily) and 4) control (placebo). At inclusion and after 12
 weeks treatment, arterial function is assessed: endothelial function (brachial artery
 flow-mediated dilation (FMD), reactive hyperemia index (RHI)) and arterial stiffness (carotid
 pulse wave velocity (PWV), carotid-femoral PWV (cfPWV) and common carotid artery stiffness
 (β-stiffness)).

 Background:

 Diabetes mellitus is characterized by chronic hyperglycaemia causing chronic microvascular
 and macrovascular complications. Among the microvascular complications, diabetic retinopathy,
 neuropathy and nephropathy are included. Macrovascular complications include atherosclerotic
 brain-vascular disease, coronary disease and peripheral arterial disease. Chronic
 complications of diabetes pose a greater risk of disability, development of blindness, renal
 failure, neuropathy and cardiovascular disease. Consequently, a good glycemic control is
 crucial to protect the patients from the development of chronic complications. In this
 regard, glycemic control is of primary importance, as well as the choice of treatment that
 can further improve the functioning of the arteries and thus protect against the onset of
 cardiovascular damage or complications.

 For the treatment of hyperglycemia patients with type 1 diabetes need insulin. Some oral
 anti-diabetics have been found to improve glycemic control, reduce insulin consumption (the
 total daily insulin dose), and also protect against the development of cardiovascular
 complications. Such effects have been shown in clinical studies for metformin. The latter
 improved from endothelium-dependent relaxation of the arteries and reduced insulin
 resistance, but most studies were performed in patients with type 2 diabetes and studies in
 type 1 diabetes are limited.

 A novel group of oral antidiabetics are SGLT2 inhibitors, such as empagliflozin, reduce
 glucose reabsorption in proximal kidney tubules and increase glucose excretion through urine.
 Most of the previous studies on the efficacy of empagliflozin basic antidiabetic activity and
 additional effects have been performed in patients with type 2 diabetes. They were shown to
 improve glyceamia control and also reduced blood pressure body weight. In patients with type
 1 diabetes, favorable effects of empagliflozin on the reduction of arterial wall stiffness
 and blood pressure reduction were observed, but no systematic studies were performed yet and
 the mechanisms behind the beneficial effects are not known yet.

 Methods:

 Type 1 diabetes mellitus patients are being recruited. The patients are equally randomized
 into 4 groups that receive one of the three drugs in addition to insulin. The groups were as
 follows: 1) empagliflozin group (receiving 25 mg daily), 2) metformin group (receiving 2000
 mg daily), combination group (receiving empagliflozin 25 mg daily and metformin 2000 mg
 daily) and 4) control group (receiving placebo). The duration of the study period is 12
 weeks. All subjects are voluntarily participating in this study. The study was approved by
 the National Medical Ethics Committee of Slovenia.

 At the beginning of the study, a complete history and full medical examination of each
 patient are performed. At inclusion to the study and after 12 weeks of treatment, arterial
 function measurements are performed, comprising of i) measurements of endothelial function
 (brachial artery flow-mediated dilation (FMD), reactive hyperemia index (RHI)); and ii)
 measurements of arterial stiffness (carotid artery pulse wave velocity (PWV), carotid-femoral
 PWV (cfPWV) and common carotid artery stiffness (β-stiffness)). Additionally, venous blood
 samples are obtained at the beginning and at the end of the study period. Automated
 sphygmomanometer is used for blood pressure measurements. Ultrasound measurements are
 obtained on Aloka ProSound alpha7 machine with integrated high resolution eTracking system.
 Endothelial function, by means of brachial artery FMD, was assessed in accordance to the
 current guidelines. Reactive hyperemia index is measured using Endopat 2000 device (Itamar
 Medical Ltd., Caesarea, Israel), while cfPWV is obtained using SphygmoCor device (AtCor
 Medical, Sydney, Australia) with SphygmoCor CvMS software (version 9).
Inclusion Criteria:

 -  diabetes mellitus type 1

 Exclusion Criteria:

 -  diagnosed advanced heart, kidney or liver failure

 -  benign prostatic hyperplasia

 -  prostatic carcinoma

 -  frequent urinary tract infections

 -  non-type 1 diabetes mellitus