The Effects of Empagliflozin on Arterial Wall Characteristics

The Effects of Empagliflozin on Functional and Structural 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)).

Study Overview

• Status: Unknown
• Conditions: Diabetes Complications; Diabetes Mellitus, Type 1; Vascular Stiffness; Hypoglycemic Agents
• Intervention / Treatment: Drug: Empagliflozin 25mg; Drug: Metformin; Drug: Empagliflozin/Metformin; Drug: Placebos

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Mojca Lunder, MD, PhD; Phone Number: +38615223140; Email: mojca.lunder@kclj.si
• Study Contact Backup: Name: Miodrag Janic, MD, PhD; Phone Number: +38615228012; Email: miodrag.janic@kclj.si

Study Locations

• Slovenia
  • Ljubljana, Slovenia, SI-1000
    • Recruiting
    • University Medical Centre Ljubljana
    • Contact: Mojca Lunder, MD, PhD; Phone Number: +386 1 5223140; Email: mojca.lunder@kclj.si
    • Contact: Andrej Janez, Prof; Phone Number: +386 1 5223564; Email: andrej.janez@kclj.si
    • Principal Investigator: Miodrag Janic, MD, PhD
    • Principal Investigator: Miso Sabovic, Prof

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: *empagliflozin*; empagliflozin 25 mg daily for 12 weeks, once daily, by mouth	Drug: Empagliflozin 25mg; The patients receive empagliflozin (25 mg daily) for 12 weeks.; Other Names: empagliflozin
ACTIVE_COMPARATOR: *metformin*; metformin 2000 mg daily for 12 weeks, once daily, by mouth	Drug: Metformin; The patients receive metformin (2000 mg daily) for 12 weeks.
ACTIVE_COMPARATOR: *empagliflozin/metformin*; empagliflozin 25 mg daily and metformin 2000 mg daily for 12 weeks, by mouth	Drug: Empagliflozin 25mg; The patients receive empagliflozin (25 mg daily) for 12 weeks.; Other Names: empagliflozin; Drug: Metformin; The patients receive metformin (2000 mg daily) for 12 weeks.; Drug: Empagliflozin/Metformin; The patients receive empagliflozin 25 mg daily and metformin 2000 mg daily or placebo for 12 weeks.; Other Names: empagliflozin and metformin
PLACEBO_COMPARATOR: *placebo*; placebo for 12 weeks, once daily with water, by mouth	Drug: Placebos; The patients receive for 12 weeks.; Other Names: placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Arterial function	Endothelial function and arterial stiffness will be measured.	the change of arterial function from baseline to 12 weeks of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glycemic control	HbA1c will be measured.	the change of HbA1c from baseline to 12 weeks of treatment

Collaborators and Investigators

• Sponsor: University Medical Centre Ljubljana
• Investigators: Study Chair: Andrej Janez, prof, University Medical Centre Ljubljana

Publications and helpful links

General Publications

• Lunder M, Janic M, Japelj M, Juretic A, Janez A, Sabovic M. Empagliflozin on top of metformin treatment improves arterial function in patients with type 1 diabetes mellitus. Cardiovasc Diabetol. 2018 Dec 3;17(1):153. doi: 10.1186/s12933-018-0797-6.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 1, 2018
• Primary Completion (ANTICIPATED): December 30, 2018
• Study Completion (ANTICIPATED): January 30, 2019

Study Registration Dates

• First Submitted: August 10, 2018
• First Submitted That Met QC Criteria: August 18, 2018
• First Posted (ACTUAL): August 21, 2018

Study Record Updates

• Last Update Posted (ACTUAL): August 21, 2018
• Last Update Submitted That Met QC Criteria: August 18, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Complications; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Metformin; Empagliflozin
• Other Study ID Numbers: AGE-SGLT2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No