The Effects of Empagliflozin on Arterial Wall Characteristics

NCT ID: NCT03639545

Last Updated: 2018-08-21

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 120 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-03-01
• Study Completion Date: 2019-01-30

Brief Summary

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)).

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).

Conditions

Vascular Stiffness; Hypoglycemic Agents; Diabetes Complications; Diabetes Mellitus, Type 1

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

*empagliflozin*

empagliflozin 25 mg daily for 12 weeks, once daily, by mouth

Group Type: ACTIVE_COMPARATOR

Empagliflozin 25mg

Intervention Type: DRUG

The patients receive empagliflozin (25 mg daily) for 12 weeks.

*metformin*

metformin 2000 mg daily for 12 weeks, once daily, by mouth

Group Type: ACTIVE_COMPARATOR

Metformin

Intervention Type: DRUG

The patients receive metformin (2000 mg daily) for 12 weeks.

*empagliflozin/metformin*

empagliflozin 25 mg daily and metformin 2000 mg daily for 12 weeks, by mouth

Group Type: ACTIVE_COMPARATOR

Empagliflozin 25mg

Intervention Type: DRUG

The patients receive empagliflozin (25 mg daily) for 12 weeks.

Metformin

Intervention Type: DRUG

The patients receive metformin (2000 mg daily) for 12 weeks.

Empagliflozin/Metformin

Intervention Type: DRUG

The patients receive empagliflozin 25 mg daily and metformin 2000 mg daily or placebo for 12 weeks.

*placebo*

placebo for 12 weeks, once daily with water, by mouth

Group Type: PLACEBO_COMPARATOR

Placebos

Intervention Type: DRUG

The patients receive for 12 weeks.

Interventions

Empagliflozin 25mg

The patients receive empagliflozin (25 mg daily) for 12 weeks.

Intervention Type: DRUG

Metformin

The patients receive metformin (2000 mg daily) for 12 weeks.

Intervention Type: DRUG

Empagliflozin/Metformin

The patients receive empagliflozin 25 mg daily and metformin 2000 mg daily or placebo for 12 weeks.

Intervention Type: DRUG

Placebos

The patients receive for 12 weeks.

Intervention Type: DRUG

Other Intervention Names

empagliflozin; empagliflozin and metformin; placebo

Eligibility Criteria

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

• Minimum Eligible Age: 30 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Medical Centre Ljubljana

OTHER

Sponsor Role: lead

Responsible Party

Mojca Lunder

MD, PhD, Research assistant at the Department of Endocrinology, Diabetes and Metabolic Diseases

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Andrej Janez, prof

Role: STUDY_CHAIR

University Medical Centre Ljubljana

Locations

University Medical Centre Ljubljana

Ljubljana, , Slovenia

Site Status: RECRUITING

Countries

Slovenia

Central Contacts

Mojca Lunder, MD, PhD

Role: CONTACT

mojca.lunder@kclj.si

+38615223140

Miodrag Janic, MD, PhD

Role: CONTACT

miodrag.janic@kclj.si

+38615228012

Facility Contacts

Mojca Lunder, MD, PhD

Role: primary

mojca.lunder@kclj.si

+386 1 5223140

Andrej Janez, Prof

Role: backup

andrej.janez@kclj.si

+386 1 5223564

References

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.

Reference Type: DERIVED

PMID: 30509271 (View on PubMed)

Other Identifiers

AGE-SGLT2

Identifier Type: -

Identifier Source: org_study_id