Effect of the Antidiabetic Drug Dapagliflozin on the Coronary Macrovascular and Microvascular Function in Type 2 Diabetic Patients

Study Overview
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Brief Summary
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Cardiovascular events remain a major driver of morbidity and mortality in patients with type 2 diabetes mellitus. Diffuse coronary atherosclerosis, combined with impairment of the microcirculation are frequent even in asymptomatic patients and can lead to unfavourable outcomes. In recent years, novel classes of antidiabetic drugs have been introduced, with salutary effects on cardiovascular outcomes of diabetic patients. The sodium-glucose linked transporter 2 (SGLT2) inhibitors - gliflozins - bind to the SGLT2 receptors of the proximal tubule of the nephron and cause glycosuria. They have been shown to have favourable cardiovascular effects by reducing deaths from cardiovascular causes in type 2 diabetic patients. Moreover, dapagliflozin reduces hospitalisation for heart failure in type 2 diabetic heart failure patients with and without reduced ejection fraction and reduces cardiovascular death and all causes mortality in those with reduced ejection fraction. It is currently unknown if this is mediated by improvement of coronary physiology both at the level of the epicardial coronary arteries as well as the coronary microcirculation. The purpose of the study is to explore the impact of dapagliflozin on the coronary and microcirculatory function of type 2 diabetic patients.

Official Title
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Effect of the Antidiabetic Drug DAPAgliflozin on the Coronary Macrovascular and MICROvascular Function in Type 2 Diabetic Patients

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Dapagliflozin 10 mg Tab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: type 2 diabetes mellitus (T2DM) patients presenting with stable angina and a clinical indication for cardiac catheterization T2DM patients with non ST elevation myocardial infarction (NSTEMI) or unstable angina referred for cardiac catheterization Demonstration of coronary lesion(s) with non-significant fractional flow reserve (FFR) values (>0.80), for which revascularisation is deferred Agreement to practice an acceptable method of birth control for women of childbearing potential Signed patient informed consent Exclusion Criteria: Age < 18 years old T2DM patients presenting with ST elevation myocardial infarction (STEMI) Pregnancy or breastfeeding Body mass index ≥45 kg/m2 Creatinine clearance ≤45 ml/min/1.73 m2 (as calculated by Modification of Diet in Renal Disease Study (MDRD ) formula for estimated Glomerular filtration rate (GFR)) Indication of liver disease, defined by serum levels of alanine aminotransferase, aspartate aminotransferase, or alkaline phosphatase above 3 x upper limit of normal during screening or run-in phase Uncontrolled hyperglycemia with glucose >240 mg/dL after an overnight fast Stroke, or transient ischemic attack at presentation and up to 2 months prior to informed consent Alcohol or drug abuse within 3 months of informed consent that would interfere with trial participation or any ongoing condition leading to decreased compliance with study procedures or study drug intake Any uncontrolled endocrine disorder except type 2 diabetes Treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent Treatment with anti-obesity drugs 3 months prior to informed consent or any other treatment at time of screening leading to unstable body weight Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells Bariatric surgery within the past two years and other gastrointestinal surgeries that induce chronic malabsorption Planned cardiac surgery or angioplasty within 3 months Any clinical condition that would jeopardize patient safety while participating in this clinical trial Life expectancy < 3 years

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo group<br>The patient will be treated in standard of care for type 2 diabetic mellitus and will receive a placebo (1 tablet) administered orally daily during 24 weeks | Drug: Placebo<br>* Placebo for dapagliflozin film-coated tablets 10 mg<br>|
| Experimental: dapagliflozin group<br>The patient will be treated in standard of care for type 2 diabetic mellitus and will receive Dapagliflozin 10 mg (1 tablet) administered orally daily during 24 weeks | Drug: Dapagliflozin 10 mg Tab<br>* Dapagliflozin 10 mg per day<br>* Other names: Forxiga®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the longitudinal change of the Fractional Flow Reserve (FRR) | The longitudinal change (Δ) of FFR is defined as the value at follow-up (6 months) minus the value at baseline. The complete assessment of the function of the coronary circulation will be performed by using a dedicated pressure and temperature equipped coronary guidewire (PressureWire X by Abbott Vascular) and the Coroventis CoroFlow software platform. In the presence of coronary lesions, the degree of percent diameter stenosis will be measured by quantitative coronary angiography and their hemodynamic significance will be evaluated by measuring fractional flow reserve (FFR). According to the guidelines for myocardial revascularisation, only the lesions that have an FFR value equal or less than 0.8 will be treated by coronary angioplasty . In case of angioplasty, FFR will be also measured immediately after successful implantation of the coronary stent. | up to 6 months | 
| the longitudinal change of the Coronary flow reserve (CFR) | The longitudinal change (Δ) of CFR is defined as the value at follow-up (6 months) minus the value at baseline. The complete assessment of the function of the coronary circulation will be performed by using a dedicated pressure and temperature equipped coronary guidewire (PressureWire X by Abbott Vascular) and the Coroventis CoroFlow software platform. Coronary flow reserve (CFR) will be measured in the vessels of interest, where FFR was measured. | up to 6 months | 
| the longitudinal change of the Index of Microvascular Resistance (IMR). | The longitudinal change (Δ) of IMR is defined as the value at follow-up (6 months) minus the value at baseline. The complete assessment of the function of the coronary circulation will be performed by using a dedicated pressure and temperature equipped coronary guidewire (PressureWire X by Abbott Vascular) and the Coroventis CoroFlow software platform. The Index of Microvascular Resistance (IMR) will be measured in the vessels of interest, where FFR was measured. | up to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes Mellitus, Type 2, Dapagliflozin, Physiological Effects of Drugs, Coronary Artery Disease, Microcirculation, Fraction Flow Reserve, Index of Microcirculatory Resistance, Coronary Flow Reserve