Effects of SGLT2 Inhibition on Myocardial Insulin Sensitivity

Study Overview
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Brief Summary
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A Phase III, single-centre, randomized, 2-arm, parallel-group, double blind, placebo-controlled study, consisting of a screening phase (Days -14 to -1), a 4-week double-blind, placebo-controlled treatment phase and a 4-week follow-up phase. Subjects: Type 2 diabetic patients and coronary artery diseases (CAD) not requiring revascularization or underwent percutaneous coronary intervention (PCI) but clinically stable at time of screening visit, with suboptimal glycaemic control (HbA1c 7.0-8.5%) on their current anti-hyperglycaemic regimen Subjects will be randomized in a 1:1 ratio to dapagliflozin or placebo. Subjects will undergo screening assessment in the 14-day period preceding administration of the first dose of study drug on Day 1. The primary Objective is to assess the effect of dapagliflozin on myocardial insulin sensitivity The Secondary Objective is to assess global heart function, and metabolic systemic effects of dapagliflozin, and glycemic control. The study aims to enroll patients with type 2 diabetes with suboptimal glycemic control, and with coronary artery diseases (CAD) not requiring revascularization or underwent percutaneous coronary intervention (PCI) but clinically stable, who have already undergone, under routine cardiological assessment, a positron emission tomography (PET) 13NH3 scan in order to assess the cardiovascular function. Thus, the study aims to assess whether the improvement in cardiac metabolism obtained with dapagliflozin is greater than that obtained with normal clinical practice (according to Standards of Care).

Official Title
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Study on the Effect of Dapagliflozin on Myocardial Insulin Sensitivity and Perfusion

Conditions
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Type2 Diabetes Mellitus, Stable Coronary Artery Disease

Intervention / Treatment
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* Drug: Dapagliflozin 10Mg Tab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of informed consent prior to any study-specific procedures Female or male subjects aged between 40 and 75 inclusive. Patients who have been surgically sterilized (hysterectomy or tubal-ligation) at least 12 months prior to screening, or are postmenopausal having had no regular menstrual bleeding for at least one (1) year prior to screening. Menopause will be confirmed by a plasma follicle stimulating hormone (FSH) level of > 35 IU/mL at screening, or Women with childbearing potential willing not to initiate pregnancy during the course of the study, and non-nursing women. Men having relationships with women with childbearing potential willing not to procure a pregnancy during the course of the study; Patients with type 2 diabetes Patients with established, stable CAD, defined as ≥30% coronary stenosis in at least one major coronary vessel on invasive coronary angiography (ICA) or computed tomography angiography (CTA) performed within 12 months from screening and no indication to revascularization or with no evidence of critical restenosis, if previously subjected to percutaneous coronary intervention (PCI) (>6months). Patients with a clinical indication for 13N-ammonia PET-CT, as established by a cardiologist, nuclear medicine physician or diabetologist. Patients with a body mass index (BMI) equal or greater than 25 kg/m2 but less than 35 kg/m2 [BMI = Weight (kg) / Height squared (m2)] Patients with a HbA1c between 7.0% and 8.5%, according to the actual clinical conditions of the patients; Patients with diabetes duration <10 years; Patients with stable medical therapy [including other anti-hyperglycemic agents (see Table 1, section 5.2.1 for all therapies allowed, as per current standard treatment); pioglitazone and basal-bolus insulin treatment are excluded, as reported in the exclusion criteria 15] for at least 3 months prior to the screening visit (including stable insulin dose defined as no variation more than 30% in daily insulin dose within the preceding 3 months. Patients with Fasting C-peptide > 1 ng/mL (0.33 nmol/L) at Visit 0 Exclusion Criteria: Type 1 diabetes (as assessed by medical history); previous diagnosis of Latent Autoimmune Diabetes of Adults (LADA), and or not fulfilling inclusion criteria #10 History of diabetic ketoacidosis or hyperosmolar non-ketotic coma NYHA class III or IV Unstable angina Previous re-vascularisation (either percutaneous coronary intervention or coronary artery bypass graft) in the last <6 months before screening Reduced left ventricular ejection fraction (≤ 50%) Increased likelihood of developing diabetic ketoacidosis (history of DKA, alcohol consumption, volume depletion dehydration, clinical conditions causing diarrhea, vomit and anorexia) Moderate to severe renal impairment (eGFR<60 ml/min/1.73m2 as calculated by the modification of diet in renal disease [MDRD] equation or end-stage renal disease); overt proteinuria, defined as Spot urine Microalbumin/Cr ratio of >300 mg/g at screening (Visit 0) Severe liver dysfunction Asthma Uncontrolled blood pressure Symptomatic tachy- or bradyarrhythmias Previous acute myocardial infarction Contraindications to adenosine: known hypersensitivity to adenosine or to any of the excipients; sick sinus syndrome, second or third degree atrio-ventricular block (except in patients with a functioning artificial pacemaker); chronic obstructive lung disease with evidence of bronchospasm (e.g. bronchial asthma ); long QT syndrome; severe hypotension; decompensated states of heart failure Use of pioglitazone; use of loop diuretics; basal-bolus insulin therapy; use of systemic steroids less than 3 days prior to the screening visit (Visit 0) Known hypersensitivity to the active substance or to any of the excipients in study drug Inability to provide informed consent Participation in another clinical study with an investigational product during the previous 30 days Patients with history of breast, bladder and prostate cancer Patients who will undergo surgical procedures Patients with acute urinary tract infection Patients with history of intolerance to galactose and lactose Severe/uncontrolled medical conditions, causing liquid volume depletion

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: A - placebo<br>Green, plain, diamond shaped, film coated tablet (orally), not containing active ingredient; once daily, for 4 weeks | Other: Placebo<br>* placebo<br>|
| Experimental: B - experimental drug<br>Dapagliflozin tablet available at dose of 10 mg, once daily, for 4 weeks | Drug: Dapagliflozin 10Mg Tab<br>* Dapagliflozin, will be administered according to the approved posology and to the approved dose as stated by Local Health Indication and by the Drug Brochure<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of dapagliflozin on myocardial insulin sensitivity | Myocardial Glucose Uptake (MGU) umol/min/gr during euglycemic hyperinsulinemic clamp: change from baseline | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect on Coronary flow reserve [Main Secondary Outcome] | Coronary flow reserve (CFR) obtained as ratio of myocardial blood flow (ml/min/g) (MBF) during pharmacological stress and MBF at rest: change from baseline | 4 weeks | 
| 3. Browning of white adipose tissue: change from baseline | Quantitative measurement of FDG uptake in pericardial, perirenal, interscapular fat by total body FDG PET-CT study, expressed as maximum Standard Uptake Volume (SUVmax) (change from baseline) | 4 weeks | 
| Metabolic systemic effects of dapagliflozin | Whole body glucose uptake calculated as mg/kg/min during the euglycemic hyperinsulinemic clamp: change from baseline | 4 weeks | 
| Effect on Left Ventricular Ejection Fraction at rest | Whole body glucose uptake calculated as mg/kg/min during the euglycemic hyperinsulinemic clamp: change from baseline | 4 weeks | 
| Effect on Left Ventricular Ejection Fraction during pharmacological stress | Left Ventricular Ejection Fraction (percent %) measured by Gated-PET with 13N-ammonia during pharmacological stress: change from baseline | 4 weeks | 
| Fasting glucose concentration change from baseline | Measured as fasting glucose concentration (mg/dl): change from baseline | 4 weeks | 
| Glycemic control change from baseline | Measured as Glycated hemoglobin (HbA1c) (percent %): change from baseline | 4 weeks | 
| Gut microbiota composition change from baseline | Analysis of gut microbiota composition at class, genus, and species levels: change from baseline | 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diabetes, heart, dapagliflozin,