Effects of SGLT2 Inhibition on Myocardial Insulin Sensitivity

Giaccari Andrea25 enrolled

Overview

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).

This Phase III, single-centre, randomized, double-blind, placebo-controlled study is designed to evaluate the impact of dapagliflozin on myocardial insulin sensitivity, global cardiac function, metabolic effects, and glycemic control in patients with type 2 diabetes (T2D) and stable coronary artery disease (CAD). The study consists of three phases: a 14-day screening phase (Days -14 to -1), a 4-week double-blind treatment phase, and a 4-week follow-up phase. Patients eligible for this study must have suboptimal glycemic control (HbA1c 7.0-8.5%) on a stable anti-hyperglycemic regimen and meet specific inclusion criteria, including a history of stable CAD with ≥30% coronary stenosis or prior percutaneous coronary intervention (PCI) performed at least six months prior to screening, without an indication for revascularization. These patients should have undergone a routine 13N-ammonia PET-CT scan to assess cardiovascular function before enrollment. During the study, participants are randomized in a 1:1 ratio to receive either 10 mg dapagliflozin or a placebo tablet, administered orally once daily for four weeks. Key assessments include a euglycemic hyperinsulinemic clamp to measure myocardial glucose uptake (MGU) and systemic glucose metabolism. The primary outcome focuses on the change in MGU, reflecting myocardial insulin sensitivity, while secondary outcomes evaluate: Coronary flow reserve (CFR): Determined as the ratio of myocardial blood flow (MBF) during pharmacological stress to MBF at rest, measured using PET-CT. Left ventricular function: Assessed at rest and during pharmacological stress via Gated-PET with 13N-ammonia. Metabolic effects on adipose tissue: Quantitative FDG uptake in pericardial, perirenal, and interscapular fat, measured as SUVmax. Glycemic control: Changes in fasting glucose concentration and glycated hemoglobin (HbA1c). Gut microbiota composition: Analyzed at the class, genus, and species levels to assess systemic metabolic effects. The study aims to enroll patients aged 40-75 years, with a body mass index (BMI) between 25 and 35 kg/m² and a diabetes duration of less than 10 years. Patients with type 1 diabetes, recent myocardial infarction, severe renal or hepatic impairment, or contraindications to study procedures or medications are excluded. At the end of 4 week-trial, all the patients in the placebo group will start therapy with dapagliflozin. All the patients will be followed up every 4 years. Coronary flow reserve (CFR): Determined as the ratio of myocardial blood flow (MBF) during pharmacological stress to MBF at rest, measured using PET-CT, will be re-evaluated at the end follow up. This trial seeks to determine whether the metabolic and cardiac improvements achieved with dapagliflozin are superior to those achieved with standard clinical practice, aligning with current Standards of Care. The results will provide robust evidence on the role of SGLT2 inhibitors in addressing the residual cardiovascular risk in T2D patients.

Eligibility

Sex: ALLMin age: 40 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Provision of informed consent prior to any study-specific procedures 2. 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; 3. Patients with type 2 diabetes 4. 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). 5. Patients with a clinical indication for 13N-ammonia PET-CT, as established by a cardiologist, nuclear medicine physician or diabetologist. 6. Patients with a body mass index (BMI) equal or greater than 25 kg/m2 but less than 35 kg/m2 \[BMI = Weight (kg) / Height squared (m2)\] 7. Patients with a HbA1c between 7.0% and 8.5%, according to the actual clinical conditions of the patients; 8. Patients with diabetes duration \<10 years; 9. 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. 10. Patients with Fasting C-peptide \> 1 ng/mL (0.33 nmol/L) at Visit 0 Exclusion Criteria: 1. Type 1 diabetes (as assessed by medical history); previous diagnosis of Latent Autoimmune Diabetes of Adults (LADA), and or not fulfilling inclusion criteria #10 2. History of diabetic ketoacidosis or hyperosmolar non-ketotic coma 3. NYHA class III or IV 4. Unstable angina 5. Previous re-vascularisation (either percutaneous coronary intervention or coronary artery bypass graft) in the last \<6 months before screening 6. Reduced left ventricular ejection fraction (≤ 50%) 7. Increased likelihood of developing diabetic ketoacidosis (history of DKA, alcohol consumption, volume depletion dehydration, clinical conditions causing diarrhea, vomit and anorexia) 8. 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) 9. Severe liver dysfunction 10. Asthma 11. Uncontrolled blood pressure 12. Symptomatic tachy- or bradyarrhythmias 13. Previous acute myocardial infarction 14. 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 15. 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) 16. Known hypersensitivity to the active substance or to any of the excipients in study drug 17. Inability to provide informed consent 18. Participation in another clinical study with an investigational product during the previous 30 days 19. Patients with history of breast, bladder and prostate cancer 20. Patients who will undergo surgical procedures 21. Patients with acute urinary tract infection 22. Patients with history of intolerance to galactose and lactose 23. Severe/uncontrolled medical conditions, causing liquid volume depletion

Outcomes

Primary Outcomes

Effect of dapagliflozin on myocardial insulin sensitivity

Myocardial Glucose Uptake (MGU) umol/min/gr during euglycemic hyperinsulinemic clamp: change from baseline

Time frame: 4 weeks

Secondary Outcomes

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

Time frame: 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)

Time frame: 4 weeks

Metabolic systemic effects of dapagliflozin

Whole body glucose uptake calculated as mg/kg/min during the euglycemic hyperinsulinemic clamp: change from baseline

Time frame: 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

Time frame: 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

Time frame: 4 weeks

Fasting glucose concentration change from baseline

Measured as fasting glucose concentration (mg/dl): change from baseline

Time frame: 4 weeks

Glycemic control change from baseline

Measured as Glycated hemoglobin (HbA1c) (percent %): change from baseline

Time frame: 4 weeks

Gut microbiota composition change from baseline

Analysis of gut microbiota composition at class, genus, and species levels: change from baseline

Time frame: 4 weeks

Effects of SGLT2 Inhibition on Myocardial Insulin Sensitivity

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes