Effects of SGLT2 Inhibition on Myocardial Insulin Sensitivity

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.

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