Stable Coronary Artery Disease, Type2 Diabetes Mellitus
Conditions
Keywords
diabetes, heart, dapagliflozin,
Brief summary
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).
Detailed description
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.
Interventions
DRUGDapagliflozin 10Mg Tab
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
OTHERPlacebo
placebo
Sponsors
Giaccari Andrea
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Caregiver)
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effect of dapagliflozin on myocardial insulin sensitivity | 4 weeks | Myocardial Glucose Uptake (MGU) umol/min/gr during euglycemic hyperinsulinemic clamp: change from baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect on Coronary flow reserve [Main Secondary Outcome] | 4 weeks | 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 |
| 3. Browning of white adipose tissue: change from baseline | 4 weeks | 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) |
| Metabolic systemic effects of dapagliflozin | 4 weeks | Whole body glucose uptake calculated as mg/kg/min during the euglycemic hyperinsulinemic clamp: change from baseline |
| Effect on Left Ventricular Ejection Fraction at rest | 4 weeks | Whole body glucose uptake calculated as mg/kg/min during the euglycemic hyperinsulinemic clamp: change from baseline |
| Effect on Left Ventricular Ejection Fraction during pharmacological stress | 4 weeks | Left Ventricular Ejection Fraction (percent %) measured by Gated-PET with 13N-ammonia during pharmacological stress: change from baseline |
| Fasting glucose concentration change from baseline | 4 weeks | Measured as fasting glucose concentration (mg/dl): change from baseline |
| Glycemic control change from baseline | 4 weeks | Measured as Glycated hemoglobin (HbA1c) (percent %): change from baseline |
| Gut microbiota composition change from baseline | 4 weeks | Analysis of gut microbiota composition at class, genus, and species levels: change from baseline |
Countries
Italy
Contacts
PRINCIPAL_INVESTIGATORAndrea Giaccari
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Outcome results
None listed