心筋のインスリン感受性に対するSGLT2阻害の影響 (DapaHeart)

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.