Overview
This study is a multicenter, randomized controlled trial to test whether an SGLT2 inhibitor (dapagliflozin), a type of diabetes medication, can slow down or even reverse the progression of coronary atherosclerosis (plaque buildup in the coronary arteries) in patients with type 2 diabetes. The effect may be mediated by improving the function of perivascular adipose tissue. A total of 144 adults with type 2 diabetes and stable coronary artery disease will be randomly assigned to receive either dapagliflozin plus standard diabetes and cardiovascular care (intervention group) or standard care alone (control group) for 18 months. Serial coronary CT angiography and other assessments will be performed to evaluate changes in coronary plaque volume, CT-derived fractional flow reserve, perivascular fat radiomics score, and various metabolic and inflammatory markers, to determine whether SGLT2 inhibition reduces cardiovascular risk.
Description
Randomization and blinding: Eligible participants will be randomly assigned in a 1:1 ratio to either the dapagliflozin group or the standard care control group using a centralized, computer-generated randomization sequence. This is an open-label trial; however, all outcome assessments will be performed by core laboratories blinded to treatment allocation. Imaging analyses for plaque volume, hemodynamic parameters, and perivascular adipose tissue metrics will be conducted by investigators masked to group assignment.
Intervention: Participants in the intervention group receive dapagliflozin 10 mg once daily in addition to their standard diabetes and cardiovascular care. Participants in the control group receive standard glycemic management according to current clinical guidelines, with the exclusion of SGLT2 inhibitors, GLP-1 receptor agonists, or DPP-4 inhibitors. The total study duration is 18 months.
Study procedures: At baseline, participants will undergo coronary computed tomography angiography (CCTA) using a standardized protocol. Blood samples will be collected for lipid panels and inflammatory markers. Quality of life will be assessed using the Seattle Angina Questionnaire (SAQ-7). Follow-up visits are scheduled at 6, 12, and 18 months. At each visit, adverse events, concomitant medications, and medication adherence will be recorded. The 18-month visit will include a repeat CCTA and blood sampling.
Imaging core laboratory: All CCTA images will be transferred to an independent core laboratory for quantitative analysis. Plaque volume and composition will be assessed using semi-automated software. CT-derived fractional flow reserve (CT-FFR) will be computed using a dedicated algorithm. Wall shear stress (WSS) will be derived from computational fluid dynamics. Perivascular adipose tissue parameters, including fat attenuation index (FAI) and fat volume, will be measured using a validated software tool.
Data and safety monitoring: An independent Data and Safety Monitoring Board (DSMB) will review unblinded safety data every 6 months. The DSMB will monitor for serious adverse events, including volume depletion, genital infections, hypoglycemia, diabetic ketoacidosis, and acute kidney injury. Protocol-defined stopping rules include a significant increase in any of these events in the intervention arm.
Eligibility
Inclusion Criteria:
- Age between 18 and 75 years.
- Confirmed diagnosis of type 2 diabetes mellitus with SCORE2-Diabetes risk score \>10%.
- Stable angina pectoris.
- Coronary CT angiography (CCTA) demonstrating 50%-90% stenosis in at least one coronary vessel with diameter ≥2.5 mm.
- CT-derived fractional flow reserve (CT-FFR) \>0.8 in the target vessel.
- Stable standard therapy for diabetes and cardiovascular disease, with no changes in SGLT2 inhibitors, GLP-1 receptor agonists, or DPP-4 inhibitors within the past 4 weeks.
- Able and willing to provide written informed consent.
Exclusion Criteria:
- History of coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI) with stenting, prosthetic valve replacement, or permanent pacemaker implantation.
- New York Heart Association (NYHA) functional class III or IV heart failure. Acute myocardial infarction within the previous 30 days.
- Known allergy to iodinated contrast media or other contraindications to CCTA. Severe arrhythmia or coronary artery calcium (CAC) score \>400.
- Estimated glomerular filtration rate (eGFR) \<45 mL/min/1.73 m². History of serious adverse reactions to SGLT2 inhibitors.
- Pregnancy, lactation, or planned pregnancy during the study period. Severe liver dysfunction (Child-Pugh class C).
- Any other condition that, in the investigator's opinion, makes the participant unsuitable for the trial.
