Atherosclerosis, Coronary Artery Disease, Type 2 Diabetes Mellitus (T2DM)
Conditions
Keywords
SGLT2 Inhibitors, Dapagliflozin, Perivascular Adipose Tissue, Coronary Atherosclerosis, Type 2 Diabetes, Plaque Progression, Coronary CT Angiography, Cardiovascular Risk, PVAT, Randomized Controlled Trial
Brief summary
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.
Detailed 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.
Interventions
Dapagliflozin 10 mg tablet administered orally once daily for 18 months, in addition to standard diabetes and cardiovascular care, to evaluate its effects on coronary atherosclerosis progression mediated by perivascular adipose tissue in patients with type 2 diabetes.
Standard glycemic and cardiovascular management according to clinical guidelines, excluding SGLT2 inhibitors, GLP-1 receptor agonists, or DPP-4 inhibitors, for 18 months.
Sponsors
Junjie Yang
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a prospective, multicenter, 1:1 randomized, open-label trial where participants are assigned to parallel groups: one receiving dapagliflozin 10 mg daily plus standard diabetes care, and the other receiving standard care alone, for 18 months to assess effects on coronary atherosclerosis progression.
Eligibility
Sex/Gender
ALL
Age
18 Years to 78 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression of Coronary Plaque Volume and Proportion from Baseline to the 18-Month Follow-Up | Baseline to 18 months | Progression of total plaque volume (TPV) （mm³）from baseline or appearance of new plaques, assessed by coronary CT angiography (CCTA). Includes changes in plaque components (e.g., necrotic core, fibrous cap, calcification)（mm³）. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Coronary Perivascular Fat Radiomics Score (FRS) from Baseline to 18 Months | Baseline to 18 months | Change from baseline to the 18-month follow-up in the coronary perivascular fat radiomics score (FRS), measured in "points", where a higher score indicates a higher inflammatory activity state and a stronger correlation with the risk of major adverse cardiovascular events. |
| Change in CT-derived fractional flow reserve (CT-FFR) from Baseline to 18 Months | Baseline to 18 months | Change from baseline to the 18-month follow-up in CT-derived fractional flow reserve (CT-FFR), expressed as a pure number between 0 and 1 (no units), where a higher value indicates a lower likelihood of ischemia. |
| Change in Fat Attenuation Index （FAI）from Baseline to 18 Months | Baseline to 18 months | Change from baseline to the 18-month follow-up in fat attenuation index (FAI)(HU) .FAI is defined as the mean attenuation value of pericoronary adipose tissue observed on CT scan, ranging from approximately -190 to -30 HU. Higher values indicating increased perivascular adipose tissue inflammation and coronary vulnerability, and lower values suggesting a more stable, anti-inflammatory vascular state. |
| Change in the Degree of Coronary Artery Stenosis from Baseline to 18 Months | Baseline to 18 months | Change from baseline to the 18-month follow-up in the degree of coronary artery stenosis, expressed as CAD-RADS category or quantitatively measured percent stenosis. CAD-RADS grades range from 0 to 5, with higher grades indicating greater stenosis severity. Quantitatively measured percent stenosis ranges from 0% to 100%, with higher percentages indicating greater stenosis severity. |
| Change in C-reactive protein (CRP) from baseline to 18 months | Baseline to 18 months | Change from baseline to the 18-month follow-up in C-reactive protein (CRP). Reference range: 0-0.8 mg/L; Unit: mg/dL. |
| Change in Quality of Life Score as Assessed by the Seattle Angina Questionnaire (SAQ-7) from Baseline to 18 Months | Baseline to 18 months | Change from baseline to the 18-month follow-up in quality of life score measured by the Seattle Angina Questionnaire (SAQ-7). The total score ranges from 0 to 100, with higher scores indicating better quality of life and better angina control. |
| Occurrence of Major Adverse Cardiovascular Events (MACE) from Baseline to 18 Months | Baseline to 18 months | Occurrence of major adverse cardiovascular events (MACE), including but not limited to cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, from baseline to the 18-month follow-up. |
| Change in Self-Rating Anxiety Scale（SAS） Score from Baseline to 18 Months | Baseline to 18 months | Change from baseline to the 18-month follow-up in the Self-Rating Anxiety Scale (SAS) score. The SAS is a 20-item self-reported scale with 4-point scoring, designed to assess the subjective experience of anxiety in patients. Total scores range from 0 to 60, with higher scores indicating greater anxiety severity. The scores are interpreted as follows: A (0-8): no anxiety disorder B (9-21): occasional anxiety C (22-32): mild anxiety disorder D (33-44): moderate anxiety disorder E (45-60): severe anxiety disorder |
| Change in Hamilton Anxiety Scale (HAMA) Score from Baseline to 18 Months | Baseline to 18 months | Change from baseline to the 18-month follow-up in the Hamilton Anxiety Scale (HAMA) score. HAMA is a clinician-rated scale consisting of 14 items, each scored from 0 to 4, where: 0 = asymptomatic 1. = mild symptoms 2. = moderate symptoms (clearly present but does not affect daily life) 3. = severe symptoms (significantly affects daily life) 4. = extremely severe symptoms (unable to function normally) Total scores range from 0 to 56, with higher scores indicating more severe anxiety. The score is interpreted as follows: \<7: no anxiety symptoms 7-13: possible anxiety 14-20: mild anxiety 21-28: marked anxiety 29: severe anxiety |
| Change in wall shear stress (WSS) from Baseline to 18 Months | Baseline to 18 months | Change from baseline to the 18-month follow-up in wall shear stress (WSS)(Pa).Both excessively high and abnormally low WSS are pathological: high WSS promotes plaque destabilization and rupture, while low WSS accelerates atherogenesis and plaque growth. |
| Change in Pericoronary Adipose Tissue Volume from Baseline to 18 Months | Baseline to 18 months | Change from baseline to the 18-month follow-up in Pericoronary Adipose Tissue Volume (mm³).Larger volume indicates higher inflammatory activity or greater disease burden, whereas smaller volume indicates the opposite. |
| Change in lipoprotein(a) (Lp(a)) from baseline to 18 months | Baseline to 18 months | Change from baseline to the 18-month follow-up in lipoprotein(a) (Lp(a)). Reference range: \<30 mg/dL; Unit: mg/dL. |
| Change in low-density lipoprotein cholesterol (LDL-C) from baseline to 18 months | Baseline to 18 months | Change from baseline to the 18-month follow-up in low-density lipoprotein cholesterol (LDL-C). Reference range: 0-3.4; Unit: mmol/L. |
| Change in high-density lipoprotein cholesterol (HDL-C) from baseline to 18 months | Baseline to 18 months | Change from baseline to the 18-month follow-up in high-density lipoprotein cholesterol (HDL-C). Reference range: 1-1.6 ; Unit: mmol/L. |
| Change in triglycerides (TG) from baseline to 18 months | Baseline to 18 months | Change from baseline to the 18-month follow-up in triglycerides (TG). Reference range: 0.4-1.7; Unit: mmol/L. |
| Change in total cholesterol (TC) from baseline to 18 months | Baseline to 18 months | Change from baseline to the 18-month follow-up in total cholesterol (TC). Reference range: 3.1-5.7; Unit: mmol/L. |
| Change in interleukin-6 (IL-6) from baseline to 18 months | Baseline to 18 months | Change from baseline to the 18-month follow-up in interleukin-6 (IL-6). Reference range: 0-5.9 pg/mL; Unit: pg/mL. |
| Change in tumor necrosis factor-alpha (TNF-α) from baseline to 18 months | Baseline to 18 months | Change from baseline to the 18-month follow-up in tumor necrosis factor-alpha (TNF-α). Reference range: \<20; Unit: ng/L. |
Countries
China
Contacts
CONTACTJunjie Yang, MD
Outcome results
None listed