Effects of DAPAgliflozin on CARDiac substrate uptake, myocardial efficiency, and myocardial contractile work in type 2 diabetes patients—a description of the DAPACARD study

Figures & data

Figure 1. Overview of the DAPACARD trial. Screening visit (visit 1) is 0 to 21 days prior to randomization. The randomization (visit 2) is day 1, and the patients perform both PET and MRI scans prior to starting the randomized treatment. Visit 3 is a telephone call. Visit 4 is with both PET and MRI scans. A final follow-up call (visit 5) is also planned.

Table 1. Inclusion criteria.

Provision of signed and dated, written informed consent prior to any study-specific procedures, and:
1. Females or males ≥40 years up to 75 years of age.
2. Patients with type 2 diabetes on stable dose of metformin for at least 6 weeks prior to screening and HbA1c at screening visit of ≥42 mmol/mol and ≤75 mmol/mol.
3. No significant signs or symptoms of coronary artery disease or, if known coronary artery disease, currently free of symptoms^a and (i) all major epicardial vessels with <50% stenosis within 12 months prior to screening, or (ii) if revascularized, with all major epicardial vessels with <50% remaining stenosis after stenting or bypass surgery procedure between 3 and 12 months prior to screening.
4. Normal left ventricular ejection fraction (≥50%) assessed within 1 year prior to informed consent, and, if applicable, after most recent acute episode of coronary artery syndrome, or at screening visit.
5. Subjects with BMI ≥25 kg/m^2.
6. Female subjects must be 1 year post-menopausal, surgically sterile, or using an acceptable method of contraception (an acceptable method of contraception is defined as a barrier method in conjunction with a spermicide) for the duration of the study (from the time they sign consent) to prevent pregnancy.^b

^aCardiac symptoms include, but are not limited to, angina pectoris, dyspnea, and fatigue on exertion judged by a physician to be of cardiac origin.

^bIn addition, oral contraceptives, approved contraceptive implant, long-term injectable contraception, intrauterine device, or tubal ligation are allowed. Oral contraception alone is not acceptable; additional barrier methods in conjunction with spermicide must be used.

Table 2. Exclusion criteria.

Medical conditions:
1. Blood pressure at screening that would require a change in blood pressure treatment over the study period or any of the following: systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg.
2. History of stroke or other clinically significant cerebrovascular disease.
3. Any of the following cardiovascular diseases known within 3 months prior to signing the consent at enrollment: Atrial fibrillation, or other unstable or severe arrhythmia affecting heart function; Unstable heart failure or any heart failure with NYHA class III and IV; Significant valvular disease; Significant peripheral artery disease.
4. Planned cardiac surgery or angioplasty within 3 months from enrollment.
5. Clinical diagnosis of type 1 diabetes, maturity onset diabetes of the young (MODY), secondary diabetes, or diabetes insipidus.
6. Verified body weight variability of >3 kg during the 3 months before screening (by interviews).
7. Active malignancy requiring treatment at the time of visit 1 (with the exception of successfully treated basal cell or treated squamous cell carcinoma).
8. Patients with severe hepatic impairment (Child–Pugh class C).
9. Unstable or rapidly progressing renal disease.
10. Clinically significant disease or disorder which, in the opinion of the investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject’s ability to participate in the study.
Prior/concomitant therapy:
11. Ongoing treatment with other antidiabetic drugs than metformin.
12. Ongoing treatment with loop diuretics.
13. Ongoing weight loss diet (hypocaloric diet) or use of weight loss agents.
14. Contraindications to dapagliflozin therapy.
15. Ongoing treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent or any other uncontrolled endocrine disorder except for T2DM.
Prior/concurrent clinical study experience:
16. Previous enrollment in the present study or participation in another clinical study with an investigational product during the last 1 month prior to screening.
Diagnostic assessments:
17. Estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m^2, based on the MDRD study equation (www.kidney.org/content/mdrd-study-equation) (eGFR =175 × (SCr) − 1.154 × (age) − 0.203 × 0.742 [if female] × 1.212 [if black]).
18. Alcohol or drug abuse within the 3 months prior to informed consent that would interfere with trial participation or any ongoing condition leading to a decreased compliance to study procedures or study drug intake.
19. Any condition in which MRI and PET are contraindicated such as, but not limited to, having a metallic implant (such as pacemaker or cochlear implant), permanent make up, claustrophobia, or BMI ≥40 kg/m^2.
Other exclusions:
20. Involvement in the planning and/or conduct of the study (applies to AstraZeneca, UCR, and/or Antaros staff and/or staff at the study site).
21. Plasma donation within one month of screening or any blood donation/blood loss >450 mL during the 3 months prior to screening.
22. Women who has a positive pregnancy test at enrollment or randomization, or are breastfeeding.