SGLT-2 Inhibitor and Myocardial Perfusion, Function and Metabolism in T2 DM Patients at High Cardiovascular Risk (SIMPLE)

Inclusion Criteria:

• A diagnosis of type 2 diabetes mellitus at least 3 months prior to baseline visit
• For patients on background therapy: stable dose of anti-diabetics within 30 days prior to baseline
• HbA1c of ≥6.5% and ≤10% at screening for patients on background therapy or HbA1c of ≥6.5 % and ≤ 9.0% at screening for drug-naïve patients.
• BMI ≤ 45 kg/m2 at screening
• Age ≥18 years
• Negative pregnancy test (fertile women). Fertile women must use safe contraceptives (spiral, hormonal contraceptives) for the duration of the study
• Able to understand the written patient information and to give informed consent
• Patients must have high cardiovascular risk, defined as at least one of the following:
• Albuminuria ( albumin/creatinine ratio ≥ 30 mg/g or plasma NT-proBNP ≥ 70 pg/ml)
• Confirmed history of myocardial infarction (>2 months prior to baseline)
• Heart failure according to the Framingham Heart Failure Criteria
• Or patient discharged from hospital with a documented diagnosis of unstable angina within 12 months prior to baseline
• Evidence of coronary artery disease by CAG in 1 or more major coronary arteries

OR at least one of the following: a positive noninvasive stress test, or A positive stress echocardiography showing regional systolic wall motion abnormalities, or A positive scintigraphic test showing stress-induced ischemia,

• History of ischemic or haemorrhagic stroke (>2 months prior to informed consent)
• Presence of peripheral artery disease (symptomatic or not ) documented by either: previous limb angioplasty, stenting or bypass surgery; or previous limb or foot amputation due to circulatory insufficiency; or angiographic evidence of significant (> 50%) peripheral artery stenosis in at least one limb; or evidence from a non-invasive measurement of significant (>50% or as reported as hemodynamically significant) peripheral artery stenosis in at least one limb; or ankle brachial index of < 0.9

Exclusion Criteria:

• Allergic to the study medication
• Treatment with SGLT-2 inhibitor within 3 months prior to baseline
• Impaired kidney function, eGFR ≤ 30 ml/min
• Severe liver insufficiency (Child-Pugh class C)
• ECG showing malign ventricular arrhythmia or prolonged QT-interval (>500ms)
• Untreated clinical significant heart valve disease
• Planned cardiac surgery or angioplasty within 3 months.
• Myocardial infarction (MI) ≤ 30 days prior to baseline
• Percutaneous coronary intervention (PCI) ≤ 4 weeks prior to baseline
• History of coronary artery bypass graft (CABG) ≤ 8 weeks prior to enrollment
• Prior history of heart transplantation
• Unstable angina, known severe left main coronary artery stenosis, severe heart failure, uncontrolled arrhythmias, symptomatic hypotension or severe hypertension (systolic blood pressure < 90 or > 180 mmHg, respectively), sick sinus syndrome or > 1st degree atrioventricular block in the absence of a functioning pacemaker
• Requirement of emergent cardiac medical intervention or catheterization
• Treatment with theophylline, or theophylline containing medications
• History of known or suspected bronchoconstrictive or bronchospastic lung disease (e.g., asthma)
• Pregnancy or desire hereof or breastfeeding.

Additional exclusion criteria for hemodynamics substudy

• LVEF ≤ 40 % evaluated at baseline echocardiography
• Inability to perform a VO2 max test
• Hypertrophic cardiomyopathy
• Left ventricular assist device