The study design is a double blinded randomised control trial study that aims to conduct a randomised controlled trial of empagliflozin and determine if empagliflozin will improve myocardial blood flow in asymptomatic high risk type 2 diabetic patients. Also, to determine a cut-off using maximum upslope ratio and myocardial perfusion reserve index in which patients would demonstrate an improvement in myocardial blood flow.

It is unknown whether empagliflozin will improve myocardial blood flow and resolve myocardial ischaemia caused by microvascular coronary artery disease in asymptomatic patients with type 2 diabetes.This study proposes to perform a randomised controlled trial to compare optimised medical therapy against empagliflozin in addition to optimised medical therapy to improve myocardial blood flow as measured by stress CMR. This trial would provide evidence if 10mg of empagliflozin given for 6 months could be an indicated treatment in asymptomatic high risk type 2 diabetic patients using stress CMR. The duration of 6 months is slightly longer than the mouse study (ie. 5 months) which showed an improvement in myocardial blood flow but not too long that the risk of increased patient withdrawal from the study will occur.

All patients will undergo coronary CT angiography in order to assess degree of coronary artery narrowing non-invasively before allocation to the control or intervention group. Patients will also undergo coronary CT angiography at the end of the study after 6 months of placebo or empagliflozin.

Inclusion Criteria:

• Onset of type 2 diabetes at ≥30yrs old with no history of ketoacidosis

• 40-90yrs old

• Any 2 risk factors which include:

  i) Smoking (ie. current or ex-smokers) ii) Dyslipidaemia (defined as low density lipoprotein ≥2.6mmol/L, triglyceride >1.7mmol/L or decreased high density lipoprotein cholesterol <1.04mmol/L [man] or <1.29mmol/L [woman] or on lipid-lowering agent)(17, 18) iii) Hypertension (ie. systolic blood pressure >140mmHg or diastolic blood pressure >90mmHg or patients treated for hypertension) iv) Obesity (using definition adapted for chinese ethnicity, body mass index >25kg/m2)(19) v) Family history of premature heart disease (defined as 1st degree relative [ie. parent or sibling] with development of atherosclerotic cardiovascular disease or cardiovascular related death <55 years of age in male and <65 years of age in female)

• HbA1c ≥ 6.5% and <10.0%

Exclusion Criteria:

• Angina pectoris or chest discomfort
• Prior coronary artery bypass grafts
• Coronary artery stenting within 6 months of study enrolment
• Previous myocardial infarct
• Any contraindication for stress CMR testing
• Renal impairment with eGFR <45ml/min/1.73m2
• Limited life expectancy <5 years, for example due to pulmonary disease, cancer or significant hepatic failure
• Contraindication to dual antiplatelet therapy
• Contraindication to empagliflozin or other SGLT2 inhibitors
• Unable to take empagliflozin
• Patients currently on empagliflozin or given empagliflozin in the last 6 months
• Planned need for concomitant cardiac surgery or coronary intervention
• Refusal or inability to sign an informed consent.
• Potential for non-compliance towards the requirements in the trial protocol (especially the medical treatment) or follow-up visits

A stratified block randomisation process will be used. Two blocks will be created for randomisation which are 1) Positive stress CMR patients who did not have significant coronary artery disease; 2) Negative stress CMR patients. This will ensure equal spread of these two groups of patients into the control and intervention arm.

Patients will be randomised into control and intervention arms. Control group: Patients will have placebo and optimised medical therapy and will continue to have protocol driven therapy and follow-up appointments (currently 1 appointment every 3 months).

Intervention group: Patients will be prescribed empagliflozin 10mg once a day and optimised medical therapy for 6 months and standard follow-up like the control group.