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

Study Overview
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Brief Summary
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Patients with type 2 diabetes (T2 DM) have a markedly increased risk of heart disease and it is estimated that, in the danish population, up 80% percent of patients with type 2 diabetes die from heart disease. The sodium glucose cotransport-2 (SGLT-2) inhibitors were developed as an anti-diabetic therapy reducing blood glucose and weight by decreasing glucose reabsorption in the kidneys, leading to glucose excretion via the urine. However, in 2015 the EMPA-REG study showed that treatment with the SGLT-2 inhibitor empagliflozin significantly reduced the cardiovascular mortality and risk of admission under the diagnosis of heart failure in a population of patients with type 2 diabetes in addition to other risk factors for heart disease. The mechanism behind this surprising result is unknown and warrants further study. The primary hypothesis of the present study is that treatment with empagliflozin improves the function and blood supply of the heart muscle cells in patients with type 2 diabetes and high risk of heart disease. The investigators will test this hypothesis by enrolling 92 participants with type 2 diabetes and other risk factors for heart disease, and treating them with either empagliflozin or a placebo. During the study period the investigators will monitor the effects of the treatment with various techniques such as heart scans using CT and ultrasound, measurements of the fluid pressures in the heart chambers, body composition measurements and a variety of relevant blood test.

Official Title
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Effects of SGLT-2 Inhibitor on Myocardial Perfusion, Function and Metabolism in Type 2 DM Patients at High Cardiovascular Risk: The SIMPle Randomized Clinical Trial

Conditions
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Type2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Empagliflozin
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be treated with either empagliflozin or placebo
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Empagliflozin<br>Empagliflozin, coated tablets, 25mg, once daily, for 13 weeks | Drug: Empagliflozin<br>* Empagliflozin tablet<br>* Other names: Jardiance;|
| Placebo Comparator: Placebo<br>Placebo, coated tablets, once daily, for 13 weeks | Drug: Placebo Oral Tablet<br>* Sugar pill, visually identical to active comparator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rb-82 PET | Between group difference in the change in myocardial flow reserve (MFR) by Rb-82 PET. Measured as change in global perfusion from rest to adenosine-induced stress. | 13 weeks | 
| Invasive hemodynamics | Substudy, performed on 38 participants from the main group. Using right heart catheterisation to measure between group difference in the change in pulmonary capillary weight pressure (PCWP) at 25 watts (supine bicycle ergometer) | 13 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Echocardiography | Between group difference in the change in global left ventricular function assessed by echocardiography | 13 weeks | 
| GFR | Between group difference in the change in renal function assessed by Cr-51 EDTA | 13 weeks | 
| U-alb/crea | Between group difference in the change urinary albumin/creatinine ratio | 13 weeks | 
| 24 hour BP | Between group difference in the change in 24 hour BP | 13 weeks | 
| Pulse wave analysis | Between group difference in the change in pulse wave analysis | 13 weeks | 
| Insulin resistance | Between group difference in the changes in insulin resistance by Matsuda index | 13 weeks | 
| Insulin resistance | Between group difference in the changes in insulin resistance by HOMA | 13 weeks | 
| Biomarkers | Between group difference in the change in NT-proBNP, MR-proANP, MR-proADM, GAL-3, hsTNT, GDF-15, PIGF, sFlt-1, FFA, ADPN, leptin, TNF-α, IL-6, MCP-1, MAC-1, COLL-A1, FGF-21, beta-hydroxybutyrate, AGEs CML, sRAGE | 13 weeks | 
| Questionnaires | Between group difference in the change in Health status, assessed by the EuroQol EQ-5D-5L questionnaire | 13 weeks | 
| Questionnaires, continued | Between group difference in the change in Health status, assessed by the Minnesota Living with Heart Failure questionnaire | 13 weeks | 
| DEXA | Between group difference in the change in body composition by DEXA scan | 13 weeks | 
| Invasive hemodynamics - continued | Between group difference in the change in CO at rest, 25 watts and peak exercise | 13 weeks | 
| Invasive hemodynamics - continued | Between group difference in the change in CVP at rest, 25 watts and peak exercise | 13 weeks | 
| Invasive hemodynamics - continued | Between group difference in the change in PCWP at rest, 25 watts and peak exercise | 13 weeks | 
| Invasive hemodynamics - continued | Between group difference in the change in PAP at rest, 25 watts and peak exercise | 13 weeks | 
| Invasive hemodynamics - continued | Between group difference in the change in SvO2 at rest, 25 watts and peak exercise | 13 weeks | 
| Adipose tissue | Between group difference in the changes in levels of adipocyte differentiation | 13 weeks | 
| Adipose tissue | Between group difference in the changes in macrophage infiltration | 13 weeks | 
| Adipose tissue | Between group difference in the changes in extracellular matrix fibrosis | 13 weeks | 
| Daily activity | Between group difference in the change in daily activity levels measured by patient-worn accelerometers. | 13 weeks |