Safety and Effectiveness of SGLT-2 Inhibitors in Patients With Heart Failure and Diabetes

Study Overview
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Brief Summary
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Patients with diabetes are at increased risk of developing heart failure (HF) which can lead to increased shortness of breath, reduced ability to exercise and in some cases premature death as the heart becomes less efficient at pumping blood around the body. However the treatment options for such patients remain limited. This study will test the safety and benefits of using a new class of drug, the SGLT2 Inhibitor (Dapagliflozin), in treating HF and diabetes. Participants will have a Magnetic Resonance Imaging (MRI) scan of the heart, to measure the efficiency and the extent of thickening of the heart muscle before they start on treatment of dapagliflozin, or placebo for one year. They will also do exercise testing on an exercise bike (if capable) and a walking test plus fill in some questionnaires on how their heart failure affects their quality of life. Participants will then continue as normal with currently prescribed medication for their diabetes and heart failure. After a year the tests will be repeated to determine if patients receiving Dapagliflozin benefited more than those who weren't on the drug. This study is funded by the European Foundation for the Study of Diabetes (EFSD)

Detailed Description
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Men and women with diabetes have a 2-5-fold increased risk of heart failure (HF). The prevalence and incidence of HF is increasing in diabetes and mortality rates remain alarmingly high. This highlights the need for novel therapies in diabetes that will reduce HF risk and /or delay disease progression. Drug options are currently limited as some diabetic therapies such as thiazolidinediones are contra-indicated in HF. SGLT2 inhibitors, the newest class of anti-diabetic drugs, are an exciting new approach to diabetes management that may have additional beneficial effects in diabetes and HF. SGLT2 inhibitors may have beneficial effects on adverse left ventricular (LV) remodelling that occurs in patients with diabetes and heart failure by reducing the load on the heart through its diuretic and blood pressure lowering actions. Exercise intolerance is a cardinal symptom of patients with HF and improving insulin sensitivity has been shown to improve exercise capacity. SGLT2 inhibition has been shown to improve insulin sensitivity and to reduce weight and therefore has the potential to improve exercise capacity in HF. This study will assess the potential beneficial effects of the oral SGLT2 inhibitor, dapagliflozin, on LV remodelling and exercise capacity in patients with diabetes and HF. The findings of this study may help to establish the utility of SGLT2 inhibitors in diabetic patients with HF and provide important clinical data on the impact of SGLT2 inhibition on LV remodelling.

Official Title
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Research Into the Effect of SGLT2 Inhibition on Left Ventricular Remodeling in Patients With Heart Failure and Diabetes Mellitus

Conditions
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Heart Failure, Diabetes

Intervention / Treatment
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* Drug: Dapagliflozin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: were previously diagnosed with Type 2 Diabetes are diagnosed with NYHA functional class I-III HF with prior echocardiographic evidence of Left Ventricular Systolic Dysfunction (LVSD) (At least mild LV systolic dysfunction on sonographer assessment or ejection fraction at 45% or less) on furosemide 80mg daily or less, or equivalent loop diuretic have stable HF symptoms for at least three months prior to consent on stable therapy for HF for at least three months prior to consent have not been hospitalised for HF for at least three months prior to consent Exclusion Criteria: severe hepatic disease renal disease defined as Chronic Kidney Disease (CKD) class 3b or worse (i.e. estimated glomerular filtration rate (eGFR) / creatinine clearance CrCl <45ml/min) systolic BP <95mmHg at screening visit screening HbA1c <6.0% unable to walk to perform cardio pulmonary exercise testing or 6MWT malignancy (receiving active treatment) or other life threatening diseases pregnant or lactating women any contraindication to MRI (e.g. claustrophobia, metal implants, penetrative eye injury or exposure to metal fragments in eye requiring medical attention) patients who have participated in any other clinical trial of an investigational medicinal product within the previous 30 days patients who are unable to give informed consent any other reason considered by a study physician to be inappropriate for inclusion.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment<br>Dapagliflozin 10mg once daily | Drug: Dapagliflozin<br>* Sodium Glucose Linked Transporter Type 2 (SGLT-2) Inhibitor<br>* Other names: Forxiga;|
| Placebo Comparator: Control<br>Capsules containing microcrystalline cellulose Ph Eur overencapsulated in a hard gelatine capsule shell to match the active comparator | Drug: Placebo<br>* Capsules containing microcrystalline cellulose Ph Eur overencapsulated in a hard gelatine capsule shell to match the active comparator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in LV end systolic volume (absolute value and indexed for BSA) or LV end diastolic volume (absolute value and indexed for BSA) | Cardiac MRI will be performed to determine the change in end systolic and diastolic volumes between both groups of patients | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in LV mass, LV ejection fraction, RV end diastolic volume, RV end systolic volume, RV ejection fraction, atrial dimensions and volumes, and LV remodelling index (LV mass / LVEDV) | MRI will be performed to study the effects of the intervention on various other cardiac parameters. | 1 year | 
| Fluid status (Bioelectrical Impedence Analysis (BIA) | Bioelectrical Impedence Analysis (BIA) will be conducted to determine the effect of the study dug on overall fluid balance | 1 year | 
| Objective functional capacity (6 Minute Walk Test (6MWT) | 6 Minute Walk Test (6MWT) will be performed to objectively determine the functional capacity of participants | 1 year | 
| Exercise capacity (Cardio-pulmonary Exercise Testing (CPET) | Cardio-pulmonary Exercise Testing (CPET) will be performed to determine the exercise capacity of participants | 1 year | 
| Quality of life (Minnesota Living with Heart Failure and SF-36 questionnaire) | will be conducted to determine the impact of the intervention on subjective quality of life | 1 year | 
| Cardiac and inflammatory biomarkers | Brain natriuretic peptide (BNP) and other inflammatory & oxidative stress markers will be measured | 1 year | 
| Diuretic requirement (total diuretic requirement to maintain euvolemia) | The total diuretic requirement to maintain euvolemia will be compared between the beginning and end of the trial | 1 year | 
| Change in degree of microalbuminuria | Urinary analysis will be performed to determine if there has been any change in the severity of microalbuminuria | 1 year | 
| Quantify amount of natriuresis | Urinary analysis will be performed to quantify the amount of sodium excretion. | 1 year | 
| The safety of dapagliflozin use in diabetic, heart failure patients with regard to worsening HF, hospitalization and death will be evaluated |  | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart failure, Diabetes, Left ventricular remodelling, SGLT-2 inhibitors