SGLT2 Inhibition in Combination With Diuretics in Heart Failure

Study Overview
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Brief Summary
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The RECEDE-CHF trial is a single centre phase IV, randomised, double-blind, placebo-controlled, crossover trial conducted in NHS Tayside, Scotland comparing empagliflozin 25mg, to placebo in patients with Type 2 Diabetes and mild Chronic Heart Failure with left ventricular systolic dysfunction who are already on a loop diuretic. Renal physiological testing will be performed at two points on each arm to assess the effect of empagliflozin, on urinary volume, compared to placebo. The secondary outcomes are to assess the effect of empagliflozin in addition to loop diuretics on natriuresis, to assess the safety of add-on SGLT2 inhibitor therapy as measured by changes to serum creatinine and eGFR, to assess effects of empagliflozin on urinary protein/creatinine ratio, albumin/creatinine ratio and cystatin C when compared to placebo.

Detailed Description
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Type 2 Diabetes (T2D) and Heart Failure (HF) are a frequent combination, where treatment options remain limited. There has been increasing interest around the sodium-glucose co-transporter 2 (SGLT2) inhibitors and their use in patients with HF. This is following publication of EMPA-REG OUTCOME trial that reported a 14% reduction in the primary composite outcome of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and >30% reductions in cardiovascular mortality, overall mortality and HF hospitalisations in patients randomised to the SGLT2 inhibitor, empagliflozin, when compared to placebo. Data on the effect of SGLT2 inhibitor use with diuretics is limited. We hypothesize that, in the diabetic CHF population, SGLT2 inhibition may augment the effects of loop diuretics. Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. The investigational medicinal product will be administered, followed by an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose. This proof of concept trial will aim to shed light on the mechanism of the cardiovascular and renal outcomes demonstrated in the recent EMPA-REG study by documenting the influence of the SGLT2 inhibitors when used in combination with a loop diuretic on diuresis and natriuresis when compared to placebo. The RECEDE-CHF trial is funded by the British Heart Foundation (BHF grant number: 807998). NAM is a BHF funded clinical research fellow.

Official Title
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Renal and Cardiovascular Effect of Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibition in Combination With Loop Diuretics in Diabetic Patients With Chronic Heart Failure

Conditions
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Heart Failure, Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Empagliflozin 25mg
* Drug: Placebo oral capsule
* Drug: Frusemide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of NYHA Functional class II-III HF with prior echocardiographic evidence of LVSD. On stable doses of furosemide, or alternative loop diuretic for at least one month. Stable Type 2 Diabetes (HbA1c, in the last 3 months, of 6.5% ≤ and ≤10.0%) eGFR ≥ 45 ml/min. Have stable HF symptoms for at least three months prior to consent On stable HF therapy for at least three months prior to consent Have not been hospitalised for HF for at least three months prior to consent. Women of childbearing potential must agree to take precautions to avoid pregnancy throughout the trial and for 4 weeks after intake of the last dose. Exclusion Criteria: A diagnosis of chronic liver disease and/or liver enzymes that are twice the upper limit of normal Systolic BP of <95mmHg at screening visit. Participants on thiazide diuretics. Participants receiving renal dialysis Participants who have previously had an episode of diabetic ketoacidosis. Participants with type 1 diabetes mellitus Malignancy (receiving active treatment) or other life threatening disease. Pregnant or lactating women Participants with difficulty in micturition e.g. severe prostate enlargement Allergy to any SGLT2 inhibitor or lactose or galactose intolerance Past or current treatment with any SGLT2 inhibitor Participants who have participated in any other clinical interventional trial of an investigational medicinal product within 30 days. Participants who are unable to give informed consent Any other reason considered by the physician to be inappropriate for inclusion.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Crossover Assignment
Interventional Model Description: 6 week period of Investigational Medicinal Product (Empagliflozin 25 mg od) or placebo. A 2 week washout period will then be observed, followed by the second arm with a further 6 week period of placebo or IMP. At week 1 and week 6 of each arm, detailed Renal Physiology Test days will be performed.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Empagliflozin/Placebo<br>Empagliflozin (SGLT2 inhibitor) 25mg capsules once daily for 6 weeks, minimum of a 2 week washout period, then 6 weeks placebo | Drug: Empagliflozin 25mg<br>* Empagliflozin (SGLT2 inhibitor) 25 mg once daily for 6 weeks<br>* Other names: Jardiance;Drug: Placebo oral capsule<br>* Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator once daily for 6 weeks<br>* Other names: Placebo;Drug: Frusemide<br>* Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. At a set time point, an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose will be administered.<br>|
| Active Comparator: Placebo/Empagliflozin<br>Placebo for 6 weeks, minimum of a 2 week washout period, followed by Empagliflozin (SGLT2 inhibitor) 25mg capsules once daily for 6 weeks | Drug: Empagliflozin 25mg<br>* Empagliflozin (SGLT2 inhibitor) 25 mg once daily for 6 weeks<br>* Other names: Jardiance;Drug: Placebo oral capsule<br>* Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator once daily for 6 weeks<br>* Other names: Placebo;Drug: Frusemide<br>* Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. At a set time point, an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose will be administered.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Effect of Empagliflozin Versus Placebo on the Change in Urine Output. | Change from urinary volume from baseline (mls). | Change from baseline to 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Effect of Empagliflozin Versus Placebo on the Change in Urinary Sodium Excretion. | The effect of empagliflozin versus placebo on the change in urinary sodium excretion: change in fractional urinary sodium excretion from baseline (%). | Change from baseline to 6 weeks | 
| Number of Participants With a Change in CKD Category as Dictated by the Glomerular Filtration Rate | The effect of empagliflozin versus placebo on the change in glomerular filtration rate: Change in estimated glomerular filtration rate from baseline (ml/min/1.73m2). Data was recorded as a persistent reduction in CKD category in the empagliflozin group versus placebo | From baseline to 6 weeks | 
| The Effect of Empagliflozin Versus Placebo on the Change in Serum Creatinine. | Change in serum creatinine from baseline (mmol/L). | Change from baseline to 6 weeks | 
| The Effect of Empagliflozin Versus Placebo on the Change to Urinary Protein/Creatinine Ratio. | The effect of empagliflozin versus placebo on the change to urinary protein/creatinine ratio: Change in urinary protein/creatinine ratio from baseline (mg/mmol). | Change from baseline to 6 weeks | 
| The Effect of Empagliflozin Versus Placebo on the Change to Urinary Albumin/Creatinine Ratio. | The effect of empagliflozin versus placebo on the change to urinary albumin/creatinine ratio: Change in urinary albumin/creatinine ratio from baseline (mg/mmol). | Change from baseline to 6 weeks | 
| The Effect of Empagliflozin Versus Placebo on the Change to the Renal Biomarker, Cystatin C. | The effect of empagliflozin versus placebo on the change to the renal biomarker, cystatin C: Change in Cystatin C from baseline (ng/ml). | Change from baseline to 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart Failure, Type 2 Diabetes Mellitus, Sodium-Glucose co-Transporter 2 (SGLT2) inhibitors, Natriuresis, Diuresis