Heart Failure, Type 2 Diabetes Mellitus
Conditions
Keywords
Heart Failure, Type 2 Diabetes Mellitus, Sodium-Glucose co-Transporter 2 (SGLT2) inhibitors, Natriuresis, Diuresis
Brief summary
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
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.
Interventions
DRUGPlacebo oral capsule
Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator once daily for 6 weeks
DRUGFrusemide
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.
Empagliflozin (SGLT2 inhibitor) 25 mg once daily for 6 weeks
Sponsors
British Heart Foundation
University of Dundee
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double-Blind
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Effect of Empagliflozin Versus Placebo on the Change in Urine Output. | Change from baseline to 6 weeks | Change from urinary volume from baseline (mls). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Change in CKD Category as Dictated by the Glomerular Filtration Rate | From baseline to 6 weeks | 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 |
| The Effect of Empagliflozin Versus Placebo on the Change in Serum Creatinine. | Change from baseline to 6 weeks | Change in serum creatinine from baseline (mmol/L). |
| The Effect of Empagliflozin Versus Placebo on the Change in Urinary Sodium Excretion. | Change from baseline to 6 weeks | The effect of empagliflozin versus placebo on the change in urinary sodium excretion: change in fractional urinary sodium excretion from baseline (%). |
| The Effect of Empagliflozin Versus Placebo on the Change to Urinary Albumin/Creatinine Ratio. | Change from baseline to 6 weeks | The effect of empagliflozin versus placebo on the change to urinary albumin/creatinine ratio: Change in urinary albumin/creatinine ratio from baseline (mg/mmol). |
| The Effect of Empagliflozin Versus Placebo on the Change to the Renal Biomarker, Cystatin C. | Change from baseline to 6 weeks | The effect of empagliflozin versus placebo on the change to the renal biomarker, cystatin C: Change in Cystatin C from baseline (ng/ml). |
| The Effect of Empagliflozin Versus Placebo on the Change to Urinary Protein/Creatinine Ratio. | Change from baseline to 6 weeks | The effect of empagliflozin versus placebo on the change to urinary protein/creatinine ratio: Change in urinary protein/creatinine ratio from baseline (mg/mmol). |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Baseline Characteristics N = 23, Crossover study design. Baseline characteristics | 23 |
| Total | 23 |
Baseline characteristics
| Characteristic | Baseline Characteristics |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 18 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants |
| Age, Continuous | 69.8 years STANDARD_DEVIATION 5.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 23 Participants |
| Region of Enrollment United Kingdom | 23 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 23 | 0 / 23 |
| other Total, other adverse events | 1 / 23 | 2 / 23 |
| serious Total, serious adverse events | 2 / 23 | 0 / 23 |
Outcome results
Primary
The Effect of Empagliflozin Versus Placebo on the Change in Urine Output.
Change from urinary volume from baseline (mls).
Time frame: Change from baseline to 6 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Empagliflozin | The Effect of Empagliflozin Versus Placebo on the Change in Urine Output. | 545 mL |
| Placebo | The Effect of Empagliflozin Versus Placebo on the Change in Urine Output. | -113 mL |
Comparison: Details on the statistical analysis are published in the Circulation, DOI: 10.1161/CIRCULATIONAHA.120.048739~Analyses were performed on the primary and secondary measures comparing empagliflozin versus placebo and assessed by 2-way analysis of covariance correcting for treatment order, baseline value, and any percentage change in furosemide dose at the visit. Data for continuous outcome measures were assessed for normality before analysis.p-value: =0.005ANCOVA
Secondary
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
Time frame: From baseline to 6 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Empagliflozin | Number of Participants With a Change in CKD Category as Dictated by the Glomerular Filtration Rate | 6 Participants |
| Placebo | Number of Participants With a Change in CKD Category as Dictated by the Glomerular Filtration Rate | 5 Participants |
Secondary
The Effect of Empagliflozin Versus Placebo on the Change in Serum Creatinine.
Change in serum creatinine from baseline (mmol/L).
Time frame: Change from baseline to 6 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Empagliflozin | The Effect of Empagliflozin Versus Placebo on the Change in Serum Creatinine. | -0.44 mmol/L |
| Placebo | The Effect of Empagliflozin Versus Placebo on the Change in Serum Creatinine. | -10.81 mmol/L |
Secondary
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 (%).
Time frame: Change from baseline to 6 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Empagliflozin | The Effect of Empagliflozin Versus Placebo on the Change in Urinary Sodium Excretion. | 0.11 percentage of change in FENa |
| Placebo | The Effect of Empagliflozin Versus Placebo on the Change in Urinary Sodium Excretion. | -0.00 percentage of change in FENa |
Secondary
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).
Time frame: Change from baseline to 6 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Empagliflozin | The Effect of Empagliflozin Versus Placebo on the Change to the Renal Biomarker, Cystatin C. | 31.35 ng/ml |
| Placebo | The Effect of Empagliflozin Versus Placebo on the Change to the Renal Biomarker, Cystatin C. | 22.5 ng/ml |
Secondary
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).
Time frame: Change from baseline to 6 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Empagliflozin | The Effect of Empagliflozin Versus Placebo on the Change to Urinary Albumin/Creatinine Ratio. | 1.18 mg/mmol |
| Placebo | The Effect of Empagliflozin Versus Placebo on the Change to Urinary Albumin/Creatinine Ratio. | -1.1 mg/mmol |
Secondary
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).
Time frame: Change from baseline to 6 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Empagliflozin | The Effect of Empagliflozin Versus Placebo on the Change to Urinary Protein/Creatinine Ratio. | 2.26 mg/mmol |
| Placebo | The Effect of Empagliflozin Versus Placebo on the Change to Urinary Protein/Creatinine Ratio. | -3.05 mg/mmol |