Ketones, Muscle Metabolism, and SGLT2 Inhibitors - Protocol 1

Study Overview
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Brief Summary
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To examine the effect of an increase in plasma beta-hydroxy-butyrate (B-OH-B) levels, spanning the physiologic and pharmacologic range (+0.5, +2.0, and +5.0 mmol/L), on: (i) parameters of left ventricular (LV) systolic and diastolic function utilizing cardiac magnetic resonance imaging (MRI) and (ii) myocardial glucose uptake using positron emission tomography (PET) with 18F-fluoro-2-deoxy-D-glucose in type 2 diabetic patients with Class II-III New York Heart Association (NYHA).

Detailed Description
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Purpose/Objectives The EMPA-REG OUTCOME (NCT01131676) trial demonstrated that SGLT2 (sodium-glucose co-transporter) inhibition with empagliflozin markedly reduced cardiovascular (CV) mortality and hospitalization for heart failure. In diabetic patients treated with SGLT2 inhibitors, a rise in plasma ketone concentration consistently has been observed. This has led to the ketone hypothesis in which a shift from glucose/FFA (Free Fatty Acids) to ketone utilization by the heart results in enhanced left ventricular systolic/diastolic function and could, at least in part, explain the reduction in CV mortality and hospitalization for heart failure observed in the EMPA-REG OUTCOME trial. Methods Type 2 diabetic subjects with New York Heart Association (NYHA) Class II-III heart failure and ejection fraction less than 50% will be studied. Eligible subjects will undergo a baseline cardiac MRI to obtain quantitative measures of baseline cardiac functional parameters: chamber volumes and pressures, wall thickness, LV diastolic function (E/A ratio, peak LV filling rate, diastolic volume), LV systolic function (cardiac output, stroke volume, systolic volume, peak LV ejection rate). Baseline samples will be drawn for measurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) , B-OH-butyrate, acetoacetate, glucose, FFA, lactate, pyruvate, glycerol, HCO3 (bicarbonate), insulin, glucagon, renin and aldosterone. Following completion of the baseline MRI and blood samples, subjects will be divided into three groups (12 subjects per group). Each group will receive a 6-hour (3-hour in group III) prime-continuous infusion of racemic B-OH-B (100 mg/mL solution; pH adjusted to 7.4) to increase the plasma B-OH-B concentration by  0.5,  2.0, and  5.0 mmol/L. At the end of the infusion the MRI will be repeated. As a time control GROUP II subjects will receive a continuous infusion of sodium bicarbonate (0.12 M) for 6 hours (0.08 mg/kg/min) to mimic the rise in plasma bicarbonate concentration observed with B-OH-B infusion. Group II will return again to the RII (UT Health Research Imaging Institute) on a separate day for a cardiac positron emission tomography (PET) study to examine the effect of hyperketonemia on myocardial glucose uptake and blood flow. In  14 days subjects will return for a repeat PET/18F-2-DOG (deoxyglucose) study with one exception: NaHCO3 (Sodium bicarbonate) will be infused instead of B-OH-B. The two studies will be performed in random order.

Official Title
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Ketones, Muscle Metabolism, and SGLT2 Inhibitors - Protocol 1.

Conditions
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Heart Failure, Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Beta-hydroxy-butyrate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 diabetes. Class II-III New York Heart Association (NYHA) heart failure with ejection fraction less than 50 %. Age 18-80 years. BMI 23-38 kg/m2. HbA1c 6.0-9.0 %. Blood pressure < 145/85 mmHg. eGFR > 30 mL/min/1.73 m2. NT-proBNP ≥ 500 pg/mL (or ≥ 300 pg/mL if ejection fraction is less than 35 %). Exclusion Criteria: Treatment with Glucagon-like peptide-1 receptor agonist (GLP-1 RA), Dipeptidyl peptidase-4 inhibitors (DPP4i), pioglitazone, SGLT2 inhibitor or insulin. Women who are pregnant or breastfeeding. Contraindications for MRI include metal plates, parts, screws, shrapnel, pins in the body, or cardiac pacemaker. Any other condition that in the opinion of the investigator create a hazard to the subject safety, endanger the study procedures or interfere with the interpretation of study results.

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: Basic Science
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Type 2 diabetic subjects with New York Heart Association (NYHA) Class II-III heart failure and ejection fraction <50% (documented by patient's medical records with an Echocardiogram (ECHO) or any other heart imaging) will be studied.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group I Beta-Hydroxy-Butyrate<br>Administration of beta-hydroxy-butyrate at 0.4 mg/kg.min for 20 minutes and then at a constant rate of 0.2 mg/kg.min until study end | Drug: Beta-hydroxy-butyrate<br>* Following completion of the baseline MRI and blood samples, subjects will be divided into three groups (26 subjects per group). Each group will receive a 6-hour (3-hour in group III) prime-continuous infusion of racemic B-OH-B (100 mg/mL solution; pH adjusted to 7.4) to increase the plasma B-OH-B concentration by 0.5, 2.0, and 5.0 mmol/L. GROUP I: Prime = 0.4 mg/kg.min for 20 minutes and constant rate = 0.2 mg/kg.min until study end GROUP II: Prime = 1.5 mg/kg.min for 20 minutes and constant rate = 0.75 mg/kg.min until study end GROUP III: Prime = 4.0 mg/kg.min for 20 minutes and constant rate = 2.0 mg/kg.min until study end<br>* Other names: Infusion of Beta-Hydroxy-Butyrate (B-OH-B);|
| Active Comparator: Group II Beta-Hydroxy-Butyrate<br>Administration of beta-hydroxy-butyrate at 1.5 mg/kg.min for 20 minutes and then at a constant rate of 0.75 mg/kg.min until study end | Drug: Beta-hydroxy-butyrate<br>* Following completion of the baseline MRI and blood samples, subjects will be divided into three groups (26 subjects per group). Each group will receive a 6-hour (3-hour in group III) prime-continuous infusion of racemic B-OH-B (100 mg/mL solution; pH adjusted to 7.4) to increase the plasma B-OH-B concentration by 0.5, 2.0, and 5.0 mmol/L. GROUP I: Prime = 0.4 mg/kg.min for 20 minutes and constant rate = 0.2 mg/kg.min until study end GROUP II: Prime = 1.5 mg/kg.min for 20 minutes and constant rate = 0.75 mg/kg.min until study end GROUP III: Prime = 4.0 mg/kg.min for 20 minutes and constant rate = 2.0 mg/kg.min until study end<br>* Other names: Infusion of Beta-Hydroxy-Butyrate (B-OH-B);|
| Active Comparator: Group III Beta-Hydroxy-Butyrate<br>Administration of beta-hydroxy-butyrate at 4.0 mg/kg.min for 20 minutes and then at a constant rate of 2.0 mg/kg.min until study end | Drug: Beta-hydroxy-butyrate<br>* Following completion of the baseline MRI and blood samples, subjects will be divided into three groups (26 subjects per group). Each group will receive a 6-hour (3-hour in group III) prime-continuous infusion of racemic B-OH-B (100 mg/mL solution; pH adjusted to 7.4) to increase the plasma B-OH-B concentration by 0.5, 2.0, and 5.0 mmol/L. GROUP I: Prime = 0.4 mg/kg.min for 20 minutes and constant rate = 0.2 mg/kg.min until study end GROUP II: Prime = 1.5 mg/kg.min for 20 minutes and constant rate = 0.75 mg/kg.min until study end GROUP III: Prime = 4.0 mg/kg.min for 20 minutes and constant rate = 2.0 mg/kg.min until study end<br>* Other names: Infusion of Beta-Hydroxy-Butyrate (B-OH-B);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiac Function | Parameters of left ventricular (LV ) diastolic and systolic function | 300-360 minutes after the start of infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Myocardial energetics | Myocardial glucose uptake | 300-360 minutes after the start of infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ketone Body Metabolism, Myocardial Glucose Uptake, Positron Emission Tomography, Myocardial Function