Ketones, Muscle Metabolism, and SGLT2 Inhibitors - Protocol 1

NCT ID: NCT03560323

Last Updated: 2025-09-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 41 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-01-07
• Study Completion Date: 2024-12-30

Brief Summary

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

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.

Conditions

Heart Failure; Type 2 Diabetes Mellitus

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Group I Beta-Hydroxy-Butyrate

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

Group Type: ACTIVE_COMPARATOR

Beta-hydroxy-butyrate

Intervention Type: DRUG

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

Group II Beta-Hydroxy-Butyrate

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

Group Type: ACTIVE_COMPARATOR

Beta-hydroxy-butyrate

Intervention Type: DRUG

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

Group III Beta-Hydroxy-Butyrate

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

Group Type: ACTIVE_COMPARATOR

Beta-hydroxy-butyrate

Intervention Type: DRUG

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

Interventions

Beta-hydroxy-butyrate

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

Intervention Type: DRUG

Other Intervention Names

Infusion of Beta-Hydroxy-Butyrate (B-OH-B)

Eligibility Criteria

Inclusion Criteria

1. Type 2 diabetes.

2. Class II-III New York Heart Association (NYHA) heart failure with ejection fraction less than 50 %.

3. Age 18-80 years.

4. BMI 23-38 kg/m2.

5. HbA1c 6.0-9.0 %.

6. Blood pressure < 145/85 mmHg.

7. eGFR > 30 mL/min/1.73 m2.

8. NT-proBNP ≥ 500 pg/mL (or ≥ 300 pg/mL if ejection fraction is less than 35 %).

Exclusion Criteria

1. Treatment with Glucagon-like peptide-1 receptor agonist (GLP-1 RA), Dipeptidyl peptidase-4 inhibitors (DPP4i), pioglitazone, SGLT2 inhibitor or insulin.

2. Women who are pregnant or breastfeeding.

3. Contraindications for MRI include metal plates, parts, screws, shrapnel, pins in the body, or cardiac pacemaker.

4. 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

The University of Texas Health Science Center at San Antonio

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Ralph A DeFronzo, MD

Role: PRINCIPAL_INVESTIGATOR

UT Health San Antonio

Locations

Texas Diabetes Institute - University Health System

San Antonio, Texas, United States

University of Texas Health Science Center San Antonio

San Antonio, Texas, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

2R01DK107680-06A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

HSC20180077H

Identifier Type: -

Identifier Source: org_study_id