Ketones, Muscle Metabolism, and SGLT2 Inhibitors - Protocol 1 (Protocol1)

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

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).

Study Overview

• Status: Recruiting
• Conditions: Heart Failure; Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Beta-hydroxy-butyrate

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.

• Study Type: Interventional
• Enrollment (Estimated): 78
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Ralph A. DeFronzo, MD; Phone Number: 210-567-6691; Email: defronzo@uthscsa.edu
• Study Contact Backup: Name: Carolina Solis-Herrera, MD; Phone Number: 210-358-7200; Email: solisherrera@uthscsa.edu

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78207
      • Recruiting
      • Texas Diabetes Institute - University Health System
      • Contact: Carolina Solis-Herrera, MD; Phone Number: 210-358-7200; Email: solisherrera@uthscsa.edu
    • San Antonio, Texas, United States, 78229
      • Active, not recruiting
      • University of Texas Health Science Center San Antonio

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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	Drug: 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; Other Names: Infusion of Beta-Hydroxy-Butyrate (B-OH-B)
Active Comparator: 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	Drug: 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; Other Names: Infusion of Beta-Hydroxy-Butyrate (B-OH-B)
Active Comparator: 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	Drug: 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; Other Names: Infusion of Beta-Hydroxy-Butyrate (B-OH-B)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: The University of Texas Health Science Center at San Antonio
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Ralph A DeFronzo, MD, UT Health San Antonio

Study record dates

Study Major Dates

• Study Start (Actual): January 7, 2019
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): February 1, 2027

Study Registration Dates

• First Submitted: June 4, 2018
• First Submitted That Met QC Criteria: June 5, 2018
• First Posted (Actual): June 18, 2018

Study Record Updates

• Last Update Posted (Estimated): December 15, 2023
• Last Update Submitted That Met QC Criteria: December 14, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Positron Emission Tomography; Ketone Body Metabolism; Myocardial Glucose Uptake; Myocardial Function
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
• Other Study ID Numbers: HSC20180077H; 2R01DK107680-06A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No