Ketones, Muscle Metabolism, and SGLT2 Inhibitors - Protocol 1

NCT03560323 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: HSC20180077H2R01DK107680-06A1
• Study Type: interventional
• Target: 41
• Locations: 1 country
• Sites: 2

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).

Conditions

Heart Failure; Type 2 Diabetes Mellitus

Keywords

Ketone Body Metabolism; Myocardial Glucose Uptake; Positron Emission Tomography; Myocardial Function

Outcome Measures

Primary Outcomes (3)

• Cardiac Output (CO)

  Within 2 weeks after the screening visit, subjects return to the Research Institute (RII) at 7:00AM for a cardiac MRI on 3.0T MRI System (TIM, Trio, Siemens Medical Solution, Malvern, PA). Cardiac output (CO) is measured using velocity encoded phase contrast MRI. The patient lies in the MRI scanner, and the imaging plane is positioned perpendicular to the ascending aorta where blood flow can be measured accurately. The MRI scan is synchronized with the patient's heartbeats using ECG gating. Two types of images are collected: magnitude images, which provide anatomical reference, phase images, which encode the speed and direction of blood flow. The system multiplies velocity by the cross-sectional area of the vessel to calculate the volume of blood passing through the vessel at each moment. Integrating the flow values over the entire cardiac cycle, the system calculates the stroke volume. Cardiac Output = Stroke Volume × Heart Rate

  Baseline at 0 minute before B-OH-B infusion and 360 minutes after B-OH-B infusion for Group I & II. For Group III was baseline at 0 minute and 180 minutes after infusion

• Ejection Fraction (EF)

  A measurement, expressed as a percentage, of how much blood the left ventricle pumps out with each heartbeat. It's a key indicator of heart function and can help diagnose and track heart failure. A normal EF typically falls between 55% and 70%. Values below 40% are often considered indicative of heart failure.

  Baseline at 0 minute before infusion and 360 minutes after infusion for Group I & II. Group III was baseline at 0 minute of infusion and 180 minutes after infusion

• Left Ventricular Stroke Volume (LVSV)

  Represents the amount of blood ejected from the heart's left ventricle with each heartbeat. It's a crucial indicator of cardiac function, reflecting how effectively the heart pumps blood to the body.

  Baseline at 0 minute before infusion and 360 minutes after infusion for Group I & II. Group III was baseline at 0 minute of infusion and 180 minutes after infusion

Secondary Outcomes (2)

• Myocardial Energetics-Myocardial Glucose Uptake (MGU)

  MGU after B-OH-B or NaHCO3 infusion for 6 hours at minute 360 minutes

• Myocardial Energetics- Myocardic Blood Flow (MBF)

  MBF after B-OH-B or NaHCO3 infusion for 6 hours at 360 minutes (the results showed the difference betweenB-OH-B and NaHCO3 infusion for 6 hours)

Study Arms (3)

Group I Beta-Hydroxy-Butyrate

ACTIVE COMPARATOR

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

Group II Beta-Hydroxy-Butyrate

ACTIVE COMPARATOR

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

Group III Beta-Hydroxy-Butyrate

ACTIVE COMPARATOR

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

Interventions

Beta-hydroxy-butyrate 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

Also known as: Infusion of Beta-Hydroxy-Butyrate (B-OH-B)

Group I Beta-Hydroxy-Butyrate; Group II Beta-Hydroxy-Butyrate; Group III Beta-Hydroxy-Butyrate

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 %).

You may not qualify if:

• 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.

Sponsors & Collaborators

• The University of Texas Health Science Center at San Antonio: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (2)

Texas Diabetes Institute - University Health System

San Antonio, Texas, 78207, United States

Location

University of Texas Health Science Center San Antonio

San Antonio, Texas, 78229, United States

Location

MeSH Terms

Conditions

Heart Failure; Diabetes Mellitus, Type 2

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Results Point of Contact

• Title: Yuejuan Qin, Assistant Professor
• Organization: University of Texas Health -San Antonio

qiny@uthscsa.edu

210-358-7200

Study Officials

• Ralph A DeFronzo, MD

  UT Health San Antonio

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: June 4, 2018
• First Posted: June 18, 2018
• Study Start: January 7, 2019
• Primary Completion: August 30, 2024
• Study Completion: December 30, 2024
• Last Updated: September 29, 2025
• Results First Posted: September 29, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)