Purpose

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).

Category

IRB Number
20180077HU
NCT Number
NCT03560323
Open to Enrollment
Yes
Sponsor
The University of Texas Health Science Center at San Antonio -



Study Contact

Local Recruitment Point of Contact
Andrea Hansis-diarte
+1 (210) 617-5300
hansisdiarte@uthscsa.edu

Principal Investigator
Ralph DeFronzo

Regulatory Point of Contact
Andrea Hansis-diarte
+1 (210) 617-5300
hansisdiarte@uthscsa.edu



Eligibility

Eligible Ages
Between 30 Years and 70 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

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 30-70 years.
    4. BMI 23-38 kg/m2.
    5. 18 males/18 females.
    6. HbA1c 6.0-9.0 %.
    7. Blood pressure < 145/85 mmHg.
    8. eGFR > 30 mL/min/1.73 m2.
    9. 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 Design

Phase
Phase 1
Study Type
Interventional
Allocation
Non-Randomized
Intervention Model
Single Group Assignment
Intervention Model Description
36 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. Other inclusion criteria: age = 30-70 years; BMI =23-38 kg/m2; 18 males/18 females; HbA1c = 6.0-9.0%; BP < 145/85 mmHg; Estimated glomerular filtration rate (eGFR) > 45 ml/min•1.73 m2. Subjects must have an NT-proBNP = 500 pg/ml (or = 300 pg/ml if ejection fraction is less than 35 %) and be on a stable dose of guideline-directed heart fail medication (i.e. ACE inhibitor (ACEI), Angiotensin II receptor blocker (ARB), Angiotensin Receptor-Neprilysin Inhibitor (ARNI), beta blocker, diuretic and/or mineralocorticoid receptor antagonist). Patients must be on stable antihypertensive therapy for at least 2 months. Only diabetic subjects treated with diet/exercise, metformin monotherapy, sulfonylurea monotherapy (SU) or combination metformin/SU therapy.
Primary Purpose
Basic Science
Masking
None (Open Label)
Condition
  • Heart Failure
  • Type 2 Diabetes Mellitus

    • Arm Groups

    ArmDescriptionIntervention
    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 (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. 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 (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. 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 (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. 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)

    •