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Understanding the Cardiovascular Benefits of the Anti-Diabetes Medication SGLT2 Inhibitors

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ClinicalTrials.gov Identifier: NCT03560323
Recruitment Status : Recruiting
First Posted : June 18, 2018
Last Update Posted : August 5, 2021
Sponsor:
Information provided by (Responsible Party):
The University of Texas Health Science Center at San Antonio

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).

Condition or disease Intervention/treatment Phase
Heart Failure Type 2 Diabetes Mellitus Drug: Beta-hydroxy-butyrate Phase 1

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 36 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
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.
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: SGLT2 Inhibitors, Ketones, & Cardiovascular Benefit
Actual Study Start Date : January 7, 2019
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine


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




Primary Outcome Measures :
  1. Cardiac Function [ Time Frame: 300-360 minutes after the start of infusion ]
    Parameters of left ventricular (LV ) diastolic and systolic function


Secondary Outcome Measures :
  1. Myocardial energetics [ Time Frame: 300-360 minutes after the start of infusion ]
    Myocardial glucose uptake



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Ages Eligible for Study:   30 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03560323


Contacts
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Contact: Ralph A. DeFronzo, MD 210-567-6691 defronzo@uthscsa.edu
Contact: Carolina Solis-Herrera, MD 210-358-7200 solisherrera@uthscsa.edu

Locations
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United States, Texas
Texas Diabetes Institute - University Health System Recruiting
San Antonio, Texas, United States, 78207
Contact: Carolina Solis-Herrera, MD    210-358-7200    solisherrera@uthscsa.edu   
University of Texas Health Science Center San Antonio Recruiting
San Antonio, Texas, United States, 78229
Contact: Jane Qin, MD    210-358-7200    qiny@uthscsa.edu   
Contact: Henri Honka, MD PhD    210-567-6691    honka@uthscas.edu   
Sponsors and Collaborators
The University of Texas Health Science Center at San Antonio
Investigators
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Principal Investigator: Ralph A DeFronzo, MD UT Health San Antonio
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Responsible Party: The University of Texas Health Science Center at San Antonio
ClinicalTrials.gov Identifier: NCT03560323    
Other Study ID Numbers: HSC20180077H
First Posted: June 18, 2018    Key Record Dates
Last Update Posted: August 5, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by The University of Texas Health Science Center at San Antonio:
Ketone Body Metabolism
Myocardial Glucose Uptake
Positron Emission Tomography
Myocardial Function
Additional relevant MeSH terms:
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Diabetes Mellitus, Type 2
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases