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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03560323
Recruitment Status : Active, not recruiting
First Posted : June 18, 2018
Last Update Posted : January 12, 2022
Sponsor:
Information provided by (Responsible Party):
The University of Texas Health Science Center at San Antonio

Tracking Information
First Submitted Date  ICMJE June 4, 2018
First Posted Date  ICMJE June 18, 2018
Last Update Posted Date January 12, 2022
Actual Study Start Date  ICMJE January 7, 2019
Actual Primary Completion Date October 13, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 5, 2018)
Cardiac Function [ Time Frame: 300-360 minutes after the start of infusion ]
Parameters of left ventricular (LV ) diastolic and systolic function
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 5, 2018)
Myocardial energetics [ Time Frame: 300-360 minutes after the start of infusion ]
Myocardial glucose uptake
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Understanding the Cardiovascular Benefits of the Anti-Diabetes Medication SGLT2 Inhibitors
Official Title  ICMJE SGLT2 Inhibitors, Ketones, & Cardiovascular Benefit
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 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE 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
Condition  ICMJE
  • Heart Failure
  • Type 2 Diabetes Mellitus
Intervention  ICMJE 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)
Study Arms  ICMJE
  • 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
    Intervention: Drug: Beta-hydroxy-butyrate
  • 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
    Intervention: Drug: Beta-hydroxy-butyrate
  • 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
    Intervention: Drug: Beta-hydroxy-butyrate
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: June 5, 2018)
36
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2022
Actual Primary Completion Date October 13, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 30 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03560323
Other Study ID Numbers  ICMJE HSC20180077H
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Current Responsible Party The University of Texas Health Science Center at San Antonio
Original Responsible Party Same as current
Current Study Sponsor  ICMJE The University of Texas Health Science Center at San Antonio
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Ralph A DeFronzo, MD UT Health San Antonio
PRS Account The University of Texas Health Science Center at San Antonio
Verification Date January 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP