Ketones, SGLT2, HFrEF

Purpose

The study team will examine the effects of elevated plasma ketone levels following initiation of SGLT2 inhibitor therapy in high-risk type 2 diabetes mellitus (T2DM) individuals with heart failure (HF) with reduced ejection fraction (HFrEF) providing an energy-rich fuel that is taken up with great avidity by the myocardium, to measure change in Left Ventricle diastolic and systolic function

Conditions

  • Type2diabetes
  • Heart Failure With Reduced Ejection Fraction

Eligibility

Eligible Ages
Between 18 Years and 70 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

Inclusion Criteria

  • Type 2 Diabetes Mellitus - Class II-III New York Heart Association (NYHA) heart failure and reduced ejection fraction (EF) <50% - Age 18-80 years - BMI 23-38 kg/m2 - Glycated hemoglobin (HbA1c) 5.5-10% - Blood Pressure (BP) ≤ 145/85 mmHg - Estimated glomerular filtration rate (eGFR) ≥30 ml/min•1.73 m2 - Stable dose of guideline-directed medications for heart failure - Stable body weight (±4 pounds) over the last 3 months

Exclusion Criteria

  • Subjects treated with an SGLT2 inhibitor, a glucagon-like peptide-1 receptor agonist (GLP-1 RA) or pioglitazone - Resting heart rate >120 bpm - Systolic BP>180mmHg and/or diastolic BP >100mmHg - Resting percentage of blood oxygen saturation (SpO2) < 85% - Physical disability preventing safe performance of the exercise protocol.

Study Design

Phase
Early Phase 1
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Intervention Model Description
A randomized (2:1) placebo controlled double blind study
Primary Purpose
Basic Science
Masking
Double (Participant, Investigator)
Masking Description
Participants, and investigators will be blinded to the randomization

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Empagliflozin Group 		Subjects will be randomized 2:1 to receive empagliflozin, 25mg/day for 3 months
  • Drug: Empagliflozin 25 MG Oral Tablet
    Empagliflozin 25MG will be administered orally once per day for 3 months
    Other names:
    • jardiance
  • Drug: Acipimox 250 Mg Oral Capsule
    subjects will be started on acipimox 250mg every 6 hours for 8 days while on continued empagliflozin/placebo therapy. This will be added at the end of 3 months after they finished baseline studies
Placebo Comparator
Placebo group 		Subjects will be randomized to receive the empagliflozin placebo for 3 months
  • Drug: Placebo
    The placebo will be administered orally once per day for 3 months
  • Drug: Acipimox 250 Mg Oral Capsule
    subjects will be started on acipimox 250mg every 6 hours for 8 days while on continued empagliflozin/placebo therapy. This will be added at the end of 3 months after they finished baseline studies

Recruiting Locations

Texas Diabetes Institute - University Health System
San Antonio, Texas 78207
Contact:
Sivaram Neppala, MD
210-358-7200
neppalas@uthscsa.edu

More Details

Status
Recruiting
Sponsor
The University of Texas Health Science Center at San Antonio

Study Contact

Ralph DeFronzo, MD
210-567-6691
defronzo@uthscsa.edu

Detailed Description

The study team will examine the effects of elevated plasma ketones caused by 12-week treatment with an SGLT2i (empagliflozin) treatment in participants with T2DM and HF. The study team will focus on three possible mechanisms of action for these effects and test the following: (i) Skeletal muscle bioenergetics. Using 31P-MRS, the team will quantify phosphocreatine [PCr], ATP, inorganic phosphate, phosphodiester, and intracellular pH. With 1H-MRS, and will measure intramyocellular lipid content at rest and ATPmax production after exercise. The team will examine the relationships between phosphorous metabolite concentrations, intramyocellular lipid content, and ATP generation before and after 12 weeks of SGLT2 inhibition. (ii) LV systolic and diastolic function using cardiac MRI in type 2 diabetic patients with Class II-III NYHA heart failure and reduced EF. (iii) To examine the contribution of the SGLT2i-induced increase in plasma ketone concentration on myocardial function and myocardial blood flow by inhibiting the rise in plasma ketone concentration with acipimox while continuing empagliflozin. (iv) Improvements in Patient-Reported Outcomes (PRO). Kansas City Cardiomyopathy Questionnaire ( KCCQ) scoring will be used to evaluate self-reported physical function and well-being. This tool is a well-developed and validated method to obtain patient self-reported parameters of health in adults.