Ketones, SGLT2, HFrEF

The University of Texas System (UT)

Status and phase: Enrolling; Early Phase 1

Conditions: Type2diabetes; Heart Failure With Reduced Ejection Fraction

Treatments: Drug: Acipimox 250 Mg Oral Capsule; Drug: Placebo; Drug: Empagliflozin 25 MG Oral Tablet

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT06229678

STUDY00000012

R01DK107680 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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

Full 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.

Enrollment: 71 estimated patients

Sex: All

Ages: 18 to 70 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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71 participants in 2 patient groups, including a placebo group

Empagliflozin Group

Experimental group

Description:

Subjects will be randomized 2:1 to receive empagliflozin, 25mg/day for 3 months

Treatment:

Drug: Empagliflozin 25 MG Oral Tablet

Drug: Acipimox 250 Mg Oral Capsule

Placebo group

Placebo Comparator group

Description:

Subjects will be randomized to receive the empagliflozin placebo for 3 months

Treatment:

Drug: Placebo

Drug: Acipimox 250 Mg Oral Capsule