SGLT2 Inhibitors, Ketones, and Cardiovascular Benefit Research Plan

The University of Texas System (UT)

Status and phase: Enrolling; Early Phase 1

Conditions: Type2 Diabetes; Heart Failure With Preserved Ejection Fraction

Treatments: Drug: Placebo; Drug: Empagliflozin 25 MG

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT05057806

HSC20210528H

2021176 (Other Grant/Funding Number)

Details and patient eligibility

About

The study team will examine the effects of SGLT2i (and SGLT2i-induced increases in plasma ketone concentrations) on skeletal muscle and cardiac ketone uptake, skeletal muscle bioenergetics, cardiopulmonary exercise capacity, and patient-reported functional outcomes.

Full description

The study team will examine 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 quantitate 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) Cardiopulmonary functional capacity.

(iii) Improvements in Patient-Reported Outcomes (PRO). The Patient-Reported Outcomes Measure Information System (PROMIS) Item Bank v2.0 - Physical Function - Short Form 20a 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: 30 estimated patients

Sex: All

Ages: 18 to 80 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

---

30 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

Placebo group

Placebo Comparator group

Description:

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

Treatment:

Drug: Placebo