SGLT2 Inhibitors, Ketones, and Cardiovascular Benefit Research Plan

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors, Ketones, and Cardiovascular Benefit Research Plan

Conditions
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Type2 Diabetes, Heart Failure With Preserved Ejection Fraction

Intervention / Treatment
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* Drug: Empagliflozin 25 MG
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A randomized (2:1) placebo controlled double blind study
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Empagliflozin Group<br>Subjects will be randomized 2:1 to receive empagliflozin, 25mg/day for 3 months | Drug: Empagliflozin 25 MG<br>* Empagliflozin 25MG will be administered orally once per day for 3 months<br>* Other names: Jardiance;|
| Placebo Comparator: Placebo group<br>Subjects will be randomized to receive the empagliflozin placebo for 3 months | Drug: Placebo<br>* The placebo will be administered orally once per day for 3 months<br>* Other names: Placebo for Empagliflozin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Phosphocreatine | A measure of phosphocreatine change from baseline to study end | Baseline to 3 months | 
| Change in Adenosine Triphosphate (ATP) | A measure of ATP change from baseline to study end | Baseline to 3 months | 
| Change in Inorganic Phosphate | A measure of inorganic phosphate change from baseline to study end | Baseline to 3 months | 
| Change in Phosphodiester | A measure of phosphodiester change from baseline to study end | Baseline to 3 months | 
| ATPmax production | Exercise induced ATPmax production change | Baseline to 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Beta-hydroxybutyrate (β-OH-B) | Change in β-OH-B | Baseline to 3 months | 
| Acetoacetate concentrations | Change in acetoacetate concentrations | Baseline to 3 months | 
| Cardiopulmonary Function | Change in cardiopulmonary functional capacity using oxygen uptake (VO2) | Baseline to 3 months | 
| 6 minute walk test | Change in the distance that can be covered in a 6 minute walk test | Baseline to 3 months | 
| Patient-Reported Outcomes Measure Information System (PROMIS) | Change in Physical function will be assessed by the PROMIS Item band v2.0 -Physical Function -Short Form 20a to evaluate patient-reported outcomes of physical function and well being. | Baseline to 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ketones, Cardiovascular benefit