Clinical trial NCT05057806: SGLT2 Inhibitors, Ketones, and Cardiovascular Benefit Research Plan
Official title: Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors, Ketones, and Cardiovascular Benefit Research Plan
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: EARLY_PHASE1
Conditions: Type2 Diabetes
Heart Failure With Preserved Ejection Fraction
Keywords: Ketones
Cardiovascular benefit
Lead sponsor: The University of Texas Health Science Center at San Antonio
Sponsor class: OTHER
Collaborators: name: Doris Duke Charitable Foundation
name: Max and Minnie Tomerlin Voelcker Fund
First posted: 2021-09-27
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A randomized (2:1) placebo controlled double blind study
Primary purpose: BASIC_SCIENCE

Brief summary: 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: 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.

Eligibility criteria: 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 and Diabetes
* Stable body weight (±4 pounds) over the last 3 months
* Does not suffer from severe claustrophobia
* No contraindication for MRI (metal plates, screws, shrapnel, pins, or cardiac pacemaker)

Exclusion Criteria:

* Subjects treated with an SGLT2 inhibitor, a glucagon-like peptide-1 receptor agonist (GLP-1 RA) or pioglitazone
* Pregnancy, lactation or plans to become pregnant
* Allergy/sensitivity to study drugs or their ingredients
* Cancer
* Current drug or alcohol use or dependence
* Inability or unwillingness of individual or legal guardian/representative to give written informed consent

Primary outcomes:
measure: Change in Phosphocreatine
timeFrame: Baseline to 3 months
measure: Change in Adenosine Triphosphate (ATP)
timeFrame: Baseline to 3 months
measure: Change in Inorganic Phosphate
timeFrame: Baseline to 3 months
measure: Change in Phosphodiester
timeFrame: Baseline to 3 months
measure: ATPmax production
timeFrame: Baseline to 3 months
Secondary outcomes:
measure: Plasma Beta-hydroxybutyrate (β-OH-B)
timeFrame: Baseline to 3 months
measure: Acetoacetate concentrations
timeFrame: Baseline to 3 months
measure: Cardiopulmonary Function
timeFrame: Baseline to 3 months
measure: 6 minute walk test
timeFrame: Baseline to 3 months
measure: Patient-Reported Outcomes Measure Information System (PROMIS)
timeFrame: Baseline to 3 months
Other outcomes:
Locations:
city: San Antonio
country: United States
facility: Texas Diabetes Institute - University Health System
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
Study officials:
affiliation: University of Texas Health Science Center San Antonio
name: Carolina Solis-Herrera, MD
role: PRINCIPAL_INVESTIGATOR
References: