SGLT2 Inhibitors, Ketones, and Cardiovascular Benefit Research Plan

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

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.

Study Overview

• Status: Recruiting
• Conditions: Type2 Diabetes; Heart Failure With Preserved Ejection Fraction
• Intervention / Treatment: Drug: Empagliflozin 25 MG; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Carolina Solis-Herrera, MD; Phone Number: 210-567-4900; Email: solisherrera@uthscsa.edu
• Study Contact Backup: Name: Francisca M Acosta, PhD; Phone Number: 210-450-8677; Email: acostafm@uthscsa.edu

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78229
      • Recruiting
      • University of Texas Health Science Center at San Antonio
      • Principal Investigator: Carolina Solis-Herrera, MD
      • Contact: Carolina Solis-Herrera, MD; Phone Number: 210-567-4800; Email: solisherrera@uthscsa.edu
      • Contact: Francisca M Acosta, PhD; Phone Number: 210-450-8677; Email: acostafm@uthscsa.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Empagliflozin Group; Subjects will be randomized 2:1 to receive empagliflozin, 25mg/day for 3 months	Drug: Empagliflozin 25 MG; Empagliflozin 25MG will be administered orally once per day for 3 months; Other Names: Jardiance
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; Other Names: Placebo for Empagliflozin

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: The University of Texas Health Science Center at San Antonio
• Collaborators: Doris Duke Charitable Foundation; Max and Minnie Tomerlin Voelcker Fund
• Investigators: Principal Investigator: Carolina Solis-Herrera, MD, The University of Texas Health Science Center at San Antonio

Study record dates

Study Major Dates

• Study Start (Actual): January 13, 2021
• Primary Completion (Estimated): November 30, 2026
• Study Completion (Estimated): March 31, 2027

Study Registration Dates

• First Submitted: September 15, 2021
• First Submitted That Met QC Criteria: September 15, 2021
• First Posted (Actual): September 27, 2021

Study Record Updates

• Last Update Posted (Actual): April 6, 2026
• Last Update Submitted That Met QC Criteria: March 30, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Ketones; Cardiovascular benefit
• Additional Relevant MeSH Terms: Metabolic Diseases; Acid-Base Imbalance; Acidosis; Nutritional and Metabolic Diseases; Ketosis; Sodium-Glucose Transporter 2 Inhibitors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; empagliflozin
• Other Study ID Numbers: HSC20210528H; 2021176 (Other Grant/Funding Number: Doris Duke Charitable Foundation)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The PI will actively participate in journal clubs and symposia and present abstracts at national meetings, as well as submitting manuscripts to top peer-reviewed journals.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No