Ketones, SGLT2, HFrEF

Ketones, Muscle Metabolism, and SGLT2 Inhibitors

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

Study Overview

• Status: Recruiting
• Conditions: Heart Failure With Reduced Ejection Fraction; Type2diabetes
• Intervention / Treatment: Drug: Placebo; Drug: Empagliflozin 25 MG Oral Tablet; Drug: Acipimox 250 Mg Oral Capsule

Detailed 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.

• Study Type: Interventional
• Enrollment (Estimated): 71
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Sivaram Neppala, MD; Phone Number: 210-358-7200; Email: neppalas@uthscsa.edu
• Study Contact Backup: Name: Ralph DeFronzo, MD; Phone Number: 210-567-6691; Email: defronzo@uthscsa.edu

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78207
      • Recruiting
      • Texas Diabetes Institute - University Health System
      • Contact: Sivaram Neppala, MD; Phone Number: 210-358-7200; Email: neppalas@uthscsa.edu
      • Principal Investigator: Ralph DeFronzo, MD
      • Sub-Investigator: Sivaram Neppala, MD
      • Contact: Jemema Rajan, MD; Phone Number: 210-358-7200; Email: rajanj@uthscsa.edu
      • Sub-Investigator: Jemema Rajan, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 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
• 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.

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 Oral Tablet; Empagliflozin 25MG will be administered orally once per day for 3 months; Other Names: jardiance; Drug: Acipimox 250 Mg Oral Capsule; subjects will be started on acipimox 250mg every 6 hours for 8 days while on continued empagliflozin/placebo therapy. This will be added at the end of 3 months after they finished baseline studies
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; Drug: Acipimox 250 Mg Oral Capsule; subjects will be started on acipimox 250mg every 6 hours for 8 days while on continued empagliflozin/placebo therapy. This will be added at the end of 3 months after they finished baseline studies

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 with medication	baseline to 3 months
Acetoacetate concentrations	Change in acetoacetate concentrations	baseline to 3 months
6-min walking 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	By checking KCCQ (Kansas City Cardiomyopathy) scoring: Responses are categorized under 3 sub scales (symptom burden, physical limitation and quality of life) with a range of possible subscale scores from 0 to 100, with 100 representing the least burden of symptoms. The total KCCQ score represents the mean of the three sub scale scores.	baseline to 3 months
plasma ketone concentration on myocardial function	To examine the contribution of the SGLT2i-induced increase in plasma ketone concentration on myocardial function by inhibiting the rise in plasma ketone concentration with acipimox while continuing empagliflozin.	Baseline to 3months + 8 days
plasma ketone concentration on myocardial blood flow	To examine the contribution of the SGLT2i-induced increase in plasma ketone concentration on myocardial blood flow by inhibiting the rise in plasma ketone concentration with acipimox while continuing empagliflozin.	Baseline to 3months + 8 days

Collaborators and Investigators

• Sponsor: The University of Texas Health Science Center at San Antonio
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Ralph DeFronzo, MD, University of Texas Health Science Center San Antonio

Study record dates

Study Major Dates

• Study Start (Actual): January 25, 2024
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): March 1, 2027

Study Registration Dates

• First Submitted: December 18, 2023
• First Submitted That Met QC Criteria: January 18, 2024
• First Posted (Actual): January 29, 2024

Study Record Updates

• Last Update Posted (Actual): February 15, 2024
• Last Update Submitted That Met QC Criteria: February 13, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: ketones; cardiovascular benefit
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Hypolipidemic Agents; Lipid Regulating Agents; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin; Acipimox
• Other Study ID Numbers: STUDY00000012; R01DK107680 (U.S. NIH Grant/Contract)

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 submit 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