Ketones, SGLT2, HFrEF

NCT ID: NCT06229678

Last Updated: 2025-05-21

Basic Information

• Recruitment Status: SUSPENDED
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 71 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-01-25
• Study Completion Date: 2027-03-01

Brief Summary

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

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.

Conditions

Type2diabetes; Heart Failure With Reduced Ejection Fraction

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: DOUBLE

Study Groups

Empagliflozin Group

Subjects will be randomized 2:1 to receive empagliflozin, 25mg/day for 3 months

Group Type: EXPERIMENTAL

Empagliflozin 25 MG Oral Tablet

Intervention Type: DRUG

Empagliflozin 25MG will be administered orally once per day for 3 months

Acipimox 250 Mg Oral Capsule

Intervention Type: DRUG

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 group

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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

The placebo will be administered orally once per day for 3 months

Acipimox 250 Mg Oral Capsule

Intervention Type: DRUG

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

Interventions

Empagliflozin 25 MG Oral Tablet

Empagliflozin 25MG will be administered orally once per day for 3 months

Intervention Type: DRUG

Placebo

The placebo will be administered orally once per day for 3 months

Intervention Type: 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

Intervention Type: DRUG

Other Intervention Names

jardiance

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 23-44 kg/m2
• Glycated hemoglobin (HbA1c) 6.0-10.0%
• Blood Pressure (BP) ≤ 145/85 mmHg
• Estimated glomerular filtration rate (eGFR) ≥30 ml/min•1.73 m2
• Only Type 2 diabetics treated with diet/exercise, metformin, sulfonylureas, metformin/sulfonylurea, Glucagon-like peptide-1 receptor agonist (GLP-1 RA), or insulin
• Stable body weight (±4 pounds) over the previous 3 months prior to enrollment
• Ability to understand study procedures and to comply with them for the entire length of the study.

Exclusion Criteria

• Heart failure due to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, severe valvular heart disease, hypertrophic obstructive cardiomyopathy.
• Significant change in diuretic management during the month prior to screening (defined by doubling of diuretic dose or addition of another heart failure medication)
• Type 2 Diabetics treated with Dipeptidyl Peptidase-4 Inhibitor (DPP4i) or pioglitazone
• Pregnancy, lactation, or plans to become pregnant. A negative pregnancy test will be performed before each MRI study to assess current status. For women of child-bearing age (WOCBA) willingness to use contraception, if applicable.
• Allergy/sensitivity to study drugs or their ingredients.
• Cancer.
• Current drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
• Inability or unwillingness of individual or legal guardian/representative to give written informed consent.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

The University of Texas Health Science Center at San Antonio

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Ralph DeFronzo, MD

Role: PRINCIPAL_INVESTIGATOR

University of Texas Health Science Center San Antonio

Locations

Texas Diabetes Institute - University Health System

San Antonio, Texas, United States

Countries

United States

Other Identifiers

R01DK107680

Identifier Type: NIH

Identifier Source: secondary_id

View Link

STUDY00000012

Identifier Type: -

Identifier Source: org_study_id