Ketones, SGLT2, HFrEF

Early Phase 1

Suspended

• Conditions: Type2diabetes; Heart Failure With Reduced Ejection Fraction
• Interventions: Drug: Empagliflozin 25 MG Oral Tablet; Drug: Placebo; Drug: Acipimox 250 Mg Oral Capsule

• Registration Number: NCT06229678
• Lead Sponsor: The University of Texas Health Science Center at San Antonio

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.

Study Timeline

• Study First Submitted: 2023-12-18
• Study First Submitted QC: 2024-01-18
• Study Start: 2024-01-25
• Study First Posted: 2024-01-29
• Status Verified: 2025-05
• Last Update Submitted: 2025-05-16
• Last Update Posted: 2025-05-21
• Primary Completion: 2026-11-01
• Study Completion: 2027-03-01

Recruitment & Eligibility

• Status: SUSPENDED
• Sex: All
• Target Recruitment: 71

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Empagliflozin Group	Empagliflozin 25 MG Oral Tablet	Subjects will be randomized 2:1 to receive empagliflozin, 25mg/day for 3 months
Placebo group	Placebo	Subjects will be randomized to receive the empagliflozin placebo for 3 months
Empagliflozin Group	Acipimox 250 Mg Oral Capsule	Subjects will be randomized 2:1 to receive empagliflozin, 25mg/day for 3 months
Placebo group	Acipimox 250 Mg Oral Capsule	Subjects will be randomized to receive the empagliflozin placebo for 3 months

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Acetoacetate concentrations	baseline to 3 months	Change in acetoacetate concentrations
6-min walking test	baseline to 3 months	Change in the distance that can be covered in a 6 minute walk test
Patient-Reported Outcomes Measure Information System	baseline to 3 months	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.
Plasma Beta-hydroxybutyrate (β-OH-B)	baseline to 3 months	Change in β-OH-B with medication
plasma ketone concentration on myocardial function	Baseline to 3months + 8 days	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.
plasma ketone concentration on myocardial blood flow	Baseline to 3months + 8 days	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.

Trial Locations

Locations (1)

Texas Diabetes Institute - University Health System; 🇺🇸 San Antonio, Texas, United States