Ketones, SGLT2, HFrEF

Heart Failure With Reduced Ejection Fraction Clinical Trial

Official title:

Ketones, Muscle Metabolism, and SGLT2 Inhibitors

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06229678
• Other study ID #: STUDY00000012
• Secondary ID: R01DK107680
• Status: Recruiting
• Phase: Early Phase 1
• Start date: January 25, 2024
• Est. completion date: March 1, 2027

Study information

• Verified date: February 2024
• Source: The University of Texas Health Science Center at San Antonio
• Contact: Ralph DeFronzo, MD
• Phone: 210-567-6691
• Email: defronzo[@]uthscsa.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 71
• Est. completion date: March 1, 2027
• Est. primary completion date: November 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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.

Related Conditions & MeSH terms

• Heart Failure
• Heart Failure With Reduced Ejection Fraction

Intervention

Drug:
• Empagliflozin 25 MG Oral Tablet
Empagliflozin 25MG will be administered orally once per day for 3 months
• Placebo
The placebo will be administered orally once per day for 3 months
• 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

Locations

Country	Name	City	State
United States	Texas Diabetes Institute - University Health System	San Antonio	Texas

Sponsors (2)

Lead Sponsor	Collaborator
The University of Texas Health Science Center at San Antonio	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Phosphocreatine	A measure of phosphocreatine change from baseline to study end	Baseline to 3 months
Primary	Change in Adenosine Triphosphate (ATP)	A measure of ATP change from baseline to study end	Baseline to 3 months
Primary	Change in Inorganic Phosphate	A measure of inorganic phosphate change from baseline to study end	Baseline to 3 months
Primary	Change in Phosphodiester	A measure of phosphodiester change from baseline to study end	Baseline to 3 months
Primary	ATPmax production	Exercise induced ATPmax production change	Baseline to 3 months
Secondary	Plasma Beta-hydroxybutyrate (ß-OH-B)	Change in ß-OH-B with medication	baseline to 3 months
Secondary	Acetoacetate concentrations	Change in acetoacetate concentrations	baseline to 3 months
Secondary	6-min walking test	Change in the distance that can be covered in a 6 minute walk test	baseline to 3 months
Secondary	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
Secondary	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
Secondary	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