Effect of Genetic Polymorphisms on the Clinical Response to SGLT2 Inhibitors in Heart Failure Patients

Effect of Genetic Polymorphisms on the Clinical Response to Sodium-glucose Cotransporter 2 (SGLT2) Inhibitors in Prevention of Cardiac Remodeling and Fibrosis in Heart Failure Patients

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown further reductions in heart failure hospitalization, cardiovascular events, and mortality, especially for heart failure patients.

The SGLT2 gene, also known as SLC5A2 (solute carrier family 5 member 2), is located on chromosome 16 and is responsible for encoding SGLT2.

Several SLC5A2 mutations alter SGLT2 expression, membrane location, or transporter function.

Several common genetic variations were found in the SLC5A2 gene that may affect the response to treatment with SGLT2 inhibitors.

Study Overview

• Status: Recruiting
• Conditions: Heart Failure; Genetic Polymorphisms
• Intervention / Treatment: Drug: SGLT2 inhibitors (Dapagliflozin and Empagliflozin)

Detailed Description

Sodium-glucose cotransporter-2 inhibitors (SGLT-2i), which were first investigated and licensed for the treatment of diabetes, are now emerging as a promising class of drugs for the treatment of heart failure (HF), even in people without diabetes.

Significant reductions in worsening heart failure or cardiovascular death were shown under treatment with dapagliflozin and empagliflozin in the trials of patients with heart failure.

Several common genetic variations were found in the SLC5A2 gene that may affect the response to treatment with SGLT2 inhibitors.

The most recent SLC5A2 Single Nucleotide Polymorphisms (SNPs) that reduce the risk of heart failure included two intronic SLC5A2 SNPs, s9934336, and rs3116150, both associated with the expression levels of the transporter.

This study aims to detect the association between SLC5A2 single nucleotide polymorphisms and variability in response to SGLT2 Inhibitors as well as the association between cardiac biomarkers and non-coding RNA in patients with Heart Failure.

• Study Type: Observational
• Enrollment (Estimated): 282

Contacts and Locations

• Study Contact: Name: Ahmed Essam, MSc; Phone Number: +201007647696; Email: ahmed.essam@o6u.edu.eg

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32610
      • Recruiting
      • University of Florida
      • Contact: Julio Duarte, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

The study population consist of established Heart failure with reduced ejection fraction (HFrEF) or Heart failure with preserved ejection fraction (HFpEF) and New York Heart Association (NYHA) functional classes II-III, who will be candidates for add-on treatment with SGLT2i.

Description

Inclusion Criteria:

• Heart failure patients NYHA class II to III.
• Heart failure patients with reduced left ventricular ejection fraction (LVEF) < 45% or with preserved left ventricular ejection fraction (LVEF) > 45%
• Patients who will be candidate for add-on treatment with SGLT2.
• Patients who will be able to sign informed consent to participate in the study.

Exclusion Criteria:

• Contraindications to SGLT2.
• Significant coronary artery diseases (CAD), coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), or valve surgery within 3 months.
• Pregnant or breastfeeding women.
• Patients with estimated glomerular filtration rates less than 30 mL/min/1.73 m2, as determined using the CKD-EPI equation.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Heart Failure Patients with reduced or preserved Ejection Fraction; Patients with reduced or preserved ejection fraction that have received the Guided Therapy (β-blockers, Diuretics, Angiotensin-converting enzyme (ACE) inhibitors or Angiotensin receptor blockers (ARBs) or Angiotensin Receptor-Neprilysin Inhibitor (ARNi) and Mineralocorticoid receptor antagonists (MRAs) then Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) (10 mg of dapagliflozin or empagliflozin) will be added at the study entry.

Drug: SGLT2 inhibitors (Dapagliflozin and Empagliflozin); 10 mg of dapagliflozin or empagliflozin; Other Names: Forxiga; Jardiance

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median / Mean of Left Ventricular Ejection Fraction (LVEF) among studied genetic polymorphisms	Change in median / mean of Left Ventricular Ejection Fraction (LVEF) before and after drug administration	6 months
Median / Mean of Left Ventricular End Systolic Volumes among studied genetic polymorphisms	Change in median / mean of Left Ventricular End Systolic Volume (LVESV)	6 months
Median / Mean of Left Ventricular End Diastolic Volumes among studied genetic polymorphisms	Change in median / mean of Left Ventricular End Diastolic Volume (LVEDV) before and after drug administration	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median / Mean of quality of life measure {Kansas City Cardiomyopathy Questionnaire (KCCQ-12)} among studied genetic polymorphisms	Change in median / mean of Kansas City Cardiomyopathy Questionnaire (KCCQ-12) before and after drug administration	6 months

Collaborators and Investigators

• Sponsor: October 6 University
• Collaborators: University of Florida; Beni-Suef University; National Heart Institute, Egypt
• Investigators: Study Director: Rania Sarhan, PhD, Beni-Suef University; Study Director: Neven Sarhan, PhD, Misr International University; Study Director: Bassem Zarif, MD, National Heart Institute; Study Chair: Julio Duarte, PhD, University of Florida

Study record dates

Study Major Dates

• Study Start (Actual): December 27, 2023
• Primary Completion (Estimated): July 1, 2024
• Study Completion (Estimated): September 1, 2024

Study Registration Dates

• First Submitted: December 27, 2023
• First Submitted That Met QC Criteria: January 10, 2024
• First Posted (Actual): January 11, 2024

Study Record Updates

• Last Update Posted (Estimated): February 7, 2024
• Last Update Submitted That Met QC Criteria: February 6, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Dapagliflozin; Empagliflozin; Sodium-Glucose Transporter 2 Inhibitors
• Other Study ID Numbers: IHC00068

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes