Effects of Empagliflozin on Exercise Capacity and Left Ventricular Diastolic Function in Patients With Heart Failure With Preserved Ejection Fraction and Type-2 Diabetes Mellitus

A Phase 4, Single-center, Randomized, Parallel Group Study to Assess Effects of Empagliflozin on Exercise Capacity and Left Ventricular Diastolic Function in Patients With Heart Failure With Preserved Ejection Fraction and Type-2 Diabetes Mellitus

Patients enrolled into the study will be randomly allocated either to Empagliflozin group or control group. In the Empagliflozin group patients will be receiving standard care + Empagliflozin 10 mg o.d., in the control group patients will be receiving standard care without sodium glucose contransporter 2 (SGLT2) inhibitors.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2; Heart Failure, Diastolic
• Intervention / Treatment: Drug: Empagliflozin; Other: Standard care

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 4

Contacts and Locations

Study Locations

• Russian Federation
  • Moscow, Russian Federation, 121552
    • National Medical Research Center for Cardiology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Males and females aged 45 to 80 years at screening
2. Diagnosis of type-2 diabetes mellitus with stable glucose-lowering background therapy for at least 12 weeks
3. HbA1c ≥ 6,5% and ≤ 10% at screening

4. Diagnosis of HFpEF which includes:

   • Symptoms ± signs (as defined in 2016 European Society of Cardiology guidelines for the diagnosis and treatment of acute and chronic heart failure)
   • Ejection fraction ≥ 50% (by Simpson)
   • Increased LV filling pressures at rest or during exercise determined by echocardiography (LV diastolic dysfunction grade II/III and/or positive diastolic stress test) [according to American Society of Echocardiography and European Association of Cardiovascular Imaging (ASE/EACVI) Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography, 2016]
5. Signed and dated informed consent

Exclusion Criteria:

1. Pretreatment with empagliflozin or other SGLT-2 inhibitor within the last 2 months
2. Type-1 diabetes mellitus
3. NYHA classification IV or acute decompensated heart failure at screening
4. Impaired renal function, defined as eGFR <30 ml/min/1.73 m² of body-surface-area (CKD-EPI)
5. Systolic blood pressure > 180 mmHg or < 90 mmHg
6. Permanent atrial flutter or atrial fibrillation
7. Other conditions that may be responsible for impaired diastolic function such as hypertrophic/restrictive cardiomyopathy, constrictive pericarditis and etc.
8. Anemia (Hb < 100 g/l)
9. Myocardial infarction, coronary artery bypass graft surgery within the last 3 months
10. Stroke or TIA within the last 3 months
11. Indications of liver disease
12. Acute genital infection or urinary tract infection
13. Pregnancy
14. Additional exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Empagliflozin; Patients will receive standard care for Heart Failure and Diabetes Mellitus + Empagliflozin 10mg once daily	Drug: Empagliflozin; 10 mg tablet
ACTIVE_COMPARATOR: Control; Patients will receive standard care for Heart Failure and Diabetes Mellitus with no SGLT-2 inhibitors	Other: Standard care; Standard care with no SGLT-2 inhibitors

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in 6-minute walking distance (6MWD)	Difference in distance walked during 6-minute walking test (6MWT) between 24 weeks after baseline and at baseline	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in left atrial volume index (LAVI)	Difference in LAVI assessed by echocardiography between 24 weeks after baseline and at baseline	24 weeks
Change in left ventricular mass index (LVMI)	Difference in LVMI assessed by echocardiography between 24 weeks after baseline and at baseline	24 weeks
Change of New York Heart Association (NYHA) functional classification	Difference in NYHA class between 24 weeks after baseline and at baseline	24 weeks
Change in N-terminal pro b-type natriuretic peptide (NT-proBNP)	Difference in NT-proBNP plasma levels between 24 weeks after baseline and at baseline	24 weeks
Change in high-sensitivity C-reactive protein (hsCRP)	Difference in hsCRP plasma levels between 24 weeks after baseline and at baseline	24 weeks
Change in Growth/differentiation factor 15 (GDF-15)	Difference in GDF-15 plasma levels between 24 weeks after baseline and at baseline	24 weeks
Change in Galectin-3	Difference in Galectin-3 plasma levels between 24 weeks after baseline and at baseline	24 weeks
Change in left atrial stiffness	Difference in left atrial stiffness assessed as a ratio of mitral E/e' ratio to left atrial strain s between 24 weeks after baseline and at baseline	24 weeks
Change estimated pulmonary artery systolic pressure (PASP)	Difference in PASP assessed by echocardiography both at rest and during diastolic stress test (DST) between 24 weeks after baseline and at baseline	24 weeks
Change in average e' velocity	Difference in average e' velocity assessed by echocardiography both at rest and during diastolic stress test (DST) between 24 weeks after baseline and at baseline	24 weeks
Change in average E/e' ratio	Difference in average E/e' ratio assessed by echocardiography both at rest and during diastolic stress between 24 weeks after baseline and at baseline	24 weeks
Change in Cyclic guanosine monophosphate (cGMP)	Difference in cGMP plasma levels between 24 weeks after baseline and at baseline	24 weeks
Change in Endothelin 1 (ET-1)	Difference in ET-1 plasma levels between 24 weeks after baseline and at baseline	24 weeks
Change in ST2	Difference in ST2 plasma levels between 24 weeks after baseline and at baseline	24 weeks
Change in carboxyterminal propeptide of type I collagen (PICP)	Difference in PICP plasma levels between 24 weeks after baseline and at baseline	24 weeks
Change in Human Pentraxin 3 (PTX3)	Difference in PTX3 plasma levels between 24 weeks after baseline and at baseline	24 weeks
Change in Interleukin-6 (IL-6)	Difference in IL-6 plasma levels between 24 weeks after baseline and at baseline	24 weeks
Change in Minnesota Living With Heart Failure Questionnaire (MLHFQ) score	Difference in MLHFQ score between 24 weeks after baseline and at baseline. The questionnaire is comprised of 21 important physical, emotional and socioeconomic ways heart failure can adversely affect a patient's life. After receiving brief standardized instructions, the patient marks a 0 (zero) to 5 scale to indicate how much each itemized adverse of heart failure has prevented the patient from living as he or she wanted to live during the past 4 weeks. The questionnaire is simply scored by summation of all 21 responses. Score ranges from 0 (best quality of life) to 105 (worst quality of life).	24 weeks

Collaborators and Investigators

• Sponsor: National Medical Research Center for Cardiology, Ministry of Health of Russian Federation
• Collaborators: Ministry of Health of the Russian Federation
• Investigators: Principal Investigator: Anton Borisov, MD, National Medical Research Center for Cardiology

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 16, 2019
• Primary Completion (ACTUAL): December 16, 2021
• Study Completion (ACTUAL): January 10, 2022

Study Registration Dates

• First Submitted: November 21, 2018
• First Submitted That Met QC Criteria: November 23, 2018
• First Posted (ACTUAL): November 26, 2018

Study Record Updates

• Last Update Posted (ACTUAL): January 11, 2022
• Last Update Submitted That Met QC Criteria: January 10, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: Empagliflozin; HF; Jardiance; DM; HFpEF
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Heart Failure; Diabetes Mellitus; Diabetes Mellitus, Type 2; Heart Failure, Diastolic; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin
• Other Study ID Numbers: 2018-9-25

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.: No