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Empagliflozin and Cardiac Remodelling in People Without Diabetes (EMPA-HEART 2)

Primary Purpose

Cardiovascular Diseases, Left Ventricular Hypertrophy

Status
Completed
Phase
Phase 4
Locations
International
Study Type
Interventional
Intervention
Empagliflozin
Placebo
Sponsored by
Unity Health Toronto
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cardiovascular Diseases focused on measuring Cardiovascular disease, Cardiac Magnetic Resonance Imaging, Sodium-Glucose Transporter 2 Inhibitors

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Female Not of childbearing potential and male subjects ≥40 and ≤ 80 years of age (Women Not of childbearing potential are females who are permanently sterile or postmenopausal. Postmenopausal is defined as 12 consecutive months with no menses without an alternative medical cause or ≥6 weeks post-surgical bilateral oophorectomy prior to Screening.)
  2. ≥1 of the major criteria or ≥2 of the minor criteria below:

    Major criteria:

    • Increased LVMi of ≥96 g/m2 for women and ≥116 g/m2 for men (as calculated by echocardiogram); or LVMi ≥81 g/m2 for women and ≥85 g/m2 for men (as calculated by cMRI)
    • ECG evidence of LV hypertrophy (as per the Sokolow-Lyon criteria)
    • Structural heart disease defined as interventricular septal thickness or posterior wall thickness at end-diastole of ≥11 mm (as measured by 2D echocardiography or cMRI)
    • Persistent hypertension (defined as office blood pressure ≥140/90 mmHg) despite being on ≥3 antihypertensive medications

    Minor criteria:

    • Prior history of a myocardial infarction (≥3 months ago)
    • eGFR ≥30 and ≤60 mL/min/1.73 m2 (as measured by the CKD-EPI formula)
    • Body mass index (BMI) ≥27 and ≤40 kg/m2
  3. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures

Exclusion Criteria:

  1. Female subjects who are pregnant, lactating or of childbearing potential, or are pre- menopausal
  2. Known type 1 or type 2 diabetes
  3. Hemoglobin A1C (A1C) ≥6.5%
  4. eGFR <30 mL/min/1.73m2
  5. Indication of liver disease, defined by serum levels of either alanine-aminotransferase (ALT or SGPT), aspartate-aminotransaminase (AST or SGOT), or alkaline phosphatase (ALP) above 3 x upper limit of normal (ULN) as determined at Visit 1
  6. Hemoglobin < 90 g/L at Visit 1
  7. History of ketoacidosis, or increased chance of developing diabetic ketoacidosis (DKA) e.g. patients who suffer from excessive vomiting, diarrhea, or sweating; subjects who are on a very low carbohydrate diet; or subjects who drink a lot of alcohol.
  8. Systolic blood pressure <95mmHg (as measured at the office/clinic visit)
  9. Subjects in whom coronary revascularization by either percutaneous coronary intervention or bypass surgery is being contemplated within the next 6 months, or who have undergone coronary revascularization in the prior 3 months
  10. Significant allergy or known intolerance to SGLT2is or any ingredient in the formulations
  11. Subjects currently experiencing any clinically significant or unstable medical condition that in the opinion of the investigator might limit their ability to complete the study, or to comply with the requirements of the protocol, including: dermatologic disease, hematological disease, pulmonary disease, hepatic disease, gastrointestinal disease, genitourinary disease, endocrine disease, neurological disease, and psychiatric disease
  12. Any malignancy not considered cured (except basal cell carcinoma of the skin). A subject is considered cured if there has been no evidence of cancer recurrence for the 5 years prior to screening
  13. Subjects who have participated in other interventional studies which may affect any of the primary or secondary outcomes of the study within 30 days of the screening visit
  14. BMI >40 kg/m2
  15. Contraindications or inability to undergo magnetic resonance imaging such as the presence of metallic fragments, clips, or devices
  16. Known history of infiltrative cardiomyopathy such as cardiac amyloidosis or cardiac sarcoidosis
  17. Severe aortic stenosis
  18. Severe aortic regurgitation
  19. Severe mitral stenosis
  20. Severe mitral regurgitation
  21. Low voltage on ECG limb leads defined by the amplitude of the QRS complex in each limb lead ≤0.5 mV

Sites / Locations

  • Diagnostic Assessment Centre (AMS Diagnostics)
  • St. Michael's Hospital
  • North York Diagnostic and Cardiac Centre
  • Chang Gung Memorial Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Empagliflozin

Placebo

Arm Description

Single 10 mg tablet, administered orally once daily for 6 months

Single 10 mg tablet, administered orally once daily for 6 months

Outcomes

Primary Outcome Measures

Left Ventricular (LV) mass
Change in Left Ventricular (LV) mass (indexed to body surface area (BSA)) at 6 months. This will be measured using CMRI.

Secondary Outcome Measures

LV end-diastolic volume
Change in LV end-diastolic volume (indexed to BSA) at 6 months. This will be measured using CMRI.
LV end-systolic volume
Change in LV end-systolic volume (indexed to BSA) at 6 months. This will be measured using CMRI.
Left Ventricular Ejection Fraction (LVEF)
Change in LVEF at 6 months. This will be measured using CMRI.
LV wall stress
Change in LV wall stress at 6 months. This will be measured using CMRI.
LV systolic function
Change in LV systolic function at 6 months. This will be measured using CMRI.
LV diastolic function
Change in LV diastolic function at 6 months. This will be measured using CMRI.
NT-proBNP
Change in circulating NT-proBNP at 6 months.
Systolic and diastolic blood pressure
Change in systolic and diastolic blood pressure at 6 months.
Hematocrit
Change in hematocrit at 6 months in patients.

Full Information

First Posted
July 2, 2020
Last Updated
February 16, 2023
Sponsor
Unity Health Toronto
Collaborators
Canadian Medical and Surgical Knowledge Translation Research Group, Boehringer Ingelheim, Applied Health Research Centre
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1. Study Identification

Unique Protocol Identification Number
NCT04461041
Brief Title
Empagliflozin and Cardiac Remodelling in People Without Diabetes
Acronym
EMPA-HEART 2
Official Title
Empagliflozin and Cardiac Remodelling in People Without Diabetes
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Completed
Study Start Date
April 1, 2021 (Actual)
Primary Completion Date
July 31, 2022 (Actual)
Study Completion Date
July 31, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Unity Health Toronto
Collaborators
Canadian Medical and Surgical Knowledge Translation Research Group, Boehringer Ingelheim, Applied Health Research Centre

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to evaluate the effects of empagliflozin on cardiac structure, function and circulating biomarkers in patients with cardiovascular risk factors, but without diabetes. Empagliflozin is an antihyperglycemic agent approved by Health Canada and the FDA for the treatment of type 2 diabetes. Previous post-marketing clinical trials demonstrated a reduction in cardiovascular deaths and heart failure in patients with type 2 diabetes treated with empagliflozin. In the first EMPA-HEART trial, we demonstrated that empagliflozin reduces cardiac mass in patients with type 2 diabetes, as seen through cardiac magnetic resonance imaging (cMRI). Therefore, the aim of this study, EMPA-HEART 2, is to determine whether empagliflozin can similarly impact cardiac structure in patients without diabetes, but with various cardiovascular risk factors.
Detailed Description
Sodium-glucose cotransporter 2 (SGLT2) inhibitors (empagliflozin, canagliflozin and dapagliflozin) are approved medications to improve glycemic control in adult patients with type 2 diabetes. When added to current standard-of-care diabetes treatment, SGLT2 inhibitors are associated with clinically meaningful reductions in major adverse cardiovascular events, reduced rates of hospitalization for heart failure and a decrease in major adverse kidney outcomes. Importantly, these benefits were observed consistently in people with and without type 2 diabetes and across all levels of baseline glycemic control. These data point towards a glucose-independent, cardioprotective effect of SGLT2 inhibition. How SGLT2 inhibition might reduce cardiac outcomes in people without diabetes remains unclear, and this is the specific objective of EMPA-HEART 2. The study drug, empagliflozin (marketed as Jardiance), belongs to a class of medications that lowers blood glucose (sugar) by preventing glucose from entering back into blood circulation and ensures it is eliminated in urine. Empagliflozin is approved by the FDA and Health Canada for the treatment of type 2 diabetes. This is a double-blind, randomized, placebo-controlled, parallel-group study of empagliflozin vs. placebo in patients without diabetes but with various cardiovascular risk factors. The purpose is to determine the effects of empagliflozin on cardiac structure by using cMRI. Patients who have given informed consent will undergo a baseline cMRI and will then be randomly assigned in a 1:1 basis to either empagliflozin 10 mg once daily or matching placebo. An end of study cMRI will be performed at 26 weeks (6 months after starting the study drug). The study subjects will be followed for 6 months. The patients will be assessed using cMRI, which is considered the "gold standard" for measuring left ventricular (LV) volume, mass, and ejection fraction. The investigators will assess changes from baseline in LV mass, LV end-diastolic volume, end-systolic volume, LV ejection fraction, LV diastolic and systolic function, and LV wall stress via cMRI in enrolled patients treated with empagliflozin compared to those who receive placebo. Additionally, changes from baseline in blood pressure, hematocrit, and biomarkers involved in the pathophysiology of heart failure, namely NT-proBNP, will be evaluated at 6 months. Study assessments and potential adverse events reporting will be undertaken at each study visit.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cardiovascular Diseases, Left Ventricular Hypertrophy
Keywords
Cardiovascular disease, Cardiac Magnetic Resonance Imaging, Sodium-Glucose Transporter 2 Inhibitors

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
169 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Empagliflozin
Arm Type
Active Comparator
Arm Description
Single 10 mg tablet, administered orally once daily for 6 months
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Single 10 mg tablet, administered orally once daily for 6 months
Intervention Type
Drug
Intervention Name(s)
Empagliflozin
Other Intervention Name(s)
Jardiance
Intervention Description
Single oral tablet
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo tablet manufactured to mimic empagliflozin 10 mg tablet
Primary Outcome Measure Information:
Title
Left Ventricular (LV) mass
Description
Change in Left Ventricular (LV) mass (indexed to body surface area (BSA)) at 6 months. This will be measured using CMRI.
Time Frame
6 months
Secondary Outcome Measure Information:
Title
LV end-diastolic volume
Description
Change in LV end-diastolic volume (indexed to BSA) at 6 months. This will be measured using CMRI.
Time Frame
6 months
Title
LV end-systolic volume
Description
Change in LV end-systolic volume (indexed to BSA) at 6 months. This will be measured using CMRI.
Time Frame
6 months
Title
Left Ventricular Ejection Fraction (LVEF)
Description
Change in LVEF at 6 months. This will be measured using CMRI.
Time Frame
6 months
Title
LV wall stress
Description
Change in LV wall stress at 6 months. This will be measured using CMRI.
Time Frame
6 months
Title
LV systolic function
Description
Change in LV systolic function at 6 months. This will be measured using CMRI.
Time Frame
6 months
Title
LV diastolic function
Description
Change in LV diastolic function at 6 months. This will be measured using CMRI.
Time Frame
6 months
Title
NT-proBNP
Description
Change in circulating NT-proBNP at 6 months.
Time Frame
6 months
Title
Systolic and diastolic blood pressure
Description
Change in systolic and diastolic blood pressure at 6 months.
Time Frame
6 months
Title
Hematocrit
Description
Change in hematocrit at 6 months in patients.
Time Frame
6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Female Not of childbearing potential and male subjects ≥ 18 and ≤ 85 years of age (Women Not of childbearing potential are females who are permanently sterile or postmenopausal. Postmenopausal is defined as 12 consecutive months with no menses without an alternative medical cause or ≥6 weeks post-surgical bilateral oophorectomy prior to Screening.) ≥1 of the major criteria or ≥2 of the minor criteria below: Major criteria Increased LVMi of ≥96 g/m2 for women and ≥116 g/m2 for men (as calculated by echocardiogram); or LVMi ≥81 g/m2 for women and ≥85 g/m2 for men (as calculated by cMRI) ECG evidence of LV hypertrophy (as per the Sokolow-Lyon criteria) Structural heart disease defined as interventricular septal thickness or posterior wall thickness at end-diastole of ≥11 mm (as measured by 2D echocardiography or cMRI) Persistent hypertension (defined as office blood pressure ≥140/90 mmHg) despite being on ≥3 antihypertensive medications Minor criteria Prior history of a myocardial infarction (≥3 months ago) eGFR ≥30 and ≤60 mL/min/1.73 m2 (as measured by the CKD-EPI formula) Body mass index (BMI) ≥27 kg/m2 Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures Exclusion Criteria: Female subjects who are pregnant, lactating or of childbearing potential, or are pre-menopausal Known type 1 or type 2 diabetes Hemoglobin A1C (A1C) ≥6.5% eGFR <30 mL/min/1.73m2 Known history of severe liver disease (e.g. Child Pugh Class B or C) Known history of severe symptomatic untreated anemia in the last 3 months (e.g. hemoglobin < 90 g/L) History of ketoacidosis, or increased chance of developing diabetic ketoacidosis (DKA) e.g. patients who suffer from excessive vomiting, diarrhea, or sweating; subjects who are on a very low carbohydrate diet; or subjects who drink a lot of alcohol. Systolic blood pressure <95mmHg (as measured at the office/clinic visit) Subjects in whom coronary revascularization by either percutaneous coronary intervention or bypass surgery is being contemplated within the next 6 months, or who have undergone coronary revascularization in the prior 3 months Significant allergy or known intolerance to SGLT2is or any ingredient in the formulations Subjects currently experiencing any clinically significant or unstable medical condition that in the opinion of the investigator might limit their ability to complete the study, or to comply with the requirements of the protocol, including: dermatologic disease, hematological disease, pulmonary disease, hepatic disease, gastrointestinal disease, genitourinary disease, endocrine disease, neurological disease, and psychiatric disease Any malignancy not considered cured (except basal cell carcinoma of the skin). A subject is considered cured if there has been no evidence of cancer recurrence for the 5 years prior to screening Subjects who have participated in other interventional studies which may affect any of the primary or secondary outcomes of the study within 30 days of the screening visit Contraindications or inability to undergo magnetic resonance imaging such as severe obesity (e.g. weight >500 lbs) or the presence of metallic fragments, clips, or devices Known history of infiltrative cardiomyopathy such as cardiac amyloidosis or cardiac sarcoidosis Severe aortic stenosis Severe aortic regurgitation Severe mitral stenosis Severe mitral regurgitation Low voltage on ECG limb leads defined by the amplitude of the QRS complex in each limb lead ≤0.5 mV
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Subodh Verma, MD PhD
Organizational Affiliation
Unity Health Toronto
Official's Role
Principal Investigator
Facility Information:
Facility Name
Diagnostic Assessment Centre (AMS Diagnostics)
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M1S 4N6
Country
Canada
Facility Name
St. Michael's Hospital
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5B 1W8
Country
Canada
Facility Name
North York Diagnostic and Cardiac Centre
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M6B 3H7
Country
Canada
Facility Name
Chang Gung Memorial Hospital
City
Keelung
Country
Taiwan

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
36335517
Citation
Connelly KA, Mazer CD, Puar P, Teoh H, Wang CH, Mason T, Akhavein F, Chang CW, Liu MH, Yang NI, Chen WS, Juan YH, Opingari E, Salyani Y, Barbour W, Pasricha A, Ahmed S, Kosmopoulos A, Verma R, Moroney M, Bakbak E, Krishnaraj A, Bhatt DL, Butler J, Kosiborod MN, Lam CSP, Hess DA, Rizzi Coelho-Filho O, Lafreniere-Roula M, Thorpe KE, Quan A, Leiter LA, Yan AT, Verma S. Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial. Circulation. 2023 Jan 24;147(4):284-295. doi: 10.1161/CIRCULATIONAHA.122.062769. Epub 2022 Nov 6.
Results Reference
derived

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Empagliflozin and Cardiac Remodelling in People Without Diabetes

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