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Evaluating Metabolic Mechanisms of Ertugliflozin in Diabetes & Heart Failure (EMMED-HF)

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ClinicalTrials.gov Identifier: NCT04071626
Recruitment Status : Recruiting
First Posted : August 28, 2019
Last Update Posted : January 3, 2022
Sponsor:
Information provided by (Responsible Party):
Trevor Jenkins, University Hospitals Cleveland Medical Center

Study Description
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Brief Summary:
This clinical trial will determine if subjects with heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes mellitus (DM2) receiving sodium-glucose cotransporter 2 (SGLTi2) inhibitor therapy (ertugliflozin) alters cardiac metabolism compared to placebo in a single blinded (to subject), randomized, parallel group, active controlled, single center experimental design.

Condition or disease Intervention/treatment Phase
Heart Failure, Diastolic Diabetes Mellitus, Type 2 Drug: Ertugliflozin 5 mg Drug: Placebo oral tablet Phase 4

Detailed Description:

The results of recent sodium-glucose cotransporter 2 (SGLT2) inhibitor therapy clinical trials demonstrate clinically significant reductions in cardiovascular endpoints (myocardial infarction, cardiac death, heart failure hospitalization). SGLT2 inhibition appears to exert cardiovascular protection through pleiotrophic effects involving both the myocardium and peripheral organs but the primary pathway of risk reduction of heart failure incidents has not been elucidated. SGLT2 inhibitors induce a loss of 50-100 grams of glucose through urinary excretion daily. There is a compensatory increase in ketone body production in the liver after initiation of SGLT inhibition. Ketone bodies are the most energy efficient myocardial fuel source and reduce myocardial oxidative stress when consumed as the primary energy substrate. Inducing a shift to ketone body metabolism to improves cardiac diastolic performance suggests a unifying paradigm of direct myocardial effect and peripheral metabolic flexibility through which SGLT2 inhibition mediates myocardial protection in HFpEF.

Specific Aims Aim 1: Determine if 12 weeks of SGLTi2 therapy improves peak exercise oxygen uptake compared to placebo. We will perform cardiac MRI exercise testing (CPET-ExMR) before and & post 12 weeks of therapy to measure cardiopulmonary fitness by metabolic cart gas exchange and left ventricular myocardial mass.

Aim 2: Evaluate the short term (12 weeks effect of SGLTi on metabolic flexibility in HFpEF compared to baseline function and control group. We will measure glucose and lipid metabolism response to SGLT2 inhibition. Serum samples of glucose and ketone bodies (β-hydroxybutyrate) will be assessed before & post 12 weeks of therapy. Serial serum samples will allow us to generate metabolomics profiles before and after treatment. This experimental design will provide insight into ketone body production, peripheral glucose flux, and circulating lipoparticles in response to SGLTi therapy.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 52 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Parallel assignment, active controlled, single center experimental design.
Masking: Double (Participant, Care Provider)
Masking Description: Single-blind study
Primary Purpose: Treatment
Official Title: The EMMED-HF Study: Evaluating Metabolic Mechanisms of Ertugliflozin in Diabetes & Heart Failure
Actual Study Start Date : March 1, 2020
Estimated Primary Completion Date : June 30, 2023
Estimated Study Completion Date : June 30, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

Arms and Interventions
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Arm Intervention/treatment
Experimental: Ertugliflozin Treatment Arm
Ertugliflozin 5 mg tablet once a day for 12 weeks
 Drug: Ertugliflozin 5 mg
Ertugliflozin 5 mg once a day for 12 weeks
Placebo Comparator: Placebo
Placebo tablet once a day for 12 weeks
 Drug: Placebo oral tablet
Placebo oral tablet once a day for 12 weeks


Outcome Measures
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Primary Outcome Measures :
  1. Peak VO2, ml/kg/min, as measured by metabolic gas exchange [ Time Frame: 12 weeks ]
    The difference in peak oxygen uptake as measured by peak VO2 (ml/kg/min) between ertugliflozin and placebo as measured at baseline and after 12 weeks of treatment


Secondary Outcome Measures :
  1. Left ventricular mass index (gm/m2), as measured by cardiac MRI [ Time Frame: 12 weeks ]
    The difference in LV mass index (gm/m2) measured by cardiac MRI between ertugliflozin and placebo as measured at baseline and after 12 weeks of treatment

  2. Serum ketone bodies (betahydroxybutyrate) [ Time Frame: 12 weeks ]
    The difference in serum ketone bodies (betahydroxybutyrate) levels between ertugliflozin and placebo as measured at baseline and after 12 weeks of treatment


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age > 18 years old but < 75 years old
  • No HF hospitalization within 6 months
  • Overweight or Obesity defined as BMI > 29 but < 42
  • History of insulin resistance or T2DM and on oral diabetes agents other than SGLT2i (HgbA1c > 5.8% and < 10.5%)
  • EF calculated based on a recent echo/cath/nuclear study at screening (pre-enrollment) > 50%
  • Stable HFpEF (HF with preserved ejection fraction) medications use of 3 months with no plans to changes or add medications for at least 12 weeks course of the study)

Exclusion Criteria:

  • Acute HFpEF hospitalization within 6 months of enrollment.
  • CKD stage 4 or 5 (eGFR < 30 ml/min by CKD-EPI equation).
  • Other known causes of HF including poorly controlled hypertension (SBP >160 mm Hg) or ischemic cardiomyopathy (etc).
  • Anemia (Hgb < 11.0 mg/dL for women and < 12.0 mg/dL for men) or severe thrombocytopenia (platelets < 50,000 mm3)
  • Anticipated changing of HF medication during anticipated study period.
  • HFREF (LV EF < 50%).
  • Acute coronary syndrome, transient ischemic attack, CVA or critical limb ischemia during the last 6 months or coronary/peripheral revascularization within the last 3 months. Severe life threatening illness or live expectancy < 6 months.
  • Contraindications to MRI (metallic implants, severe claustrophobia) or treadmill exercise (limb amputation, severe osteoarthritis or equivalent functional mechanical limitation).
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04071626


Contacts
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Contact: Trevor L Jenkins, MD 2168441229 trevor.jenkins@uhhospitals.org
Contact: Heather Conger, RN 216-286-6550 Heather.Conger2@UHhospitals.org

Locations
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United States, Ohio
University Hospitals Cleveland Medical Center Recruiting
Cleveland, Ohio, United States, 44106
Contact: Heather Conger, BSN RN    216-286-6550    Heather.Conger2@uhhospitals.org   
Contact: An Dever, BSN RN    216-286-5038    Ann.Dever@uhhospitals.org   
Sponsors and Collaborators
University Hospitals Cleveland Medical Center
Investigators
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Principal Investigator: Trevor L Jenkins, MD University Hospitals Cleveland Medical Center
More Information
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Responsible Party: Trevor Jenkins, Assistant Professor of Medicine, Department of Medicine, Case Western Reserve University / UH Cleveland Medical Center, University Hospitals Cleveland Medical Center
ClinicalTrials.gov Identifier: NCT04071626    
Other Study ID Numbers: MISP 58605
First Posted: August 28, 2019    Key Record Dates
Last Update Posted: January 3, 2022
Last Verified: December 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Trevor Jenkins, University Hospitals Cleveland Medical Center:
ertugliflozin
SGLT2 inhibtion
Cardiovascular Diseases
Sodium-Glucose Transporter 2 Inhibitors
Glucose Metabolism Disorders
 Physiological Effects of Drugs
Diabetes Mellitus
Diabetes Mellitus, Type 2
Endocrine System Diseases
Additional relevant MeSH terms:
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Heart Failure
Heart Failure, Diastolic
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
 Heart Diseases
Cardiovascular Diseases
Ertugliflozin
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs