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

The EMMED-HF Study: Evaluating Metabolic Mechanisms of Ertugliflozin in Diabetes & Heart Failure

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.

Study Overview

• Status: Terminated
• Conditions: Diabetes Mellitus, Type 2; Heart Failure, Diastolic
• Intervention / Treatment: Drug: Ertugliflozin 5 mg; Drug: Placebo oral tablet

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 Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak VO2, ml/kg/Min, as Measured by Metabolic Gas Exchange	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	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left Ventricular Mass Index (gm/m2), as Measured by Cardiac MRI	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	12 weeks
Serum Ketone Bodies (Betahydroxybutyrate)	The difference in serum ketone bodies (betahydroxybutyrate) levels between ertugliflozin and placebo as measured at baseline and after 12 weeks of treatment	12 weeks

Collaborators and Investigators

• Sponsor: University Hospitals Cleveland Medical Center
• Investigators: Principal Investigator: Trevor L Jenkins, MD, University Hospitals Cleveland Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2020
• Primary Completion (Actual): January 11, 2023
• Study Completion (Actual): January 11, 2023

Study Registration Dates

• First Submitted: August 26, 2019
• First Submitted That Met QC Criteria: August 26, 2019
• First Posted (Actual): August 28, 2019

Study Record Updates

• Last Update Posted (Estimated): December 13, 2023
• Last Update Submitted That Met QC Criteria: December 11, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Cardiovascular Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Physiological Effects of Drugs; Glucose Metabolism Disorders; Endocrine System Diseases; ertugliflozin; SGLT2 inhibtion; Sodium-Glucose Transporter 2 Inhibitors
• 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; Ertugliflozin
• Other Study ID Numbers: STUDY20190016

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No