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.

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.

Eligibility 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).