Understanding the Cardiovascular Benefits of the Anti-Diabetes Medication SGLT2 Inhibitors

Purpose/Objectives The EMPA-REG OUTCOME (NCT01131676) trial demonstrated that SGLT2
(sodium-glucose co-transporter) inhibition with empagliflozin markedly reduced cardiovascular
(CV) mortality and hospitalization for heart failure. In diabetic patients treated with SGLT2
inhibitors, a rise in plasma ketone concentration consistently has been observed. This has
led to the "ketone hypothesis" in which a shift from glucose/FFA (Free Fatty Acids) to ketone
utilization by the heart results in enhanced left ventricular systolic/diastolic function and
could, at least in part, explain the reduction in CV mortality and hospitalization for heart
failure observed in the EMPA-REG OUTCOME trial.

Methods 36 type 2 diabetic subjects with New York Heart Association (NYHA) Class II-III heart
failure and ejection fraction less than 50% will be studied. Eligible subjects will undergo a
baseline cardiac MRI to obtain quantitative measures of baseline cardiac functional
parameters: chamber volumes and pressures, wall thickness, LV diastolic function (E/A ratio,
peak LV filling rate, diastolic volume), LV systolic function (cardiac output, stroke volume,
systolic volume, peak LV ejection rate). Baseline samples will be drawn for measurement of
N-terminal pro-brain natriuretic peptide (NT-proBNP) , B-OH-butyrate, acetoacetate, glucose,
FFA, lactate, pyruvate, glycerol, HCO3 (bicarbonate), insulin, glucagon, renin and
aldosterone. Following completion of the baseline MRI and blood samples, subjects will be
divided into three groups (12 subjects per group). Each group will receive a 6-hour (3-hour
in group III) prime-continuous infusion of racemic B-OH-B (100 mg/mL solution; pH adjusted to
7.4) to increase the plasma B-OH-B concentration by ~0.5, ~2.0, and ~5.0 mmol/L. At the end
of the infusion the MRI will be repeated. As a time control GROUP II subjects will receive a
continuous infusion of sodium bicarbonate (0.12 M) for 6 hours (0.08 mg/kg/min) to mimic the
rise in plasma bicarbonate concentration observed with B-OH-B infusion. Group II will return
again to the RII (UT Health Research Imaging Institute) on a separate day for a cardiac
positron emission tomography (PET) study to examine the effect of hyperketonemia on
myocardial glucose uptake and blood flow. In ~14 days subjects will return for a repeat
PET/18F-2-DOG (deoxyglucose) study with one exception: NaHCO3 (Sodium bicarbonate) will be
infused instead of B-OH-B. The two studies will be performed in random order.

Inclusion Criteria:

1. Type 2 diabetes.

2. Class II-III New York Heart Association (NYHA) heart failure with ejection fraction
less than 50 %.

3. Age 30-70 years.

4. BMI 23-28 kg/m2.

5. 18 males/18 females.

6. HbA1c 6.0-9.0 %.

7. Blood pressure < 145/85 mmHg.

8. eGFR > 45 mL/min/1.73 m2.

9. NT-proBNP ≥ 500 pg/mL (or ≥ 300 pg/mL if ejection fraction is less than 35 %).

Exclusion Criteria:

1. Treatment with Glucagon-like peptide-1 receptor agonist (GLP-1 RA), Dipeptidyl
peptidase-4 inhibitors (DPP4i), pioglitazone, SGLT2 inhibitor or insulin.

2. Women who are pregnant or breastfeeding.

3. Contraindications for MRI include metal plates, parts, screws, shrapnel, pins in the
body, or cardiac pacemaker.

4. Any other condition that in the opinion of the investigator create a hazard to the
subject safety, endanger the study procedures or interfere with the interpretation of
study results.