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.
Source: View full study details on ClinicalTrials.gov
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