SGLT-inhibitors in patients with hypertrophic cardiomyopathy

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Project summary Patients with hypertrophic cardiomyopathy (HCM) experience a progressive disease course and bear a substantial symptomatic burden, marked by heart failure, atrial and ventricular arrhythmias and early mortality. Patients with symptomatic HCM, but without obstruction of the left ventricular outflow tract (so-called non- obstructive HCM), are a particular challenge to manage, as no treatments have proven effective at improving symptoms or impacting the trajectory of disease progression. This proposal will focus on sodium-glucose cotransporter 2 inhibitors (SGLT2i) as a potential therapeutic option for non-obstructive HCM. Initially developed as hypoglycemic drugs to treat type-2 diabetes mellitus (T2DM), SGLT2i unexpectedly conferred a remarkable cardioprotective benefit with robust reductions in cardiovascular mortality and hospitalizations for heart failure, irrespective of diabetic status or ejection fraction. While the mechanisms of action by which SGLT2i are exerting such beneficial cardiovascular effects are still unclear, an improvement in cardiac energetics has been proposed as one plausible mechanism based on evidence for increased cardiac ketone oxidation and ATP content in preclinical models of heart failure. The overall goal of this study is to determine the safety, feasibility, and preliminary efficacy of SGLT2i in patients with non-obstructive HCM. The rationale for conducting this study is based on the similarities between non-obstructive HCM and heart failure with preserved ejection fraction, and also the unique structural and functional features of HCM that make an early phase trial essential before implementation of larger phase clinical trials or adoption of “off label” use. We will perform a randomized, double-blind, cross-over study of the SGLT2i dapagliflozin vs placebo in 26 patients with non-obstructive HCM and ejection fraction >50%. Our primary safety outcomes will be rhythm monitoring and intracavitary left ventricular gradients assessed by echocardiography. Our preliminary efficacy endpoints will be change in peak oxygen consumption (VO2), left ventricular systolic and diastolic function by echocardiography, NT-proBNP, ambulatory actigraphy, and quality of life assessment. In an exploratory aim, we will test whether SGLT2i improve cardiac energetics in HCM using 31P-MR spectroscopy to quantify relative amounts of myocardial energy stores, specifically phosphocreatine and ATP. This early phase study seeks to extend the marked cardiovascular benefits of SGLT2i recently demonstrated for heart failure with reduced and preserved ejection fraction, to patients with HCM. The study team includes investigators with a strong track record in early phase clinical trials in HCM, at a high volume HCM center at the University of Pennsylvania, in collaboration with experienced clinician investigators in endocrinology and radiology at the Children's Hospital of Pennsylvania. The results of this study will provide essential preliminary data to determine if larger scale clinical trials of SGLT2i in HCM should be pursued, and explore a shift in metabolic substrate utilization as a potential mechanism of action of conferred benefit.