# SGLT-inhibitors in patients with hypertrophic cardiomyopathy

> **NIH NIH R33** · UNIVERSITY OF PENNSYLVANIA · 2024 · $666,796

## Abstract

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 essentia...

## Key facts

- **NIH application ID:** 10923375
- **Project number:** 4R33HL164376-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Sharlene M Day
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $666,796
- **Award type:** 4N
- **Project period:** 2023-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10923375

## Citation

> US National Institutes of Health, RePORTER application 10923375, SGLT-inhibitors in patients with hypertrophic cardiomyopathy (4R33HL164376-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10923375. Licensed CC0.

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