CHERISH (duCHennE caRdiomyopathy mItigation Sglt2 inHibitor)

About This Grant

PROJECT SUMMARY/ABSTRACT Duchenne muscular dystrophy (DMD) is a devastating X-linked skeletal and cardiac myopathy resulting from a defect in the gene coding for dystrophin. DMD myopathy leads to loss of ambulation, respiratory failure, cardiomyopathy (CM), and premature death. Since the discovery of the DMD gene nearly three decades ago, the field has been dominated by the expectation of a “cure”; this has not yet transpired. Gene therapies have been approved but the cardiac effects remain unknown. Supportive care advances have decreased death from respiratory failure but simultaneously unmasked the lethal and fully penetrant CM phenotype, which is now the leading cause of death in DMD. We have documented that DMD CM progresses from normal imaging to diastolic dysfunction with subtle strain abnormalities to manifest systolic dysfunction; these changes correspond pathologically with myocardial inflammation and progressive increase in myocardial fibrosis and fibrofatty infiltration. Guideline-directed medical therapy (GDMT) has become standard of care for patients with DMD, but individual response to these therapies is suboptimal and often only serves to minimally delay the inevitable progression to heart failure and early death. Sodium/glucose cotransporter-2 inhibitors (SGLT2i) have resulted in mortality benefits in adult CM patients. The mechanism of this beneficial effect is unknown. Several factors specific to DMD suggest that SGLT2i could have potential for DMD CM – 1) improved cardiac energetics and metabolism (specifically, switch from carbohydrate towards fatty acids, ketone bodies, and amino acids metabolism); 2) improved mitochondrial function and reduced oxidative stress; 3) anti-inflammatory; 4) myocardial fibrosis inhibition; 5) reduction in sarcoplasmic calcium leak; 6) improved sympathetic overdrive. Our prior work, funded by the NIH/NHLBI and the FDA, has created the DMD Cardiovascular Care Consortium (DMDCCC), a multi-center consortium of 9 institutions following over 1350 DMD patients. The primary goal of the DMDCCC is to discover surrogate outcome measures of CM for use in clinical trials and to leverage the DMDCCC infrastructure for future clinical trials for DMD CM. The central hypothesis of this proposal is that SGLT2 inhibition is safe and well-tolerated in DMD patients with early CM. Aim 1 will define the SGLT2i pharmacokinetic (PK) profile in pediatric DMD patients. Aim 2 will determine the safety and tolerability of SGLT2i in younger DMD patients with early CM. Aim 3 will evaluate the clinical efficacy and blood biomarker alterations as a result of SGLT2i therapy in DMD, with a goal of informing future, larger efficacy studies. This study performs a critical evaluation of the pharmacokinetics, safety, and tolerability of SGLT2i in DMD. The potential of SGLT2i’s in DMD is immense, but a more complete evaluation must be performed before equipoise is lost.