Research News

Pulmonary arterial hypertension (PAH) is a rare and deadly condition that kills 40% of patients within five years of diagnosis, mostly due to right heart failure. All approved PAH drugs target the lungs, not the heart. In a future national multi-site Phase 2 clinical trial, a Cleveland Clinic team will test a medication to target the right heart for the first time.

Both the Clinical Coordinating Center (led by pulmonologist and researcher Gustavo Heresi, MD) and Data Coordinating Center (led by biostatistician and trialist Jennifer Gassman, PhD) will be run through Cleveland Clinic. The National Heart, Lung, and Blood Institute has awarded two separate grants to support this work over six years, totaling $6.1 million. The trial’s aim will be to test the effects of the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin on patients with PAH. Empagliflozin is currently used as a treatment for diabetes and for left heart failure. Based on previous work done by the study team showing metabolic dysfunction in PAH, the hypothesis is that empagliflozin will work for treating right heart failure as well. 

After 20 years of treating PAH patients and delivering devastating prognoses, Dr. Heresi felt it imperative to find a drug that targets the disease’s effects on the heart to improve symptoms and life expectancy. He says the reason he chose to investigate empagliflozin is because of its proven success as a treatment for managing left heart failure and its ability to modulate key metabolic pathways dysregulated in heart failure.

“The research I’ve conducted over the past 15 years shows that metabolic abnormalities are very common in PAH — worsening the function of the heart and severely impacting the patient’s quality of life and survival,” Dr. Heresi says. “I strongly believe there’s a direct connection between those related properties of the medication and its ability to improve right heart failure.” 

Dr. Heresi believes this medication would also help lessen the common symptoms of PAH, including shortness of breath and fluid retention — symptoms which are caused by the gradual failure of the right heart.  

Vanderbilt University Medical Center and Johns Hopkins Medical Center are other planned sites for the trial. 

“It’s extremely important that we were able to secure the involvement of Vanderbilt and Johns Hopkins for this trial,” Dr. Gassman says. “A trial’s results are more credible if we can show that the treatment works not only here at the Cleveland Clinic, with our patients and clinical team, but in other locations like Nashville and Baltimore, with their different patient populations and clinical teams.” 

A collaborative effort to test a hypothesis  

The clinical trial will include experts from multiple teams throughout the Cleveland Clinic — growing exponentially since Dr. Heresi sent his first email regarding his idea three years ago. Deborah Kwon, MD; Christopher Nguyen, PhD; and Christine Jellis, MD, PhD are leading cardiac imaging. The Data Coordinating Center is led by Dr. Gassman and also includes Data Coordinating Center clinical investigator Samar Farha, MD; Suzy Comhair, PhD, who will lead the study biorepository; and Bo Hu, PhD, who will lead statistical analyses. The Clinical Coordinating Center and Data Coordinating Center are supported by separate grants — $3,816,072 and $2,174,455 respectively.

To test Dr. Heresi’s hypothesis, Dr. Gassman — a biostatistician and trialist who has been designing trials for 30 years — worked with Dr. Heresi to develop a randomized, triple-masked, parallel arm Phase 2 clinical trial of empagliflozin versus placebo that will include PAH patients who are experiencing right heart failure and are already on existing PAH therapeutic drugs that target the lungs. Dr. Hu determined the sample size needed to answer the study question and developed the statistical analysis plan for the trial.  After each patient has 24 weeks on their study medication, the team will determine the patient’s change in right heart function via cardiac MRI. Cardiac MRI is considered the gold standard for assessment of the function of the right heart, Dr. Heresi says, but has been very rarely used in clinical trials. 

The trial benefits from having a single, specified expert who will read all trial MRIs (Dr. Kwon) and another to read in all the echocardiograms (Dr. Jellis). This is great for ensuring standardization of measurements across the trial, Dr. Gassman explained. 

Dr. Heresi found it fascinating to witness the collaboration between the various teams throughout the institution, describing “a puzzle that fits together seamlessly.”  

“Working with Dr. Gassman has been amazing. We complement each other perfectly,” says Dr. Heresi. “I think it’s an asset that we have very little overlap in skills and expertise — I'm an expert in pulmonary vascular disease and right heart failure, and Dr. Gassman has this deep experience running clinical trials. Her team was critical in ensuring the trial’s integrity, safety, reliability and accuracy. Without them, we wouldn't have been able to get the funding.” 

At the end of the next six years, Dr. Heresi says he’s optimistic that empagliflozin will be part of his PAH patients’ standard of care, and at a low cost compared to the expensive therapies available to them currently — which can run up to $500,000 a year for just one medication.  

“Assuming we have a successful trial testing this medication, I expect significant improvements in PAH patients’ symptoms, quality of life and, critically, the function of their right heart. Put simply, it hopefully will prolong their lives,” Dr. Heresi says.