What Makes a Successful Heart Failure Drug Work?

SGLT2 inhibitors help the body remove excess glucose through the kidney and into the urine, which creates a diuretic effect. Although this class of drug was initially developed to control diabetes, clinical research soon showed that these drugs are also highly effective at preventing heart failure.

“From a diabetes perspective, we understand how these drugs work, but we were all surprised when clinical studies showed that they also had a cardioprotective effect,” said Gerald Shulman, MD, PhD, George R. Cowgill Professor of Medicine (Endocrinology) and Cellular & Molecular Physiology and investigator emeritus of the Howard Hughes Medical Institute.

Today, experts consider SGLT2 inhibitors the cornerstone of treatment for heart failure. These drugs also represent the first class to demonstrate a clear benefit for patients with heart failure with preserved ejection fraction.

“SGLT2 inhibitors are a revolutionary class of drug,” said Lawrence Young, MD, professor of medicine (cardiovascular medicine) and cellular & molecular physiology. “They are highly effective—yet we do not fully understand how they work.”

Over the past few decades, researchers have proposed multiple hypotheses for how SGLT2 inhibitors protect the heart. However, there has not been a consensus on how they work.

Young and Shulman and other researchers, including former Yale fellow Leigh Goedeke, PhD, now an assistant professor of medicine at Icahn School of Medicine at Mount Sinai, aimed to investigate and understand how these drugs protect the heart.

“If you understand how a drug works, it opens up new opportunities to develop even better drugs that more directly target that mechanism,” said Shulman.

Their new paper, published in The Journal of Clinical Investigation, sheds some light on how SGLT2 inhibitors work to protect the heart.

Using an integrated and highly sophisticated clinical, physiologic approach, the researchers were able to dissect specific pathways of mitochondrial substrate oxidation within the heart muscle.

They discovered that this class of drugs induces a significant shift in the type of fuels the heart uses for energy, particularly through mitochondrial oxidation.

“Our research finds SGLT2 inhibitors have multiple effects on systemic and heart metabolism that are likely responsible for the beneficial effect in heart failure,” said Shulman. “This is very different from what other researchers previously hypothesized.”

“Our paper doesn’t have all of the answers, but it starts to fill in pieces of the puzzle and increase our knowledge of how these drugs work,” Young added. “The next step is to take the research into human studies to see if evidence supports that these findings are also valid in people.”

The researchers are also applying the methods developed for this study to other conditions, including atrial fibrillation, which can lead to heart failure, strokes, and other adverse health outcomes.

The study includes contributions from several Yale laboratories in the fields of endocrinology, cardiovascular medicine, and cellular and molecular physiology.

“Many of us at Yale have been interested in the interface between metabolism and cardiovascular disease,” said Young. “We are fortunate to have a strong and fruitful collaboration within the university to tackle this complex challenge.”

This study is just the most recent example of this ongoing, multidisciplinary collaboration on the relationship between metabolism and the cardiovascular system. Young and other researchers at Yale collaborated on the IRIS study, a large, National Institutes of Health (NIH)-funded clinical study, which was one of the first to demonstrate that metabolic therapies can benefit both metabolism and the cardiovascular system.

“We are finding that liver and muscle insulin resistance, due to ectopic lipid accumulation in these organs, promotes cardiac dysfunction, heart failure, fatty liver disease, Alzheimer’s disease, and more,” Shulman said. “By bringing together experts in cardiology, endocrinology, and hepatology, we will be able to better understand how to make progress on these interrelated health challenges.”

Additional authors include Yina Ma, Rafael C. Gaspar, PhD, Ali Nasiri, Jieun Lee, Dongyan Zhang, Katrine Douglas Galsgaard, Xiaoyue Hu, Jasheng Zhang, MD, Nicole Guerrera, Xiruo Li, PhD, Traci LaMoia, Brandon Hubbard, Sofie Haedersdal, MD, PhD, Xiaohong Wu, John Stack, Sylvie Dufour, Gina Marie Butrico, Mario Kahn, Rachel Perry, PhD, and Gary Cline, PhD.

The research reported in this news article was supported by the National Institutes of Health (awards R00HL150234, R01DK119968, UC2DK134901, P30DK045735, R01HL148008, and R01HL148344). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The work was also supported by an investigator-initiated award from Astra-Zeneca.

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