A groundbreaking study led by scientists at Temple University’s Lewis Katz School of Medicine solves a long-standing mystery about why a class of diabetes drugs also reduces risk of death from heart failure.
The drugs, known as sodium-glucose cotransporter 2 (SGLT2) inhibitors, originally were developed to lower blood glucose by causing the kidneys to excrete more sugar. Yet they also dramatically reduce hospitalization and death from heart failure in people with and without diabetes—a benefit that has remained difficult to explain because their intended target, the SGLT2 enzyme, is not found in the heart.
“SGLT2 expression is limited to a region of the kidney where blood is filtered to remove and recycle nutrients and wastes,” explained Dr. Nathaniel Snyder, PhD, professor in the Aging + Cardiovascular Discovery Center in the Department of Cardiovascular Sciences at the Lewis Katz School of Medicine and one of the study’s senior investigators. “In this single part of the kidney, SGLT2 acts like a gatekeeper, allowing sugar to be taken back up into the blood.”
Published online August 27 in the journal Science, the new study shows that SGLT2 inhibitors also directly activate pantothenate kinase 1 (PANK1), an enzyme that controls the production of coenzyme A (CoA)—a molecule essential for energy metabolism in heart muscle cells.
The discovery opens a new avenue for developing more effective treatments for heart failure.
Carried out by collaborating research teams led by Dr. Snyder at Temple University and by senior author Dr. Zoltan Arany, MD, PhD, professor of physiology at the University of Pennsylvania’s Perelman School of Medicine, the study examined the effect of SGLT2 inhibitors initially using human hearts donated from heart transplant recipients. Using stable isotope infusions, the researchers detected sharp accelerations in heart muscle cell intake of pantothenate (vitamin B5), alongside increases in the use of multiple metabolic fuels, following SGLT2 perfusion. This observation led to the idea that a common biochemical denominator may serve to control major pathways of fuel consumption by the heart.
After measuring levels of various metabolic intermediates, the researchers discovered a massive spike in CoA levels, and analyses of enzymes responsible for synthesizing CoA from vitamin B5 brought them to PANK1. Through advanced simulation modeling, it was further revealed that SGLT2 inhibitors nestle into a specific site on PANK1 that blocks the enzyme’s natural “off switch,” thus causing it to remain continuously active. This state results in a substantial increase in CoA synthesis, which in turn stimulates the heart to use more metabolic fuels and thereby strengthens heart cell contraction.
“The failing human heart has been thought of as energy-starved and is lower in CoA metabolites,” Dr. Snyder said. “The drugs were somehow rescuing this deficiency, and it was through luck that we discovered that the mechanism centers on PANK1. Our findings explain why heart failure patients experience such significant improvements in survival with SGLT2 inhibitors.”
The research moreover points to PANK1 as a possible target for developing new heart-failure therapies. “The most effective route to improving survival in heart disease may be through the generation of novel PANK1 inhibitors and restoration of the heart’s energy-producing capacity,” Dr. Snyder added. “It may also be possible to repurpose SGLT2 inhibitors to improve survival outcomes for other cardiovascular and rare diseases.”
Other researchers who contributed to the study include Nicholas Forelli, Trace Thome, Deborah M. Eaton, Kollin Schultz1, Jiten Patel, Caitlyn E. Bowman, Ryo Kawakami, Jae Woo Jung, Ivan A. Kuznetsov, Kristina Li, Jialiu A. Liang, Kirsten Branch, Claire Brady, Kenneth C. Bedi Jr., Yijun Yang, Kaustubh Koya, Nesrine Bouhrira, and Kenneth B. Margulies at the Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia; Emily Megill and Daniel S. Kantner in the Aging and Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University; Louis G. Smith, Cristin F. MacIntosh, Kushol Gupta, and Gregory R. Bowman at the Department of Biochemistry and Biophysics, Perelman School of Medicine; and Jonathan Edwards in the Division of Cardiology, Cardiovascular Institute, Children’s Hospital of Philadelphia.
The research was supported in part by funding from the National Institutes of Health and a DreamTeam grant from the Penn Cardiovascular Institute and the Children’s Hospital of Philadelphia Frontier Program.