University of Pennsylvania scientists uncover a direct metabolic mechanism by which SGLT2 inhibitors like empagliflozin enhance heart function, challenging traditional views and opening new therapeutic avenues for heart failure treatment.
Researchers at the University of Pennsylvania say they have found a plausible explanation for one of cardiology’s most persistent puzzles: why SGLT2 inhibitors such as empagliflozin deliver striking heart benefits even though the drugs were originally designed to lower blood sugar through the kidneys. The new work, published in Science and summarised in the supplied materials, suggests the drugs act directly on human heart tissue rather than solely through their glucose-lowering effects. That adds a fresh layer to a class of medicines long known to reduce heart-failure hospitalisations and cardiovascular deaths, including in people without diabetes.
For years, clinicians have known that the cardioprotective effects of SGLT2 inhibitors extend well beyond their original role in type 2 diabetes. A National Library of Medicine review notes that these drugs work in the kidney by blocking glucose reabsorption, but heart-failure benefits have also been linked to changes in fluid balance and blood pressure. A separate Nature Reviews Cardiology article says earlier theories increasingly pointed to wider metabolic effects in the failing heart, including improved mitochondrial function and altered nutrient handling.
The Penn team’s new interpretation is more specific. Using perfused human heart tissue from transplant recipients and donor hearts, the researchers report that empagliflozin increased the uptake of ketones, lactate and branched-chain amino acids, while raising cellular energy stores. Their analyses pointed to pantothenate kinase 1, or PANK1, an enzyme that helps cells make coenzyme A, a crucial molecule for burning fuels. According to the paper summary, empagliflozin binds directly to PANK1 and appears to switch the enzyme into a more active form, thereby helping starved heart muscle restore energy production. The same effect was reported for other drugs in the class, including dapagliflozin and canagliflozin.
The findings could help reconcile why these medicines work so well in heart failure even when the heart itself does not express SGLT2. In single-cell experiments, empagliflozin also improved contraction and relaxation in failing human heart cells, effects that disappeared when the downstream coenzyme A pathway was blocked. The authors and secondary summaries say the work strengthens the case that SGLT2 inhibitors have a direct metabolic action in the heart, though the broader clinical significance of that mechanism still needs to be confirmed in patients.
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