SGLT2 Inhibitor Shows Promise as a Treatment for PLN Cardiomyopathy

March 16, 2026

Heart failure can come from many causes, but for patients with phospholamban (PLN) cardiomyopathy, the disease is driven by a specific genetic mutation. This mutation can progressively weaken the heart muscle and increase the risk of dangerous arrhythmias and sudden cardiac death. A new study from researchers at the Stanford Cardiovascular Institute, led by first authors Anna Hnatiuk and Alexander Li, with senior author Mark Mercola, suggests that a widely used diabetes drug (empagliflozin) may offer a promising new therapeutic strategy for this devastating condition.

PLN cardiomyopathy is caused by mutations in the phospholamban (PLN) gene, which controls calcium cycling inside the heart muscle. Calcium movement controls how heart cells contract and relax with each beat. One of the most severe forms of PLN cardiomyopathy comes from a mutation called PLN-R14del, a small deletion in the gene that disrupts normal calcium handling. Over time, this leads to dilated cardiomyopathy, arrhythmias, heart failure, and a high risk of sudden cardiac death.

There are currently no therapies that directly target the underlying disease mechanism of PLN-R14del cardiomyopathy. Instead, patients receive treatments to manage symptoms, such as medications for heart failure, implantable defibrillators, or even heart transplantation. Finding a therapy that directly addresses the underlying mechanism is of critical importance for patients with PLN-R14del cardiomyopathy, with the potential to significantly improve their quality of life.

The team of Cardiovascular Institute researchers considered that SGLT2 inhibitors could be a potential therapy. SGLT2s are a class of drugs originally developed to treat type 2 diabetes. Interestingly, SGLT2s have shown unexpected cardiovascular benefits. Clinical trials have demonstrated that they reduce hospitalization for heart failure and lower cardiovascular mortality, even in patients without diabetes, suggesting they have protective effects on the heart beyond glucose control.

One SGLT2 inhibitor, empagliflozin, has been shown to improve calcium handling and reduce activity of CaMKII, a signaling enzyme linked to heart dysfunction and arrhythmias. Because abnormal calcium signaling and CaMKII activity are hallmarks of PLN cardiomyopathy, the researchers hypothesized that empagliflozin might counteract some of the cellular defects caused by the PLN-R14del mutation.

To test this idea, the researchers used induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) with the PLN-R14del mutation, along with genetically matched control cells. The mutant iPSC-CMs showed the expected disease features, including reduced contractile strength and abnormal calcium cycling, showing the impaired ability of these cells to properly handle calcium.

The researchers conclude that empagliflozin represents a promising candidate for treating PLN cardiomyopathy, though additional studies will be needed to confirm the findings in more complex systems such as cardiac organoids, animal models, and eventually clinical trials. If successful, this approach could provide the first therapy aimed at modifying the underlying disease process rather than simply managing symptoms.

Other Stanford Cardiovascular Institute authors are Barbara Vecci, David Staudt, Ricardo Serrano, Xiaozhi Gao, and Peter Tran. Support and funding for this project was provided by the Foundation Leducq Transatlantic Alliance (CurePLaN), Phospholamban Foundation, Boehringer Ingelheim Fonds MD-Fellowship, and the NIH (R01HL130840, R33HL167258, P01HL141084, and K99CA2799895).