Few drug classes in modern cardiology have generated as much astonishment as the sodium–glucose cotransporter 2 inhibitors, the diabetes pills that turned out to be powerful heart medicines. Originally designed to flush excess glucose out of the bloodstream through the urine, these agents dramatically reduced hospitalizations and deaths in patients with heart failure across multiple landmark trials. Yet the magnitude of the benefit consistently outpaced what glucose control alone could explain, and even the celebrated ketone hypothesis, in which the drugs push the heart toward burning ketone bodies as an alternative fuel, has failed to account for the full spectrum of cardioprotection. A new commentary published in Nature Reviews Cardiology by Alessia Riccio and Gaetano Santulli now spotlights a discovery that may finally fill the mechanistic gap: SGLT2 inhibitors appear to act directly on the failing heart by activating an enzyme called pantothenate kinase 1, or PANK1, thereby restoring the production of coenzyme A, one of the most fundamental molecules in cellular metabolism.
The significance of coenzyme A in cardiac biology is difficult to overstate. This small, vitamin B5-derived cofactor sits at the crossroads of virtually every energy-generating pathway in the cell, shuttling acyl groups into the mitochondria for fatty acid oxidation, feeding the tricarboxylic acid cycle, and enabling the synthesis and breakdown of countless metabolites. Without adequate coenzyme A, the heart’s metabolic machinery grinds toward inefficiency. In the failing heart, a condition long recognized as one of profound metabolic inflexibility, the supply and utilization of this cofactor become compromised, leaving cardiomyocytes unable to fully exploit the fuels available to them. The failing heart, in this sense, is not merely an overworked pump but an energy-starved engine running on a degraded fuel system.
The pivotal evidence comes from a study by Forelli and colleagues published in Science in 2026, which demonstrated that SGLT2 inhibitors activate pantothenate kinase in the human heart. Pantothenate kinase is the first and rate-limiting enzyme of the coenzyme A biosynthesis pathway, the molecular gatekeeper that controls how much coenzyme A the cell can manufacture from pantothenate, the dietary precursor better known as vitamin B5. By stimulating PANK1, the drugs effectively reopen this gate, boosting coenzyme A availability and, with it, the myocardial metabolic capacity that heart failure erodes. Riccio and Santulli emphasize that PANK1 should now be considered a direct cardiac target of SGLT2 inhibitors, a designation that reframes how the field thinks about these drugs entirely.
What makes this finding particularly provocative is its independence from the drug’s canonical target. SGLT2, the glucose transporter in the kidney that gives the class its name, is barely expressed in cardiomyocytes, which has long puzzled researchers trying to explain why the heart benefits so much. Recent work has reinforced this disconnect: a 2024 study in Circulation Research showed that SGLT2 inhibitors confer benefit in mouse models of heart failure with reduced ejection fraction even in the absence of SGLT2, and a 2026 study in Metabolism identified early metabolic cardiac targets of empagliflozin that operate independently of SGLT2 inhibition. The PANK1–coenzyme A axis now emerges as one of the most concrete candidates for these SGLT2-independent actions, offering a direct biochemical route from drug to heart cell.
The commentary also situates the new discovery within a broader and evolving understanding of how SGLT2 inhibitors reprogram cardiac metabolism. Beyond glucose lowering, the class has been shown to enhance ketogenesis through an unexpected mechanism: rather than simply raising circulating ketone levels by shifting renal handling of glucose, the drugs act as allosteric activators of HMGCS2, the mitochondrial enzyme that catalyzes the rate-limiting step of ketone body synthesis, as reported in the Journal of Clinical Investigation in 2026. Meanwhile, the randomized, controlled EMPA-VISION trial assessed cardiac energy metabolism in patients with heart failure taking empagliflozin and provided a rigorous human window into how the drug reshapes myocardial energetics. Together, these lines of evidence paint a picture of a drug class that acts as a broad-spectrum metabolic modulator rather than a single-target agent.
Viewed through this lens, the cardioprotective portfolio of SGLT2 inhibitors begins to look like a coordinated campaign on multiple metabolic fronts. The PANK1 activation restores the coenzyme A supply needed to import and oxidize fatty acids, the heart’s preferred fuel. The HMGCS2 activation boosts ketone production, providing an oxygen-efficient alternative substrate. Additional studies, including work in frail hypertensive and diabetic patients published in Hypertension, have documented improved endothelial function and reduced mitochondrial oxidative stress with empagliflozin, extending the metabolic story to the vasculature. Each mechanism addresses a different facet of the energetic deficit that defines the failing heart, and together they may explain why the clinical benefits of these drugs have been so consistent across patient populations with and without diabetes.
The therapeutic implications of targeting the PANK1–coenzyme A axis extend well beyond explaining an existing drug class. If restoring coenzyme A biosynthesis can rescue myocardial metabolic capacity, then PANK1 itself becomes a druggable node for heart failure therapy, potentially separable from SGLT2 inhibition altogether. This matters for patients who cannot tolerate SGLT2 inhibitors or who face contraindications, and it opens the door to rational combination strategies in which metabolic restoration is pursued deliberately rather than as a side effect of glucose handling. It also invites a re-examination of nutritional and pharmacological approaches to pantothenate metabolism in cardiac disease, a corner of cardiology that has received comparatively little attention despite the centrality of coenzyme A to heart function.
There are, of course, important questions that remain before the laboratory insight can be translated into bedside practice. The precise dose–response relationship between SGLT2 inhibitor exposure and PANK1 activation in the human heart, the time course over which coenzyme A restoration translates into functional improvement, and the extent to which this mechanism contributes to benefit relative to hemodynamic and neurohormonal effects all require further study. Human trials such as EMPA-VISION have begun to map the metabolic consequences of treatment in patients, but directly interrogating the PANK1 pathway in the myocardium remains a technical challenge. Riccio and Santulli’s commentary serves as both a synthesis of the current evidence and a roadmap for the experiments that will determine whether the coenzyme A story holds up as a central pillar of cardioprotection.
For a field that has spent two decades chasing the secret behind one of medicine’s most serendipitous successes, the identification of a direct cardiac target offers a rare moment of clarity. The heart fails, in large part, because it runs out of usable energy, and a drug class that replenishes the cofactor at the very heart of energy metabolism addresses the disease at its biochemical root. Whether PANK1 activation proves to be the dominant mechanism or one strand in a richer web of metabolic actions, the convergence of evidence from human hearts, mouse models, and clinical trials suggests that the era of thinking about SGLT2 inhibitors as mere glucose-lowering agents is definitively over. What began as a diabetes treatment has become a master key to cardiac metabolism, and the PANK1–coenzyme A axis may be one of its most important locks.
Subject of Research: Cardioprotective mechanisms of SGLT2 inhibitors through PANK1-mediated coenzyme A restoration in heart failure
Article Title: Beyond glucose lowering and ketogenesis: unveiling new cardioprotective mechanisms of SGLT2 inhibitors
Article References: Riccio, A., & Santulli, G. (2026). Beyond glucose lowering and ketogenesis: unveiling new cardioprotective mechanisms of SGLT2 inhibitors. Nature Reviews Cardiology. https://doi.org/10.1038/s41569-026-01357-w
Image Credits: AI Generated
DOI: 10.1038/s41569-026-01357-w
Keywords: SGLT2 inhibitors, heart failure, PANK1, coenzyme A, cardiac metabolism, pantothenate kinase, ketogenesis, empagliflozin, HMGCS2, mitochondria, cardioprotection, metabolic flexibility
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Daisy Hatcher. (October 2, 2026). SGLT2 Inhibitors Found to Repair Heart Metabolism Through Coenzyme A Pathway. Scienmag. https://scienmag.com/sglt2-inhibitors-found-to-repair-heart-metabolism-through-coenzyme-a-pathway/
Daisy Hatcher. “SGLT2 Inhibitors Found to Repair Heart Metabolism Through Coenzyme A Pathway.” Scienmag, 2 October 2026, https://scienmag.com/sglt2-inhibitors-found-to-repair-heart-metabolism-through-coenzyme-a-pathway/. Accessed 2 October 2026.
Daisy Hatcher. “SGLT2 Inhibitors Found to Repair Heart Metabolism Through Coenzyme A Pathway.” Scienmag. October 2, 2026. https://scienmag.com/sglt2-inhibitors-found-to-repair-heart-metabolism-through-coenzyme-a-pathway/
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Tags: cardiac energy metabolismcardiac metabolismcardioprotectioncardioprotection mechanismscellular bioenergetics in cardiologycoenzyme ACoenzyme A pathwaydiabetes medications for heart healthempagliflozinheart failureheart metabolism repairHMGCS2ketogenesisketone body utilization in heart diseasemetabolic flexibilitymitochondriamitochondrial function in heart failurenovel therapeutic targets for heart failurePANK1PANK1 enzyme activationpantothenate kinaserole of vitamin B5 in cardiac metabolismSGLT2 inhibitors
