The Metabolodiuretic Promise of Sodium-Dependent Glucose Cotransporter 2 Inhibition: The Search for the Sweet Spot in Heart Failure.

Clinical trials often yield surprising results, and in the contemporary era, undoubtedly, the Empagliflozin Removal of Excess of Glucose Outcome (EMPA-REG OUTCOME) trial stands out as one such example.1,2 No one could have predicted that a sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor, which works to promote urinary glucose excretion as a treatment approach to hyperglycemia, would cut all-cause mortality by about one-third in patients with type 2 diabetes. Just as surprising were the observations that the reductions in mortality were possibly driven by a reduction in heart failure as opposed to atherothrombotic events. Despite these salutary clinical effects, the physiological mechanisms responsible for these benefits are not yet known. The time frame of the effect precludes a glucose-mediated effect, and furthermore, many other equally or more effective antihyperglycemic therapies are not associated with reduced heart failure. The remarkable renal benefits noted in the trial were also surprising.2 Because the glycosuric effects of SGLT2 inhibition are dependent on the amount of filtered glucose and therefore diminished in participants with low glomerular filtration rate, it was surprising to note that treatment with empagliflozin resulted in a marked approximately 40% reduction in proteinuria and doubling of serum creatinine in the absence of marked differences in glycemia. While the scientific community struggles to understand the biologic basis and clinical implications of these observations, several questions related to EMPA-REG OUTCOME have come into focus: can SGLT2 inhibitors be used to treat heart failure as opposed to prevent heart failure in diabetes? Can SGLT2 inhibitors be a treatment for heart failure in patients without type 2 diabetes? It is also tempting to ask whether SGLT2 inhibitors will emerge as primary renoprotective strategies irrespective of glycemic or baseline renal status.