Inhibition of the Sodium-Proton Antiporter (Exchanger) is a Plausible Mechanism of Potential Benefit and Harm for Drugs Designed to Block Sodium Glucose Co-transporter 2

Clinical trials of sodium glucose co-transporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes and comorbid cardiovascular and kidney disease have shown reductions in major adverse cardiovascular events, heart failure hospitalizations, and attenuation of the progression of kidney disease. The magnitude of benefit appears to be greater than expected due to glycemic control, reduced blood pressure, and loss of adiposity. This impact is also independent from reduced renal function and lesser degrees of natriuresis and glycosuria. However, these agents have also been associated with limb amputation, Fournier's gangrene, diabetic ketoacidosis, metabolic bone disease, and increased hematopoiesis. A strong off-target effect of SGLT2i on the sodium-proton antiporter (exchanger) on the cell surface and intracellular organelles explains the wide-ranging effects of these agents. By slowing the restoration of pH within cells, SGLT2i activate secondary processes that mimic ischemic preconditioning in the heart and kidney and increased hematopoiesis in bone marrow which would explain salutary effects. Conversely, the inability to rapidly recover pH in ischemic peripheral tissues explains the progression of diabetic extremity ulcers, gangrene, propensity for metabolic bone disease, and diabetic ketoacidosis in patients who are predisposed. This paper will review the evidence for the strong off-target effect of SGLT2i on the sodium-proton exchanger and its potential effect on the organ systems and processes in which SGLT2i appear to have activity.