Possible mechanism of hematocrit elevation by sodium glucose cotransporter 2 inhibitors and associated beneficial renal and cardiovascular effects

Abstract

his review focuses on the postulated mechanism underlying elevation of erythropoietin, hemoglobin, and hematocrit levels in patients with type 2 diabetes mellitus receiving sodium glucose cotransporter 2 (SGLT2) inhibitors and how this phenomenon is linked to reduced progression of chronic kidney disease, lower mortality, and a lower risk of heart failure hospitalization.SGLT2 inhibitor therapy is associated with a modest increase in hematocrit (2%-4%) relative to placebo, and this effect is consistent for all 4 SGLT2 inhibitors (empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin).In patients with type 2 diabetes mellitus and stage 2 or 3 chronic kidney disease, empagliflozin increases hematocrit regardless of renal function, whereas hematocrit is not increased by SGLT2 inhibitors in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease.By their diuretic effects, SGLT2 inhibitors also increase urine volume, but this increase peaks at 24 hours after the start of SGLT2 inhibitor therapy, and urine volume returns to baseline within 1 week, whereas hematocrit continues to increase over 2 months.Thus, the time course of the change in urine volume after the initiation of SGLT2 inhibitor therapy is completely different from that of hematocrit, which means that the increase in hematocrit cannot be explained only by hemoconcentration resulting from diuresis.What other mechanisms could explain the elevation of hematocrit?The erythropoietin level increases after initiation of dapagliflozin treatment for diabetes mellitus and reaches a plateau in 2 to 4 weeks.The reticulocyte count increases concomitantly with erythropoietin, followed by elevation of hemoglobin and hematocrit. 1 These clinical observations suggest that the increase in hematocrit associated with SGLT2 inhibitor therapy can be better explained by augmentation of erythropoiesis.Thiazides have a stronger diuretic effect than SGLT2 inhibitors, but administration of these drugs does not increase either hematocrit or erythropoietin production, 1 so what mechanism is involved here?Reabsorption of glucose via SGLT2 in the proximal tubular epithelial cells consumes energy because the Na + /K + pump must also be driven, and these cells have a highly developed mitochondrial network to supply ATP for the Na + /K + pump.Glucose uptake via SGLT2 is increased in patients with diabetes mellitus, resulting in increased ATP consumption by the Na + /K + pump.Oxygen consumption by the proximal tubular mitochondria increases to meet the high demand for ATP, resulting in a decrease in the tissue oxygen partial pressure in the renal cortex. 2 Erythropoietin is produced by "neural crest-derived" fibroblasts residing near the proximal tubules in the kidney.Animal studies have shown that selective damage to the proximal tubular epithelial cells induces transdifferentiation of erythropoietin-producing fibroblasts into myofibroblasts.3 These transformed fibroblasts lose the capacity to produce erythropoietin and actively produce fibrogenic molecules instead.In chronic kidney disease, such transformation of erythropoietin-produc-