Increase in hematocrit with SGLT-2 inhibitors - Hemoconcentration from diuresis or increased erythropoiesis after amelioration of hypoxia?

Mechanistic and Clinical Comparison of the Erythropoietic Effects of SGLT2 Inhibitors and Prolyl Hydroxylase Inhibitors in Patients with Chronic Kidney Disease and Renal Anemia

“…The magnitude of the erythrocytosis with SGLT2 inhibitors is meaningful. SGLT2 inhibitors cause an increase in hemoglobin that typically averages 0.6-0.7 g/dL, resulting in the alleviation of anemia in a significant proportion of patients [20,29]. In patients with heart failure, SGLT2 inhibitors increase the likelihood of anemia correction 2-3 fold, when compared with placebo [29].…”

“…A distinctive and consistent feature of SGLT2 inhibitors in all large-scale trials is their effect to increase hemoglobin and hematocrit [19]. When first reported, the increases in hemoglobin and hematocrit with SGLT2 inhibitors were ascribed to a natriuretic effect due to their action to inhibit sodium reabsorption in the proximal renal tubule; the negative sodium balance was believed to lead to a decrease in plasma volume and hemoconcentration [20]. However, these diuretic effects of SGLT2 are transient due to the activation of compensatory mechanisms in the S3 segment and the loop of Henle [21].…”

Erythropoiesis and estimated fluid volume regulation following initiation of ipragliflozin treatment in patients with type 2 diabetes mellitus and chronic kidney disease: A post‐hoc analysis of the PROCEED trial

“…The exact mechanisms by which SGLT2 inhibitors increase haemoglobin and haematocrit levels are unclear; however, these effects might be attributed to the enhancement of erythropoiesis, rather than haemoconcentration resulting from the diuretic effect of SGLT2 inhibitors. [6][7][8] Several clinical studies have shown that the increase in serum concentrations of erythropoietin (EPO), a hormone produced in the kidney that is essential for erythropoiesis, was followed by an increase in haemoglobin and haematocrit levels, after initiation of SGLT2 inhibitor treatment in patients with heart failure, type 2 diabetes mellitus (T2DM), and patients with T2DM who had a history of coronary artery disease. [9][10][11][12][13] This indicates that SGLT2 inhibitors enhance erythropoiesis through increased EPO production in various patient populations.…”

“…These findings suggest that increased haemoglobin and haematocrit levels per se or enhancement of mediating pathways involved in increasing these parameters, after initiation of SGLT2 inhibitor treatment, improve CV and renal outcomes. The exact mechanisms by which SGLT2 inhibitors increase haemoglobin and haematocrit levels are unclear; however, these effects might be attributed to the enhancement of erythropoiesis, rather than haemoconcentration resulting from the diuretic effect of SGLT2 inhibitors 6–8 . Several clinical studies have shown that the increase in serum concentrations of erythropoietin (EPO), a hormone produced in the kidney that is essential for erythropoiesis, was followed by an increase in haemoglobin and haematocrit levels, after initiation of SGLT2 inhibitor treatment in patients with heart failure, type 2 diabetes mellitus (T2DM), and patients with T2DM who had a history of coronary artery disease 9–13 .…”

Annual banned‐substance review 16th edition—Analytical approaches in human sports drug testing 2022/2023

“…PEPTIDE HORMONES, GROWTH FACTORS, RELATED SUBSTANCES, AND MIMETICS3.1 | EPO-receptor agonists (ERAs) and hypoxiainducible factor (HIF) activating agentsWithin the class S.2 of WADA's Prohibited List, ERAs represented 70% of all reported AAFs in 2021,126 suggesting that ERAs still play an important role as illicitly administered drugs in sport, despite the risks purportedly and evidently associated with their non-therapeutic use 133. Test methods regarding ERAs have been continuously optimized and complemented concerning enhanced anti-doping applications and additional strategies to determine the presence of a natural variant of EPO (c.577del) and in the light of medicinal research134 and pharmaceuticals potentially influencing the EPO biosynthesis in humans[135][136][137] To verify the presence of a single nucleotide polymorphism (SNP) in the c.577del EPO gene, which results in a frameshift and, consequently, in an increased molecular mass of the corresponding EPO protein, Yi et al presented a testing protocol a employing clustered regularly interspaced short palindromic repeats (CRISPR)/ dCas9-based testing approach 70. With designated primers, the relevant SNP-modified EPO sequence is polymerase chain reaction (PCR)amplified from 3 μL of blood and the amplicons and incubated with a complex formed from dCas9 and a variant-specific single-guide DNA.Only the variant amplicons bind to the ribonucleoprotein, which is subsequently visualized by native polyacrylamide gel electrophoresis and enables the identification of c.577del EPO gene variant carriers to support result interpretations of routine analyses concerning recombinant human EPO (rhEPO).…”