Anemia in patients with CKD is commonly treated with erythropoiesis-stimulating agents (ESAs), typically with iron supplements. However, ESAs increase the risk of major cardiovascular events, and the cardiovascular risks of hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) inhibitors are comparable with or greater than those with ESAs.1 By contrast, in patients with CKD, sodium-glucose cotransporter 2 (SGLT2) inhibitors increase hemoglobin and hematocrit and correct anemia, but they reduce cardiovascular death and heart failure hospitalizations.2–5

Correction of Anemia by SGLT2 Inhibition in Patients with CKD

The erythrocytic effect of SGLT2 inhibitors has been evaluated in 5060 patients with CKD and anemia in four large-scale long-term trials (Table 1).2–5 Two trials focused on patients with chronic heart failure (half of whom had CKD), and two trials focused on patients with CKD, with or without diabetes. In these four trials, when compared with placebo, SGLT2 inhibition increased hemoglobin (by approximately 0.7 g/L) and hematocrit (by approximately 2.0%–2.5%), and these increases were apparent after 4–12 weeks and were sustained for 1–3 years of follow-up. During long-term therapy, anemia was more than twice as likely to be corrected in patients receiving SGLT2 inhibitors as compared with placebo.2–5 Approximately 50%–70% of treated patients achieved hemoglobin and hematocrit levels in the nonanemic range. This correction of anemia by SGLT2 inhibition was observed although <10% of patients received iron supplements or other treatments of anemia.

Table 1 - Large-scale trials of SGLT2 inhibitors in patients with anemia and CKD Study Patients Average Baseline eGFR (ml/min per 1.73 m2) in Patients with Anemia Baseline Hemoglobin (g/dl) Placebo-Corrected Change in RBC Indices with SGLT2i Correction of Anemia during Double-Blind Treatment DAPA-HF (dapagliflozin)2 1032 patients with heart failure and anemia 59.3 (no patients with eGFR <30) 11.7 ↑ Hematocrit by 2.4% at 8 mo 62% on SGLT2i versus 41% on placebo (OR, 2.37; 95 CI, 1.84 to 3.04) EMPEROR-Reduced (empagliflozin)3 713 patients with heart failure and anemia 54.2 (no patients with eGFR <20) 11.5 ↑ Hemoglobin by 0.7 g/dl
↑ Hematocrit by 1.9% at 52 wk 71% on SGLT2i versus 48% on placebo CREDENCE (canagliflozin)4 1599 patients with diabetes, CKD, and anemia Not reported (no patients with eGFR <30) Approximately 11.5 ↑ Hemoglobin by 0.7 g/dl
↑ Hematocrit by 2.4% after 2–3 yr 52% on SGLT2i versus 29% on placebo (HR, 2.59; 95% CI, 2.18 to 3.08) DAPA-CKD (dapagliflozin)5 1716 patients with CKD and anemia 39.7 (no patients with eGFR <25) 11.4 ↑ Hematocrit by 2.3% at 2 yr 53% on SGLT2i versus 29% on placebo (HR, 2.29; 95% CI, 1.96 to 2.68)

CI, confidence interval; CREDENCE, Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; DAPA-CKD, Dapagliflozin Chronic Kidney Disease Trial; DAPA-HF, Dapagliflozin Heart Failure Trial; EMPEROR, Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction; HR, hazard ratio; OR, odds ratio; RBC, red blood cell; SGLT2i, sodium-glucose cotransporter 2 inhibitor.

Importantly, in the CREDENCE trial,4 the placebo-corrected increase in hemoglobin was 0.74, 0.68, and 0.70 g/dl in patients with baseline hemoglobin levels of <10.0, 10.0 to <12.0, and 12.0 to <13.0 g/dl, respectively. Furthermore, the patients receiving an SGLT2 inhibitor had a lower likelihood of requiring iron supplementation (hazard ratio, 0.64; 95% confidence interval, 0.52 to 0.80) or an ESA (hazard ratio, 0.65; 95% confidence interval, 0.46 to 0.91) for the treatment of anemia, although utilization of these treatments was low. Similar results were seen in the other large-scale trials.2,3,5

The magnitude of the erythrocytic effect was comparable with that seen with low doses of HIF-PHDs,1 which are typically administered with iron supplements. In patients who were not anemic at baseline, treatment with the SGLT2 inhibitor reduced the risk of new-onset anemia during long-term follow-up by approximately 50%.2–5

Mechanisms by Which SGLT2 Inhibitors Induce Erythrocytosis

The effect of SGLT2 inhibitors to increase hemoglobin and hematocrit was initially ascribed to natriuresis and plasma volume contraction. However, inhibition of proximal renal tubular sodium and glucose reabsorption elicits a vigorous counter-regulatory response in distal nephron segments, truncating the duration of diuresis to <1 week. By contrast, the effect of SGLT2 inhibitors to increase hemoglobin and hematocrit emerges after the first week and peaks after 3–4 months.2–5 Furthermore, in patients with CKD, the glycosuric and natriuretic effects of SGLT2 inhibitors are impaired, but the erythrocytic effect is not attenuated (Table 1).

Instead of hemoconcentration, SGLT2 inhibitors increase hemoglobin and hematocrit by stimulating the production of erythropoietin.6 In addition, because of an effect to mute proinflammatory pathways and enhance nutrient deprivation signaling, SGLT2 inhibition reduces both hepcidin and ferritin, thus promoting the absorption of iron from the gastrointestinal tract and the mobilization of iron from both the reticuloendothelial system (as hepcidin decreases) and intracellular stores (as ferritin decreases).2,6 These effects allow SGLT2 inhibitors to stimulate a brisk reticulocytosis and increase hemoglobin and hematocrit without the need of iron supplementation. Accordingly, in large-scale trials, the magnitude and durability of the erythrocytotic response to SGLT2 inhibition is not attenuated even in patients who are iron deficient.7 This pattern of response differs from that seen with ESAs and HIF-PHD inhibitors, which typically require ongoing iron supplementation.1

The mechanisms by which SGLT2 inhibitors stimulate erythropoietin remain to be fully elucidated. Some have hypothesized that the effects of SGLT2 inhibitors to increase sodium delivery to distal nephron segments augment their workload and oxygen consumption, leading to hypoxia at the corticomedullary junction. The specialized interstitial fibroblast-like cells at this site respond to a decline in tissue oxygen tension by increasing the expression of hypoxia-inducible factor-2α (HIF-2α)—the principal endogenous stimulus to the production of erythropoietin.8 However, there are two major difficulties with this hypothesis. First, acetazolamide—which also acts to inhibit proximal tubular sodium reabsorption and thus enhances distal sodium delivery and corticomedullary workload—does not stimulate erythropoietin or erythropoiesis. Second, with the progression of CKD, the interstitial fibroblast-like cells are depleted, the synthesis of erythropoietin by the kidney becomes progressively impaired, and this impairment causes CKD-related anemia.8 Nevertheless, the effect of SGLT2 inhibitors to increase hemoglobin and hematocrit remains robust and is not attenuated in moderate-to-severe CKD (Table 1). In these patients, SGLT2 inhibitors stimulate erythrocytosis,2–5 although the interstitial fibroblast-like cells do not have the critical mass to sustain endogenous erythropoietin production by the kidney and to prevent anemia.

Therefore, it has been postulated that the enhancement of erythropoietin production after SGLT2 inhibition may rely not only on the kidney but also on the liver, which is the principal site of erythropoietin synthesis during fetal development.9 The liver may emerge as an important site of erythropoietin production in patients with CKD, and SGLT2 inhibitors can promote upregulation of sirtuin-1 (SIRT1) in the liver, which can directly stimulate HIF-2α, independent of hypoxia.9 Alternatively, the action of SIRT1 to upregulate peroxisome proliferator-activated receptor-γ coactivator-1α in the liver may allow its binding to hepatic nuclear factor 4. Hepatic nuclear factor 4 acts as an oxygen-sensitive promoter of the transcription of the erythropoietin gene in hepatocytes.9 Increased iron mobilization during SGLT2 inhibition (through their action on hepcidin and ferritin) may further facilitate erythrocyte production.6

It is noteworthy that HIF-PHD inhibitors can also increase erythropoietin synthesis in the liver, thus explaining how these drugs can stimulate erythropoiesis in patients with severe CKD and in anephric patients.9 However, HIF-PHD inhibitors stimulate both HIF-2α and HIF-1α, whereas SGLT2 inhibitors act to stimulate HIF-2α, but they suppress the expression and activity of HIF-1α in the heart and kidney.10 Differences in the effect of SGLT2 inhibitors and HIF-PHD inhibitors on HIF-1α expression and activity may be critically important because HIF-1α is not a principal driver of endogenous erythropoietin synthesis, but HIF-1α upregulation can promote both atherosclerotic plaque instability and cardiac fibrosis.10 Differential effects on HIF-1α signaling may help to explain why, in large-scale trials, HIF-PHDs increase the risk of major adverse cardiovascular events, whereas SGLT2 inhibitors reduce the risk of cardiovascular death and hospitalizations for heart failure. Upregulation of SIRT1 and proliferator-activated receptor-γ coactivator-1α by SGLT2 inhibitors may further potentiate the cardioprotective effects of these drugs.11

SGLT2 inhibitors were initially not prescribed to patients with advanced CKD because CKD impaired their glycosuric effects, which were believed to mediate their benefits, yet SGLT2 inhibitors exert favorable effects in patients with CKD independent of glycosuria. Four large-scale trials in >5000 patients have established an effect of SGLT2 inhibitors to induce erythropoiesis and correct anemia in moderate-to-marked CKD (in the absence of iron supplementation) due to stimulation of endogenous erythropoietin production. However, these trials did not include patients with eGFR <20 ml/min per 1.73 m2 or receiving renal replacement therapy. If SGLT2 inhibitors can ameliorate anemia in patients with kidney failure, they would provide physicians with an attractive alternative to erythropoietin mimetics and HIF-PHD inhibitors, which typically require iron supplements and whose use is accompanied by a higher risk of major adverse cardiovascular events.1

Disclosures

M. Packer reports personal fees for consulting from 89bio, Abbvie, Actavis, Altimmune, Amarin, Amgen, Ardelyx, AstraZeneca, Attralus, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Medtronic, Moderna, Novartis, Pharmacosmos, Reata, Regeneron, Relypsa, and Salamandra.

Funding

None.

Acknowledgments

The content of this article reflects the personal experience and views of the author and should not be considered medical advice or recommendation. The content does not reflect the views or opinions of the American Society of Nephrology (ASN) or CJASN. Responsibility for the information and views expressed herein lies entirely with the author.

Author Contributions

Conceptualization: Milton Packer.

Data curation: Milton Packer.

Investigation: Milton Packer.

Methodology: Milton Packer.

Writing – original draft: Milton Packer.

Writing – review & editing: Milton Packer.

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