Effect of Empagliflozin on Erythropoietin Levels, Iron Stores, and Red Blood Cell Morphology in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease

Mazer, C. David; Hare, Gregory M. T.; Connelly, Philip W.; Gilbert, Richard E.; Shehata, Nadine; Quan, Adrian; Teoh, Hwee; Leiter, Lawrence A.; Zinman, Bernard; Jüni, Peter; Zuo, Fei; Mistry, Nikhil; Thorpe, Kevin E.; Goldenberg, Ronald; Yan, Andrew T.; Connelly, Kim A.; Verma, Subodh

doi:10.1161/circulationaha.119.044235

Cited by 274 publications

(237 citation statements)

References 5 publications

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“…2,3 The physiology of SGLT2 inhibitor-induced erythrocytosis is complex and remains to be fully elucidated, but postulated mechanisms include hemoconcentration, modulation of iron metabolism and increased erythropoietin production, as recently reported in a Canadian study. 4 To date, we are aware of a total of 5 cases of severe erythrocytosis (hematocrit > 0.53) attributed to SGLT2 inhibitors that have been reported in the literature, [5][6][7] although anecdotally we suspect this number to be much higher and indeed rising. Two cases were associated with concomitant use of SGLT2 inhibitors and testosterone replacement therapy, 6 a well-known cause of secondary erythrocytosis.…”

Section: Erythrocytosis Induced By Sodium-glucose Cotransporter-2 Inhmentioning

confidence: 98%

Erythrocytosis induced by sodium-glucose cotransporter-2 inhibitors

Chin‐Yee

Solh

Hsia

2020

CMAJ

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Section: Erythrocytosis Induced By Sodium-glucose Cotransporter-2 Inhmentioning

confidence: 98%

Erythrocytosis induced by sodium-glucose cotransporter-2 inhibitors

Chin‐Yee

Solh

Hsia

2020

CMAJ

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“…7 Furthermore, ketonemia dilates afferent arterioles, thereby promoting glomerular hyperfiltration and its injurious effects and thus ketogenesis is likely to exacerbate (rather than ameliorate) diabetic nephropathy. 8 Additionally, SGLT2 inhibitors cause erythrocytosis by enhancing the production of erythropoietin, 9 and some have proposed that an increase in oxygen-carrying capacity of the blood might improve kidney function. However, erythropoietin mimetics that yield increases in erythrocyte counts comparable to those seen with SGLT2 inhibitors do not favorably affect the course of kidney disease.…”

Section: Potential Renoprotective Actions Of Sglt2 Inhibitorsmentioning

confidence: 99%

Mechanisms Leading to Differential Hypoxia-Inducible Factor Signaling in the Diabetic Kidney: Modulation by SGLT2 Inhibitors and Hypoxia Mimetics

Packer

2021

American Journal of Kidney Diseases

145

115

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Sodium/glucose cotransporter 2 (SGLT2) inhibitors exert important renoprotective effects in the diabetic kidney, which cannot be readily explained by their actions to lower blood glucose, blood pressure, or glomerular filtration pressures. Their effects to promote erythrocytosis suggest that these drugs act on hypoxia-inducible factors (HIFs; specifically, HIF-1α and HIF-2α), which may underlie their ability to reduce the progression of nephropathy. Type 2 diabetes is characterized by renal hypoxia, oxidative and endoplasmic reticulum stress, and defective nutrient deprivation signaling, which (acting in concert) are poised to cause both activation of HIF-1α and suppression of HIF-2α. This shift in the balance of HIF-1α/HIF-2α activities promotes proinflammatory and profibrotic pathways in glomerular and renal tubular cells. SGLT2 inhibitors alleviate renal hypoxia and cellular stress and enhance nutrient deprivation signaling, which collectively may explain their actions to suppress HIF-1α and activate HIF-2α and thereby augment erythropoiesis, while muting organellar dysfunction, inflammation, and fibrosis. Cobalt chloride, a drug conventionally classified as a hypoxia mimetic, has a profile of molecular and cellular actions in the kidney that is similar to those of SGLT2 inhibitors. Therefore, many renoprotective benefits of SGLT2 inhibitors may be related to their effect to promote oxygen deprivation signaling in the diabetic kidney. Complete author and article information provided before references.

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“…19,[59][60][61][62][63] Those that appear particularly plausible include effects on volume status, natriuresis, expansion of red blood cell mass, and myocardial energetics. 34,36,59,62,64 Future Research SGLT2 inhibitors reduce HF risks in broad cohorts of patients with T2DM and in those with reduced ejection fraction HF with or without diabetes. 46,58 Results from post hoc analyses of the DECLARE-TIMI 58 trial and the CANVAS program have suggested that patients with reduced ejection fraction may have greater benefit.…”

Section: Heart Failurementioning

confidence: 99%

SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation

Tuttle

Brosius

Cavender

et al. 2021

American Journal of Kidney Diseases

103

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Diabetes is the most frequent cause of chronic kidney disease (CKD), leading to nearly half of all cases of kidney failure requiring replacement therapy. The principal cause of death among patients with diabetes and CKD is cardiovascular disease (CVD). Sodium/glucose cotransporter 2 (SGLT2) inhibitors were developed to lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule. In clinical trials designed to demonstrate the CVD safety of SGLT2 inhibitors in type 2 diabetes mellitus (T2DM), consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death), along with reductions in CVD events, were observed. In patients with CKD, the kidney and CVD benefits of canagliflozin were established by the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial in patients with T2DM, urinary albumin-creatinine ratio > 300 mg/g, and estimated glomerular filtration rate of 30 to <90 mL/min/1.73 m 2. To clarify and support the role of SGLT2 inhibitors for treatment of T2DM and CKD, the National Kidney Foundation convened a scientific workshop with an international panel of more than 80 experts. They discussed the current state of knowledge and unanswered questions to propose therapeutic approaches and delineate future research. SGLT2 inhibitors improve glomerular hemodynamic function and are thought to ameliorate other local and systemic mechanisms involved in the pathogenesis of CKD and CVD. SGLT2 inhibitors should be used when possible by people with T2DM to reduce risks for CKD and CVD in alignment with the clinical trial entry criteria. Important risks of SGLT2 inhibitors include euglycemic ketoacidosis, genital mycotic infections, and volume depletion. Careful consideration should be given to the balance of benefits and harms of SGLT2 inhibitors and risk mitigation strategies. Effective implementation strategies are needed to achieve widespread use of these life-saving medications. Complete author and article information provided before references.

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Effect of Empagliflozin on Erythropoietin Levels, Iron Stores, and Red Blood Cell Morphology in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease

Cited by 274 publications

References 5 publications

Erythrocytosis induced by sodium-glucose cotransporter-2 inhibitors

Erythrocytosis induced by sodium-glucose cotransporter-2 inhibitors

Mechanisms Leading to Differential Hypoxia-Inducible Factor Signaling in the Diabetic Kidney: Modulation by SGLT2 Inhibitors and Hypoxia Mimetics

SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation

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