Erythropoietin (EPO) is produced in the kidneys and naturally stimulates red blood cell production in the body. Patients with diabetes mellitus (DM) often experience renal tubular and interstitial damage, leading to a decreased production of EPO. In turn, patients with DM frequently experience anemia. Studies have shown anemia to be an independent risk factor for progression of diabetic retinopathy, vascular damage, and other adverse events. However, EPO administration has shown valuable therapeutic potential in anemic DM patients. In this review, Khoshdel et al summarize recent studies to propose potential roles for EPO in the management of anemia and other complications of DM.

In several recent studies, EPO administration effectively corrected renal anemia in DM patients compared to patients without diabetes. Although only short-term studies were carried out, patients reported improved quality of life and well-being, as well as improvement of cardiac function. Additionally, EPO administration has been shown to protect against myocardial cell apoptosis, improve left ventricle function, and increase exercise capacity. Other significant advantages of EPO administration include neuroprotection, cell-to-cell junction maintenance, and improved insulin resistance.

Despite the possible benefits of EPO administration, some adverse effects have been reported. In particular, progressive worsening of hypertension is a common side effect in patients with chronic kidney disease. Thus, EPO use on hypertensive patients is often contraindicated. Also, studies have found EPO-receptors on several malignant cell lines including ovarian, uterine, and prostate. However, the results from these studies are contradictory, and do not consistently show regression or proliferation of malignant cell lines.

Because of the therapeutic potential of EPO administration, more longitudinal studies are needed to assess long-term effects in anemic DM patients. Optimal time and duration of treatment also needs to be determined by more randomized clinical trials. In addition, developing non-erythropoietic analogues of EPO will greatly enhance therapeutic efficacy. Currently, an EPO mutant is being developed with neuroprotective effects against stroke and diabetic nephropathy. Mutant analogues such as these have the potential for longer half-lives and only need to be administered once a month. The authors concluded further advances of molecular research, along with more comprehensive clinical trials like those referenced in the commentary, will help physicians make better treatment decisions for anemic DM patients.

Potential roles of erythropoietin in the management of anaemia and other complications diabetes. Khoshdel, A. Carney, S. Gillies, A. Mourad, A. Jones, B. Nanra, R. Trevillian, P. Diabetes Obes Metab. 2008 Jan;10(1):1-9. Epub 2007 Jul 21.

NAAC Expert Commentary:
In this comprehensive review, Khoshdel et al highlights the reasons that persons with diabetes get anemia earlier in the course of their kidney disease. This occurs because interstitial fibrosis often accompanies glomerular lesions. Anemia is more prevalent among persons with diabetes than those with other forms of CKD. The importance of a thorough work-up is stressed so that nutritional and other deficiencies can be managed early. Khoshdel et al summarize data from studies that show erythropoietin has receptors on many cells and tissues in the body, and may have divergent effects on tissues other than hematopoietic stem cells. Many clinical effects are speculative, such as neuroprotection and cardioprotection.

Since this article was accepted for publication, two large trials using erythropoietin therapy to drive hemoglobin levels to normal versus below normal levels were published. CHOIR(1) tested whether epoetin alpha, given to CKD patients weekly to achieve higher hemoglobin targets, would result in less cardiovascular morbidity and mortality. The study was negative, suggesting that a low-normal hemoglobin level was more appropriate for CKD patients. Of note, about half of the patients in CHOIR had diabetes. A companion study, CREATE(2), tested whether early versus late treatment with epoetin beta would reduce cardiac morbidity and mortality. The higher hemoglobin group had a non-significant increase in CV events and mortality, but reported a better quality of life.

These studies have caused clinicians, policy groups and major medical payers to take another look at erythropoiesis-stimulating agents (ESAs) in general, and to recommend more modest targets. Still ongoing is a much larger clinical trial, TREAT(3), which aims to show that treatment of anemia with darbepoetin alpha in patients with type 2 diabetes and CKD will reduce CV events and mortality. This study already has more patient years studied than CHOIR or CREATE, and is still ongoing. TREAT should add clarity to the effective use of ESA in patients with type 2 diabetes and CKD. 

(1) Correction of anemia with epoetin alfa in chronic kidney disease. Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, Reddan D; CHOIR Investigators. N Engl J Med. 2006 Nov 16;355(20):2085-98.
(2) Normalization of hemoglobin level in patients with chronic kidney disease and anemia. Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, Burger HU, Scherhag A; CREATE Investigators. N Engl J Med. 2006 Nov 16;355(20):2071-84.
(3) Rationale--Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT): evolving the management of cardiovascular risk in patients with chronic kidney disease. Mix TC, Brenner RM, Cooper ME, de Zeeuw D, Ivanovich P, Levey AS, McGill JB, McMurray JJ, Parfrey PS, Parving HH, Pereira BJ, Remuzzi G, Singh AK, Solomon SD, Stehman-Breen C, Toto RD, Pfeffer MA. Am Heart J. 2005 Mar;149(3):408-13.

Last Modified: March 6, 2008