epoetin-alfa and Diabetes-Mellitus--Type-2

The triad of diabetes mellitus, anemia, and chronic kidney disease (CKD) define a group of patients at high risk for death and cardiovascular complications. The approval of epoetin alfa in 1989 transformed the treatment of anemia in patients with CKD. However, evidence has emerged from randomized controlled trials that correcting anemia with erythropoiesis-stimulating agents in CKD patients is associated with increased risk. Most recently, the TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy) study of anemic type 2 diabetic patients with CKD reported that treatment with darbepoetin conferred no benefit in mortality or in attenuating cardiovascular or renal events. Instead, there was a twofold higher rate of stroke and thromboembolic complications and a higher rate of cancer deaths in patients randomized to treatment with darbepoetin. Furthermore, there was an inconsistent and modest improvement in health-related quality of life. TREAT raises questions about whether anemia in type 2 diabetic patients should be treated and under what circumstances.

Topics: Anemia; Darbepoetin alfa; Diabetes Mellitus, Type 2; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Recombinant Proteins

The number of diabetic patients with renal disease increased significantly in the last years worldwide. Anemia is an important and frequent component of diabetic nephropathy that may begin early in the course of the chronic renal disease of diabetics, and is more severe in diabetic patients with renal disease than in non - diabetic renal patients controlled for the same level of renal function. The reason for the anemia is decreased erythropoietin level caused by diminished production and, in a lesser degree, by increased excretion of erythropoietin in the urine. There is a close connection between diabetic nephropathy, anemia and cardiovascular complications. On the basis of small studies correction of anemia may decrease the progression of diabetic nephropathy and cardiovascular complications. However, the result of ongoing large randomised controlled studies are required to get "evidence-based" data to prove that correction of anemia has beneficial effects on microvascular and macrovascular diabetic complications, particularly cardiac disease, and on progression of diabetic nephropathy.

Topics: Anemia, Hypochromic; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Epoetin Alfa; Erythropoietin; Heart Failure; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Recombinant Proteins; Time Factors

The combination of diabetes and chronic kidney disease is associated with increased mortality and reduced quality of life. Recent studies have shown that, in general, late referral of patients to the renal unit increases mortality, and that patients with diabetes who are referred late have a particularly poor prognosis. Several co-morbid conditions have been shown to contribute to poor patient outcomes, including both cardiovascular disease and anaemia. In patients with diabetic nephropathy, anaemia is more severe and is seen earlier than in patients with non-diabetic renal disease. Although the treatment of anaemia with recombinant human erythropoietin (rhEPO; epoetin) is well established, the only data currently available concerning the effects of early intervention in patients with diabetic nephropathy are from small-scale studies. Therefore, two large-scale studies have been designed to provide information on the efficacy of epoetin treatment and on how current management strategies might be improved. The Anaemia CORrection in Diabetes (ACORD) study will provide information on the potential cardiac benefits of early anaemia management in patients with early, type 2 diabetic nephropathy. The Individualised Risk-profiling In DIabEtes Mellitus (IRIDIEM) study will provide evidence-based guidance in risk factor management, by assessing the efficacy of individualized interventions.

Topics: Anemia; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Recombinant Proteins; Referral and Consultation; Survival Rate

Type 2 diabetes mellitus (T2DM) is strongly associated with an increased risk of developing cognitive dysfunction. Numerous studies have indicated that erythropoietin (EPO) has neurotrophic effects. Ferroptosis has been reported to be associated with diabetic cognitive dysfunction. However, the impact of EPO on T2DM-associated cognitive dysfunction and its protective mechanism remain unclear. To evaluate the effects of EPO on diabetes-associated cognitive dysfunction, we constructed a T2DM mouse model and found that EPO not only decreased fasting blood glucose but also ameliorated hippocampal damage in the brain. The Morris water maze test indicated that EPO improved cognitive impairments in diabetic mice. Moreover, a ferroptosis inhibitor improved cognitive dysfunction in mice with T2DM in vivo. Furthermore, a ferroptosis inhibitor, but not other cell death inhibitors, mostly rescued high-glucose damaged PC12 cell viability. EPO had a similar effect as the ferroptosis inhibitor, which increased cell viability in the presence of a ferroptosis inducer. In addition, EPO reduced lipid peroxidation, iron levels, and regulated ferroptosis-related expression of proteins in vivo and in vitro. These findings indicate that EPO ameliorates T2DM-associated cognitive dysfunction, which might be related to decreasing iron overload and inhibiting ferroptosis.

Topics: Animals; Cognitive Dysfunction; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Epoetin Alfa; Erythropoietin; Ferroptosis; Iron Overload; Mice

HbA(1c) values are unreliable in patients with diabetes who have chronic kidney disease who receive iron and/or erythropoiesis stimulating agents. The study aimed to evaluate the utility of the complementary glycaemic markers glycated albumin, fructosamine and 1,5 anhydroglucitol in this group of patients.. A prospective study of patients with Type 2 diabetes and chronic kidney disease stage IIIB/IV undergoing intravenous iron or erythropoiesis-stimulating agent therapy. Glycaemic control was monitored using HbA(1c), seven-point daily glucose thrice weekly, continuous glucose monitoring, glycated albumin, fructosamine and 1,5 anhydroglucitol.. Fifteen patients [9 men; median age 72 years (interquartile range 68-74), follow-up period (16.4 ± 3.7 weeks)] received parenteral iron; 15 patients [11 men; 70 years (interquartile range 62-75), (17.3 ± 3.3 weeks)] received erythropoiesis-stimulating agent. HbA(1c) fell following treatment with both iron [57 mmol/mol (7.4%) to 53 mmol/mol (7.0%), P < 0.001] and erythropoiesis-stimulating agent [56 mmol/mol (7.3%) to 49 mmol/mol (6.6%), P = 0.01] despite mean blood glucose remaining unchanged (iron: 9.55 to 9.71 mmol/l, P = 0.07; erythropoiesis-stimulating agent: 8.72 to 8.78 mmol/l, P = 0.89). Unlike HbA1c , the glycated albumin, fructosamine and 1,5 anhydroglucitol levels did not change following iron [glycated albumin (16.8 to 16.3%, P = 0.10); fructosamine (259.5 to 256 μmol/l, P = 0.89); 1,5 anhydroglucitol (54.2 to 50.9 μmol/l, P = 0.89)] or erythropoiesis-stimulating agent [glycated albumin (17.9 to 17.5%, P = 0.29), fructosamine (324.3 to 306.0 μmol/l, P = 0.52), 1,5 anhydroglucitol (58.2 to 46.7 μmol/l, P = 0.35)]. Despite this, HbA(1c) was consistently the marker most closely related to mean blood glucose before and after each treatment (R range 0.7-0.88).. These data indicate that HbA(1c) was statistically most closely related to mean blood glucose, but clinical trends in glycaemia in patients undergoing iron or erythropoiesis-stimulating agent therapy are likely best assessed by including one of these additional glycaemic markers.

Topics: Administration, Intravenous; Aged; Biomarkers; Blood Glucose; Delivery of Health Care; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Fructosamine; Glycated Hemoglobin; Glycated Serum Albumin; Glycation End Products, Advanced; Hematinics; Humans; Iron; Male; Monitoring, Physiologic; Prospective Studies; Recombinant Proteins; Renal Insufficiency, Chronic; Serum Albumin; Severity of Illness Index; Time Factors; Treatment Outcome

Topics: Anemia; Cardiovascular Diseases; Darbepoetin alfa; Diabetes Mellitus, Type 2; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Recombinant Proteins; Renal Insufficiency, Chronic

Current guidelines give evidence-based advice on how best to manage anaemia in patients with renal disease, but these guidelines do not consider individual patient needs, so tailoring anaemia management to each patient still remains a challenge for the treating physician. Two case studies are described that illustrate some of the key factors that need to be considered. The first case emphasizes that haemoglobin (Hb) targets recommended in current guidelines may not suit all patients. The patient had been stably maintained on subcutaneous epoetin therapy with an average Hb concentration of >13.0 g/dl because he developed angina symptoms when his Hb level fell to 12.2 g/dl. Iron deficiency was identified as the likely cause of falling Hb in this patient. After the patient's iron supplementation was increased, his Hb level was normalized back to >13.0 g/dl without increasing the epoetin dose, and the angina symptoms were resolved. The second case involved a pre-dialysis patient with diabetes, who required a higher dose of epoetin after beginning concomitant antihypertensive treatment with an angiotensin-converting enzyme inhibitor. Previously, the treatment of renal anaemia in pre-dialysis patients has not been the focus of attention. Two ongoing randomized controlled trials have been designed to study early initiation of epoetin treatment in pre-dialysis patients and will provide much needed information in this area.

Topics: Aged; Anemia; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis