The coexistence of type 2 diabetes mellitus and chronic kidney disease is frequent. Each disease independently increases the risk of cardiovascular events and end-stage renal disease. In addition, observational studies have identified anemia as another biomarker of risk for development of cardiovascular events and end-stage renal disease.

Erythropoiesis-stimulating agents (ESAs) have been available for more than two decades. Early studies of the use of ESAs demonstrated that they were capable of reducing transfusions and improving quality of life in patients with anemia who were undergoing dialysis. This led to the wider use of ESAs in patients with early chronic kidney disease, not yet undergoing dialysis. However, the presumption of benefits associated with the use of ESAs has driven the design of non-placebo-controlled trials, which have assumed that the use of ESAs would lower the risks associated with anemia and lead to improved prognosis. Although the benefit of ESAs has long been assumed, investigators do not know whether an increase of hemoglobin (Hb) levels through the use of ESAs will lower the risk for cardiovascular events and end-stage renal disease. The Trial to Reduce Cardiovascular Events with Aranesp therapy (TREAT) was designed to test this hypothesis in patients with type 2 diabetes, chronic kidney disease, and anemia.

The TREAT was a randomized, double blinded, placebo-controlled trial conducted at 623 sites and 24 countries. Patients received either placebo or darbepoetin alpha in matching prefilled syringes. Darbepoetin alfa was administered as a rescue agent to patients in the placebo group if the patient's Hb level fell below 9.0 g/dL. Patients were returned to placebo once their Hb level achieved 9.0 g/dL or higher. At baseline, the Hb level for both groups was 10.4 g/dL. Less than 1 month after randomization, between group differences in Hb levels became apparent and became significant by 1 month. Rescue therapy was administered to 46% of the patients assigned to placebo over the course of the study.

Death or a nonfatal cardiovascular event (myocardial infarction, unstable angina, heart failure, and stroke) occurred in 632 patients in the darbepoetin alfa group (31.4%) and in 602 patients in the placebo group (29.7%) (P=0.41). Patients assigned to darbepoetin alfa were more likely to experience a fatal or nonfatal stroke. Death or end-stage renal disease occurred in 652 patients in the darbepoetin alpha group (32.4%) and in 618 patients in the placebo group (30.5%) (P=0.29).

With regard to patients that participated in the patient reported quality of life outcomes, there was a greater improvement in the mean FACT-fatigue score in the darbepoetin alfa group, compared to the placebo group. There was no significant difference between the two groups according to assessment by the 36-Item Short-Form General Health Survey. Additionally, there was a reduced need for administration of red blood cell transfusions in the darbepoetin alpha group (n= 297 patients; 14.8%) compared with the placebo group (n= 496 patients; 24.5%) (P<0.001).

There was no significant difference in systolic blood pressure between the two groups, but patients in the darbepoetin alpha group had higher diastolic blood pressures. There was no significant between-group difference in the number of patients reporting a cancer-related adverse event – however, among patients with a history of a malignant condition at baseline, more individuals in the darbepoetin alpha group (14/188 patients) died from cancer compared to individuals in the placebo group (1/160 patients) (P=0.002).

There was a higher incidence of venous thromboembolic events reported in patients in the darbepoetin alpha group (2.0% vs. 1.1%; P=0.02), as well as a higher incidence of arterial thromboembolic events reported in the darbepoetin alpha group (8.9% vs. 7.1%; P=0.04).

Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, Feyzi JM, Ivanovich P, Kewalramani R, Levey AS, Lewis EF, McGill JB, McMurray JJ, Parfrey P, Parving HH, Remuzzi G, Singh AK, Solomon SD, Toto R; the TREAT Investigators. A Trial of Darbepoetin Alfa in Type 2 Diabetes and Chronic Kidney Disease. N Engl J Med. 2009 Nov 19;361(21):2019-32.

NAAC Expert Commentary
This is an extremely important study and unique in its comparison of an ESA to placebo. When combined with results of other recent studies in patients with CKD not on dialysis, the evidence is overwhelming that there is little or no benefit gained by raising Hb levels above approximately 10 g/dL – and perhaps even lower. Given that there is so little benefit to patients (there was some reduction in transfusion and minimal impact on quality of life measures in the TREAT study) physicians should carefully and seriously consider risks. These include – based on the TREAT study outcomes – higher risk of ischemic stroke, higher risk of venous and arterial thrombosis, higher diastolic blood pressure, and more cancer-related deaths particularly in patients with a history of cancer.

Results of this study are likely to impact clinical practice – initiating therapy at an Hb level < 10 g/dL rather than a higher level may be reasonable in many patients with a therapeutic goal of achieving an Hb level around 10 g/dL. It is also likely that for some patients, perhaps many, the risk-benefit ratio will favor avoiding ESAs or using only low, intermittent doses to maintain Hb levels around 10 g/dL, notably for patients with a history of malignancy. Discontinuation of ESA treatment in patients with known malignancy should also be considered. In patients awaiting renal transplantation, the goal of avoiding transfusions may tip the balance in favor of ESA use; transfusions were reduced by more than 50% in the darbepoetin-treated patients in the TREAT study.

Last Updated: January 8, 2010