EPO (erythropoietin)

What it is

Erythropoietin is a glycoprotein hormone that controls the production of red blood cells. The body releases it when tissue receives too little oxygen; this is controlled via the so-called HIF pathway. In chronic kidney disease, EPO is often lacking, and the result is anemia.

Genetically engineered EPO entered the clinic in the 1980s. A 1987 study showed that dialysis patients can manage without blood transfusions with it: of 18 effectively treated patients, 12 no longer needed a transfusion, and in 11 the hematocrit rose to 35 percent or more. Since 1988, epoetin has been the standard treatment for renal anemia. Today there are several variants, including epoetin alfa, beta and zeta, the longer-acting darbepoetin and CERA.

The approved use

In the EU, epoetin alfa has been approved since 2007, among others as Binocrit. According to the summary of product characteristics, it is used for symptomatic anemia due to chronic renal failure, in adults as well as children and adolescents on dialysis, and in severe renal anemia before dialysis. The second major area of use is anemia during chemotherapy for solid tumors, malignant lymphomas and multiple myeloma when there is a risk of transfusion. In addition, there is autologous blood donation before major surgery, avoiding donor blood before major orthopedic procedures, and anemia in certain myelodysplastic syndromes.

Therapy takes place under medical supervision, with close monitoring of hemoglobin. The reason for this is found in the large trials.

How it works

EPO binds to the EPO receptor on precursor cells of red blood cells in the bone marrow. The receptor activates the kinase JAK2 and the JAK2/STAT5 signaling pathway; the precursor cells divide, mature and survive longer. After a few weeks, hemoglobin, hematocrit and total hemoglobin mass rise. More red blood cells mean more oxygen transport, but also thicker blood.

Why EPO is used in sport

In endurance sport, oxygen uptake is one of the deciding factors. The best controlled study on this comes from Leiden: 48 trained amateur cyclists aged 18 to 50 received EPO or placebo for 8 weeks. Under EPO, maximal oxygen uptake was 60.1 instead of 57.4 ml/min/kg and peak power 351.55 instead of 341.23 watts. In the 45-minute test and in the race up Mont Ventoux, by contrast, there was no difference: 1 hour 40 minutes 32 seconds under EPO, 1 hour 40 minutes 15 seconds under placebo.

Other work also found performance gains in a competition format. In 20 Kenyan long-distance runners, a 3000 m run improved by about 5 percent directly after 4 weeks of EPO and still by about 3 percent 4 weeks later, but without a placebo group. A systematic review of 10 studies in well-trained endurance athletes confirms the effect on blood values and maximal oxygen uptake; whether submaximal performance also increases is open.

Testing shows that EPO continues to play a role in sport: 149 adverse analytical findings for EPO receptor agonists were reported for 2024, compared with 46 in 2015.

What the studies show

TREAT: strokes almost doubled

4,038 patients with type 2 diabetes, kidney disease and anemia received darbepoetin or placebo. The primary endpoints death or cardiovascular event remained unchanged (HR 1.05), and fewer patients needed transfusions (297 versus 496). Strokes, however, occurred in 101 versus 53 patients, a hazard ratio of 1.92.

CHOIR and CREATE: normal values tend to do harm

In CHOIR with 1,432 kidney patients, a hemoglobin target of 13.5 instead of 11.3 g/dl led over a median of 16 months to 125 instead of 97 serious events, HR 1.34, without better quality of life. CREATE with 603 patients found no cardiac protection from full correction over 3 years.

Cancer patients (Cochrane 2012 and Bennett 2008)

Under EPO and darbepoetin, the risk of thromboembolism (RR 1.52) and mortality during the study period (HR 1.17) rose. A second analysis found venous thrombosis in 7.5 versus 4.9 percent, a relative risk of 1.57.

Trained cyclists (Heuberger 2020)

In an additional analysis of the Leiden study, markers of activated endothelium and activated platelets rose under EPO, P-selectin by 7.8 percent and E-selectin by 8.6 percent. After maximal exercise, E-selectin was 15.3 percent and platelet factor 4 was 32.1 percent higher than under placebo. Exercise and EPO thus reinforced each other.

Where the data stop

Nobody knows exactly how often EPO misuse in athletes leads to heart attack, stroke or thrombosis. A 2026 review notes that there are hardly any population-based data on this; what exists are case reports of cerebral venous thrombosis and acute coronary syndromes in young athletes. The cluster of sudden deaths among professional cyclists in the late 1980s and early 1990s is considered highly suspicious, but proof of EPO as the cause is lacking. The studies in athletes are small and last a few weeks. The large risk data come from sick people and cannot be transferred one to one, but they make the risk for healthy people with very high hematocrit biologically plausible. Conversely, it remains open how much competitive performance EPO delivers in practice: in the lab the effect is clear; in the only controlled race it did not materialize.

Status, approval and legal

EPO and its variants are approved, prescription-only medicines in Germany and the EU, and according to the summary of product characteristics subject to restricted medical prescription. Anyone who trades or supplies prescription-only medicines outside a pharmacy commits a criminal offense under the German Medicines Act. In sport, EPO is listed under S2.1 on the 2026 WADA Prohibited List and is banned at all times, as are darbepoetin, CERA and HIF activators such as roxadustat. The German Anti-Doping Act prohibits manufacturing, trading and supplying for doping purposes as well as acquiring and possessing more than small quantities; the threshold is set by the Doping Substances Quantities Ordinance of 2023. Penalties range up to three years’ imprisonment. Self-doping is a criminal offense for elite athletes and athletes with substantial income. Under S2.1 the list also names innate repair receptor agonists; ARA-290 (cibinetide), an EPO derivative without blood-forming effect, is counted in this group.

Safety

The summary of product characteristics lists venous and arterial thromboses and embolisms, some fatal, including deep vein thrombosis, pulmonary embolism, retinal thrombosis and heart attack, plus cerebral infarction and cerebral hemorrhage. Further risks are high blood pressure, seizures, severe skin reactions and a rare antibody-mediated pure red cell aplasia, in which the bone marrow hardly produces any red blood cells; from 1998 to 2004 this affected nearly 200 kidney patients, and only 37 percent recovered. In cancer patients, EPO can act as a growth factor. The risk rises when hemoglobin is driven above the target range, and under intense exertion and fluid loss. Without a medical indication and monitoring, EPO is not suitable for anyone.

Sources

• Eschbach et al., N Engl J Med 1987
• EMA, summary of product characteristics Binocrit (epoetin alfa)
• Pfeffer et al., N Engl J Med 2009 (TREAT)
• Singh et al., N Engl J Med 2006 (CHOIR)
• Tonia et al., Cochrane Database Syst Rev 2012
• Heuberger et al., Lancet Haematol 2017
• Heuberger et al., Eur J Appl Physiol 2020
• Chlebowska et al., Pathophysiology 2026
• WADA, Prohibited List 2026
• German Anti-Doping Act (AntiDopG)