Effects of Interleukin-1β Inhibition on Incident Anemia: Exploratory Analyses From a Randomized Trial

Ann Intern Med. 2020 Apr 21;172(8):523-532. doi: 10.7326/M19-2945. Epub 2020 Mar 24.


Background: Inflammatory cytokines, such as interleukin (IL)-1β, alter iron homeostasis and erythropoiesis, resulting in anemia, but whether inhibition of IL-1β can reverse these effects is unclear.

Objective: To determine whether IL-1β inhibition with canakinumab reduces incident anemia and improves hemoglobin levels among those with prevalent anemia.

Design: Exploratory analysis of a randomized controlled trial. (ClinicalTrials.gov: NCT01327846).

Setting: Many clinical sites in 39 countries.

Participants: 8683 CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) participants without anemia at trial entry and 1303 with prevalent anemia at trial entry.

Intervention: Random assignment to receive placebo or canakinumab (50, 150, or 300 mg) subcutaneously once every 3 months.

Measurements: Primary outcome was incident anemia (hemoglobin level <130 g/L in men or <120 g/L in women).

Results: Anemia incidence increased with rising baseline levels of high-sensitivity C-reactive protein (hsCRP), and both hsCRP and IL-6 decreased among participants receiving canakinumab compared with the placebo group. During a median follow-up of 3.7 years, participants without baseline anemia who received canakinumab at any dosage had significantly less incident anemia than those who received placebo (hazard ratio, 0.84 [95% CI, 0.77 to 0.93]; P < 0.001). Compared with placebo, the greatest benefits of IL-1β inhibition on incident anemia were observed among participants with the most robust anti-inflammatory response, an effect corroborated in formal mediation analyses. Among those with baseline anemia, canakinumab increased mean hemoglobin levels by 11.3 g/L (P < 0.001) compared with placebo after 2 years of treatment. Canakinumab increased the risk for infection and was associated with mild cases of thrombocytopenia and neutropenia, none of which was grade 3 or higher.

Limitation: CANTOS was not designed to assess the cause of anemia in individual trial participants.

Conclusion: These exploratory analyses of randomized trial data provide proof of principle that inflammation inhibition, at least through the IL-1β/IL-6 signaling pathway, reduces the incidence of anemia and improves hemoglobin levels in patients with anemia.

Primary funding source: Novartis Pharmaceuticals.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Anemia / complications
  • Anemia / drug therapy*
  • Anemia / immunology
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • C-Reactive Protein / analysis
  • C-Reactive Protein / metabolism
  • Double-Blind Method
  • Female
  • Hemoglobins / analysis
  • Humans
  • Incidence
  • Interleukin-1beta / antagonists & inhibitors*
  • Interleukin-6 / blood
  • Male
  • Middle Aged
  • Myocardial Infarction / complications


  • Antibodies, Monoclonal, Humanized
  • Hemoglobins
  • IL1B protein, human
  • Interleukin-1beta
  • Interleukin-6
  • canakinumab
  • C-Reactive Protein

Associated data

  • ClinicalTrials.gov/NCT01327846