Effects of Interleukin-1β Inhibition with Canakinumab on Hemoglobin A1c, Lipids, C-Reactive Protein, Interleukin-6, and Fibrinogen: A Phase IIb Randomized Placebo Controlled Trial
Background—To test formally the inflammatory hypothesis of atherothrombosis, an agent is needed that reduces inflammatory biomarkers such as C-reactive protein (CRP), interleukin-6 (IL-6), and fibrinogen, but that does not have major effects on lipid pathways associated with disease progression.
Methods and Results—We conducted a double-blind, multinational phase IIb trial of 556 men and women with well-controlled diabetes and high cardiovascular risk who were randomly allocated to subcutaneous placebo or to subcutaneous canakinumab at doses of 5, 15, 50, or 150 mg monthly and followed over 4 months. Compared to placebo, canakinumab had modest but non-significant effects on the change in hemoglobin A1c, glucose, and insulin levels. No effects were seen for LDL-C, HDL-C, or nonHDL-C, though triglyceride levels increased approximately 10 percent in the 50 (P=0.02) and 150 (P=0.03) mg groups. By contrast, the median reductions in CRP at 4 months were 36.4%, 53.0 %, 64.6%, and 58.7% for the 5, 15, 50, and 150 mg canakinumab doses, respectively, compared to 4.7% for placebo (all P-values ≤0.02). Similarly, the median reductions in IL-6 at 4 months across the canakinumab dose range tested were 23.9%, 32.5%, 47.9%, and 44.5%, respectively, compared to 2.9% for placebo (all P ≤ 0.008) and the median reductions in fibrinogen at 4 months were 4.9%, 11.7%, 18.5%, and 14.8%, respectively, compared to 0.4% for placebo (all P-values ≤0.0001). Effects were observed in women and men. Clinical adverse events were similar in the canakinumab and placebo groups.
Conclusions—Canakinumab, a human monoclonal antibody that neutralizes IL-1β, significantly reduces inflammation without major effect on LDL-C or HDL-C. These phase II trial data support the use of canakinumab as a potential therapeutic method to test directly the inflammatory hypothesis of atherosclerosis.
Clinical Trial Registration Information—clinicaltrials.gov Identifier: NCT00900146
- Received June 7, 2012.
- Accepted October 2, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited