To test formally the inflammatory hypothesis of atherothrombosis, an agent is needed that reduces inflammatory biomarkers such as C-reactive protein, interleukin-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 mellitus 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 with placebo, canakinumab had modest but nonsignificant effects on the change in hemoglobin A1c, glucose, and insulin levels. No effects were seen for low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or non–high-density lipoprotein cholesterol, although triglyceride levels increased ≈10% in the 50-mg (P=0.02) and 150-mg (P=0.03) groups. By contrast, the median reductions in C-reactive protein 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 with 4.7% for placebo (all P values ≤0.02). Similarly, the median reductions in interleukin-6 at 4 months across the canakinumab dose range tested were 23.9%, 32.5%, 47.9%, and 44.5%, respectively, compared with 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 with 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 interleukin-1β, significantly reduces inflammation without major effect on low-density lipoprotein cholesterol or high-density lipoprotein cholesterol. 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—
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00900146.