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

Study Questions:

What is the effect of interleukin (IL)-1β inhibition on surrogate markers of inflammation in diabetic patients at high risk for cardiovascular disease (CVD)?

Methods:

In this phase IIb dose-ranging trial (CANTOS), 556 men and women with well-controlled diabetes mellitus (DM) and high CV risk were randomly allocated to subcutaneous placebo or canakinumab at doses of 5, 15, 50, or 150 mg monthly and followed over 4 months.

Results:

Compared to placebo, canakinumab had modest but nonsignificant effects on glycated hemoglobin (HbA1c, glucose, and insulin levels. No effects were seen for low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), or non–HDL-C, although triglyceride levels increased approximately 10% in the 50 (p = 0.02) and 150 (p = 0.03) mg groups. 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 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). Adverse events were similar in the canakinumab and placebo groups.

Conclusions:

Canakinumab, a human monoclonal antibody that neutralizes IL-1β, significantly reduces inflammatory markers without major effects on LDL-C or HDL-C.

Perspective:

Targeting inflammatory pathways that reduce leukocyte recruitment to atherosclerotic plaques and/or promote plaque stability may be efficacious in reducing residual risk in patients at high risk of CV events who are otherwise on optimal medical therapy, including statins. IL-1β is one of many cytokines that may promote vascular inflammation. This trial demonstrates potentially beneficial effects of neutralizing IL-1β on circulating markers that reflect inflammatory events. These effects do not appear to be related to changes in lipids or insulin sensitivity. These results provide support for the large-scale phase 3 trial (CANTOS), which is currently recruiting subjects to test the hypothesis that targeting IL-1β will reduce CV events in high-risk patients on optimal medical therapy.

Clinical Topics: Dyslipidemia, Nonstatins, Novel Agents, Statins

Keywords: Inflammation, Risk, Plaque, Atherosclerotic, Cytokines, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Interleukin-6, Diabetes Mellitus, Type 2, Interleukin-1, Hemoglobin A, Glycosylated, Immunologic Factors, Interleukin-1beta, Biological Markers, Cardiovascular Diseases, Fibrinogen


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