Arterial Effects of Canakinumab in Patients With Atherosclerosis and Type 2 Diabetes or Glucose Intolerance

Abstract

Background: Evidence suggests that interleukin (IL)-1β is important in the pathogenesis of atherosclerosis and its complications and that inhibiting IL-1β may favorably affect vascular disease progression.

Objectives: The goal of this study was to evaluate the effects of IL-1β inhibition with canakinumab versus placebo on arterial structure and function, determined by magnetic resonance imaging.

Methods: Patients (N = 189) with atherosclerotic disease and either type 2 diabetes mellitus or impaired glucose tolerance were randomized to receive placebo (n = 94) or canakinumab 150 mg monthly (n = 95) for 12 months. They underwent magnetic resonance imaging of the carotid arteries and aorta.

Results: There were no statistically significant differences between canakinumab compared with placebo in the primary efficacy and safety endpoints. There was no statistically significant change in mean carotid wall area and no effect on aortic distensibility, measured at 3 separate anatomic sites. The change in mean carotid artery wall area was -3.37 mm2 after 12 months with canakinumab versus placebo. High-sensitivity C-reactive protein was significantly reduced by canakinumab compared with placebo at 3 months (geometric mean ratio [GMR]: 0.568; 95% confidence interval [CI]: 0.436 to 0.740; p < 0.0001) and 12 months (GMR: 0.56; 95% CI: 0.414 to 0.758; p = 0.0002). Lipoprotein(a) levels were reduced by canakinumab compared with placebo (-4.30 mg/dl [range: -8.5 to -0.55 mg/dl]; p = 0.025] at 12 months), but triglyceride levels increased (GMR: 1.20; 95% CI: 1.046 to 1.380; p = 0.01). In these patients with type 2 diabetes mellitus or impaired glucose tolerance, canakinumab had no effect compared with placebo on any of the measures assessed by using a standard oral glucose tolerance test.

Conclusions: There were no statistically significant effects of canakinumab on measures of vascular structure or function. Canakinumab reduced markers of inflammation (high-sensitivity C-reactive protein and interleukin-6), and there were modest increases in levels of total cholesterol and triglycerides. (Safety & Effectiveness on Vascular Structure and Function of ACZ885 in Atherosclerosis and Either T2DM or IGT Patients; NCT00995930).

Keywords: C-reactive protein; homeostasis model assessment; inflammation; interleukin-1.

Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Changes in Carotid Wall Area We evaluated 12-month change from baseline in wall area as an indicator of atherosclerosis progression. (A) In both left and right carotid arteries, canakinumab retarded progression of wall area compared with placebo. Consistent in magnitude and direction, the changes did not reach statistical significance in the mean carotid wall area (pre-stated endpoint) or in either carotid artery analyzed separately. Bars = means with 95% confidence intervals. (B) Within the same patient, there was a striking concordance of change in wall area between left- and right-sided arteries, which was maintained in both treatment groups (p < 0.0001 for each). Upper right quadrant = patients with progression in both carotid arteries.

Figure 2

Changes in Lipids and C-Reactive Protein Absolute level or change from baseline at 3 and 12 months are shown for (A) C-reactive protein; (B) lipoprotein(a) (Lp[a]); (C) total cholesterol; (D) high-density lipoprotein (HDL) cholesterol; and (E) triglycerides.

Central Illustration

Effects of IL-1β Inhibition Interleukin (IL)-1β seems important in the pathogenesis of atherosclerosis. In this placebo-controlled trial in patients with evidence of clinical atherosclerosis and either type 2 diabetes mellitus or impaired glucose tolerance, the IL-1β inhibitor canakinumab reduced measures of inflammation but did not significantly affect measures of vascular structure or function. LDL = low-density lipoprotein.