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

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)

A therosclerosis is well-established as a disease with an important inflammatory component (1)(2)(3). Systemic markers of inflammation such as C-reactive protein and serum amyloid A are strongly related to cardiovascular prognosis in various populations and clinical settings (4,5).
Furthermore, therapeutic interventions that reduce cardiovascular risk have also been associated with a reduction in systemic inflammatory markers (6,7). However, whether specifically targeting inflammation reduces cardiovascular risk remains unknown.
Interleukins are important mediators of inflammation, both locally and systemically.
Macrophages are key cellular components of atherosclerotic plaque and produce interleukin (IL)-1b (8), which is also promoted by cellular cholesterol activation of inflammasomes (9). IL-1b and interleukin-1a exert proinflammatory effects that are inhibited by the endogenous antagonist interleukin-1 receptor antagonist (IL-1RA). Atherosclerosis-prone mice that are deficient in IL-1b develop smaller lesions (10), and administration of IL-1RA reduces early atherogenesis in mice (11). IL-1RA-deficient mice have shown increased atherosclerosis (12) and vascular inflammation, associated with destruction of elastic tissues (13). Therefore, given the key role for IL-1b as a mediator of innate immunity and the effects of interleukin inhibition in experimental atherosclerosis, interventions to reduce inflammation through IL-1b have been proposed to treat atherosclerosis. Although evidence of benefit to vascular disease in humans remain sparse, administration of the IL-1RA anakinra to patients with rheumatoid arthritis improved several measures of vascular function, including aortic distensibility, flow-mediated vasodilation, and coronary flow reserve (14).
In addition to its key role in vascular disease, IL-1b has been implicated in the pathogenesis of type 2 diabetes mellitus (T2DM). IL-1RA expression is reduced in pancreatic islets of patients with T2DM, and high glucose concentrations induce the production of IL-1b in human pancreatic beta cells, leading to impaired insulin secretion, decreased cell proliferation, and apoptosis (15). Blockade of the interleukin-1 receptor with anakinra improved glycemia and beta-cell secretory function and reduced markers of systemic inflammation in patients with T2DM (16). Patients with T2DM are at high risk for cardiovascular disease (17) and have evidence of both increased plaque inflammation (18) and reduced arterial distensibility (19).
This group might, therefore, derive "metabolic" and "vascular" benefits from targeting IL-1b, including reduced risk of atherothrombotic complications.
A human monoclonal anti-human IL-1b antibody of the immunoglobulin G1/k isotype canakinumab functionally neutralizes IL-1b through steric hindrance of its receptor interaction. It is effective in reducing systemic markers of inflammation, including C-reactive protein and IL-6 (20). Its effects on cardiovascular outcomes are under investigation in the CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) trial (21).

Vascular magnetic resonance imaging (MRI) has
emerged as a precise, highly reproducible, and versatile tool to assess both vascular structure and function at multiple arterial loci (22)(23)(24)(25). Accordingly, we designed a randomized, placebo-controlled Phase   All authors had full access to all the data in the study and assume responsibility for publication.

Novartis
All statistical analyses were performed by using Stata 14 (StataCorp LP, College Station, Texas).

RESULTS
Of 450 patients screened, 189 were randomized to receive either placebo (n ¼ 94) or canakinumab 150 mg (n ¼ 95). The proportions of patients with diabetes, duration of diabetes, and glycemic control (estimated from HbA1 c ) were similar in the groups, and there was a high prevalence for each of hypertension, dyslipidemia, and background coronary artery disease ( Table 1); the latter was slightly higher proportionately in the placebo group. There was no Values are n (%), mean AE SD, or median (interquartile range). *Aspirin, clopidogrel, prasugrel, or ticagrelor. For HbA1c, there are 2 missing values for canakinumab and 1 for the control group.
ACE ¼ angiotensin-converting enzyme; BMI ¼ body mass index; CAD ¼ coronary artery disease; HbA1c ¼ glycosylated hemoglobin; HDL ¼ high-density lipoprotein; HOMA-IR ¼ homeostatic model assessment-insulin resistance; hs-CRP ¼ high-sensitivity C-reactive protein; IL ¼ interleukin; LDL ¼ low-density lipoprotein; Lp(a) ¼ lipoprotein(a). Lost to follow-up Values are n (%). *There was no significant difference between canakinumab compared with placebo for the overall rate of discontinuation from the study (risk ratio:  There was no statistically significant difference in wall area between canakinumab treatment and placebo at any of the 3 aortic sites at either 3 or 12 months. Aortic distensibility was calculated from measurements made at 3 sites in the aorta. There were no statistically significant differences between canakinumab treatment and placebo for change in aortic distensibility, and no significant changes occurred in systolic or diastolic blood pressure at either 3 or 12 months of treatment versus baseline. There were also no significant differences in measures of PWV between these 2 groups at either time point (Table 3).     Table 2.   Canakinumab had no effect on fasting glucose, HbA 1c , or measures of insulin sensitivity.
In common with earlier studies (19,23,24), atherosclerosis burden was quantified in the common carotid arteries and the aorta. We found no statisti-     *Change from baseline, not log-transformed. LSMs of outcomes (95% CIs) with number of patients reported from the analysis of covariance of the log-transformed outcome at 3 and 12 months, adjusted for log-transformed baseline of outcome and including the 2-level factor type 2 diabetes mellitus or impaired glucose tolerance as a covariate. Inclusion of patients is according to the protocol. The treatment effect is reported as the difference between the canakinumab arm and the placebo arm and after back-transforming the treatment effect as the ratio of the levels in the canakinumab arm to the placebo arm. The LSMs are back-transformed (geometric means).
Abbreviations as in Tables 1 and 3.  Interleukin (IL)-1b 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-1b inhibitor canakinumab reduced measures of inflammation but did not significantly affect measures of vascular structure or function. LDL ¼ low-density lipoprotein.