Original Investigation
Anti-Inflammatory Therapy With Canakinumab for the Prevention and Management of Diabetes

https://doi.org/10.1016/j.jacc.2018.03.002Get rights and content
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Abstract

Background

Subclinical inflammation mediated in part by interleukin (IL)-1β participates in peripheral insulin resistance and impaired pancreatic insulin secretion.

Objectives

The authors tested the hypothesis that the IL-1β inhibitor canakinumab reduces incident diabetes.

Methods

The authors randomized 10,061 patients with prior myocardial infarction and high-sensitivity C-reactive protein (hsCRP) ≥2 mg/l to placebo or canakinumab at doses of 50 mg, 150 mg, or 300 mg subcutaneously once every 3 months. The authors tested the effects of canakinumab on major cardiovascular events in patients with and without diabetes at baseline, and evaluated as a pre-specified analysis whether canakinumab would reduce the risk of adjudicated cases of new-onset type 2 diabetes among those with protocol-defined pre-diabetes at trial entry. The authors also evaluated the effect of canakinumab on fasting plasma glucose and glycosylated hemoglobin (HbA1c) in patients with and without established diabetes.

Results

Of the participants, 4,057 (40.3%) had baseline diabetes, 4,960 (49.3%) had pre-diabetes, and 1,044 (10.4%) had normal glucose levels. Among those without diabetes, increasing tertiles of hsCRP at baseline associated with an increased risk of developing diabetes during the median follow-up period of 3.7 years (incidence rates 3.2, 4.1, and 4.4 per 100 person-years; p = 0.003). Canakinumab 150 mg as compared with placebo had similar magnitude effects on major cardiovascular event rates among those with diabetes (hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.70 to 1.03), pre-diabetes (HR: 0.86; 95% CI: 0.70 to 1.06), and normoglycemia (HR: 0.81; 95% CI: 0.49 to 1.35). Despite large reductions in hsCRP and IL-6, canakinumab did not reduce the incidence of new-onset diabetes, with rates per 100 person-years in the placebo, 50 mg, 150 mg, and 300 mg canakinumab groups of 4.2, 4.2, 4.4, and 4.1, respectively (log-rank p = 0.84). The HR comparing all canakinumab doses to placebo was 1.02 (95% CI: 0.87 to 1.19; p = 0.82). Canakinumab reduced HbA1c during the first 6 to 9 months of treatment, but no consistent long-term benefits on HbA1c or fasting plasma glucose were observed.

Conclusions

Although IL-1β inhibition with canakinumab had similar effects on major cardiovascular events among those with and without diabetes, treatment over a median period of 3.7 years did not reduce incident diabetes. (Canakinumab Anti-inflammatory Thrombosis Outcomes Study [CANTOS]; NCT01327846)

Key Words

cardiovascular disease
diabetes
inflammation
randomized trial

Abbreviations and Acronyms

CI
confidence interval
HbA1c
glycosylated hemoglobin
HR
hazard ratio
hsCRP
high-sensitivity C-reactive protein
IL
interleukin
IQR
interquartile range
NF-κB
nuclear factor kappa-B
NLRP3
NOD-like receptor pyrin-3

Cited by (0)

Funded by Novartis, Basel, Switzerland. The sponsor of the CANTOS trial, Novartis Pharmaceuticals, was involved in the design of the trial protocol and the collection of trial data. Dr. Everett has served as a consultant to and received grant support from Novartis for work unrelated to the CANTOS trial. Dr. Thuren is an employee of and holds stock in Novartis Pharmaceuticals. Dr. Pais has received research grant support from Novartis Pharmaceuticals to conduct the CANTOS trial. Dr. Nicolau has received research grant support from Novartis Pharmaceuticals to conduct the CANTOS trial; and has received research grants and/or personal fees from Amgen, Novartis, AstraZeneca, Bayer, Dalcor, Merck, Pfizer, and Sanofi. Dr. Glynn has received research grant support from Novartis Pharmaceuticals to conduct the CANTOS trial; and has been an unpaid consultant to Novartis. Dr. Libby has served as a consultant to Novartis. Dr. Ridker has received research grant support from Novartis Pharmaceuticals to conduct the CANTOS trial, and from Pfizer and Kowa Pharmaceuticals; has served as a consultant to Novartis; and is listed as a coinventor on patents held by the Brigham and Women’s Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease and diabetes that have been licensed to AstraZeneca and Siemens. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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