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J Am Coll Cardiol. 2018 May 29;71(21):2392-2401. doi: 10.1016/j.jacc.2018.03.002. Epub 2018 Mar 12.

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

Author information

1
Center for Cardiovascular Disease Prevention, Harvard Medical School, Boston, Massachusetts; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: beverett@bwh.harvard.edu.
2
Endocrinology, Diabetes & Metabolism, University Hospital Basel, Basel, Switzerland.
3
Center for Cardiovascular Disease Prevention, Harvard Medical School, Boston, Massachusetts; Division of Cardiovascular Medicine, Department of Medicine, VA Boston Medical Center, West Roxbury, Massachusetts.
4
Novartis Pharmaceutical Corporation, East Hanover, New Jersey, and Basel, Switzerland.
5
St. John's Research Institute, Bangalore, India.
6
Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil.
7
Center for Cardiovascular Disease Prevention, Harvard Medical School, Boston, Massachusetts.
8
Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
9
Center for Cardiovascular Disease Prevention, Harvard Medical School, Boston, Massachusetts; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

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).

KEYWORDS:

cardiovascular disease; diabetes; inflammation; randomized trial

PMID:
29544870
DOI:
10.1016/j.jacc.2018.03.002

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