Anti-inflammatory therapy with canakinumab for the prevention and management of diabetes
BM Everett, MY Donath, AD Pradhan, T Thuren… - Journal of the American …, 2018 - jacc.org
Journal of the American College of Cardiology, 2018•jacc.org
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 …
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 …
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)
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