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

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

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use*
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use*
  • Antibodies, Monoclonal, Humanized
  • Blood Glucose / drug effects*
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2 / blood*
  • Diabetes Mellitus, Type 2 / diagnosis
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Disease Management*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Humans
  • Interleukin-1beta / antagonists & inhibitors*
  • Male
  • Middle Aged
  • Prediabetic State / blood
  • Prediabetic State / diagnosis
  • Prediabetic State / drug therapy

Substances

  • Anti-Inflammatory Agents
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Blood Glucose
  • Interleukin-1beta
  • canakinumab

Associated data

  • ClinicalTrials.gov/NCT01327846