Authors : Everett BM, Donath MY, Pradhan AD, Thuren T, Pais P, Nicolau JC, Glynn RJ, Libby P, Ridker PM
Publication Year : 2018
Subclinical inflammation mediated in part by interleukin-1 beta (IL-1ß) participates in peripheral insulin resistance and impaired pancreatic insulin secretion.
We tested the hypothesis that canakinumab, an IL-1ß inhibitor, reduces incident diabetes.
The Canakinumab Antiinflammatory Thrombosis Outcomes Study (CANTOS) randomized 10,061 patients with prior MI and high-sensitivity C-reactive protein (hsCRP) greater than or equal to 2 mg/L to placebo or canakinumab at doses of 50mg, 150mg, or 300mg subcutaneously once every three months. We 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. We also evaluated the effect of canakinumab on fasting plasma glucose and HbA1c in patients with and without established diabetes.
Of CANTOS participants, 4,057 (40.3%) had baseline diabetes, 4,960 (49.3%) had pre-diabetes, and 1,044 (10.4%) had normal glucose. 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 150mg as compared to placebo had similar magnitude effects on major cardiovascular event rates among those with diabetes (HR 0.85, 95% CI 0.70-1.03), pre-diabetes (0.86, 95% CI 0.70-1.06), and normoglycemia (HR 0.81, 95% CI 0.49-1.35). Despite large reductions in hsCRP and interleukin-6, canakinumab did not reduce the incidence of new onset diabetes, with rates per 100 person years in the placebo, 50mg, 150mg, and 300mg canakinumab groups of 4.2, 4.2, 4.4, and 4.1, respectively (Log-rank P=0.84). The hazard ratio comparing all canakinumab doses to placebo was HR 1.02 (95% CI 0.87-1.19, P=0.82). Canakinumab reduced HbA1c during the first 6-9 months of treatment but no consistent long-term benefits on HbA1c or fasting plasma glucose were observed.
While IL-1ß 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.