Everett BM, Donath MY, Pradhan AD, Thuren T, Pais P, Nicolau JC, Glynn RJ, Libby P, Ridker PM. Anti-Inflammatory Therapy with Canakinumab for the Prevention and Management of Diabetes. J Am Coll Cardiol. 2018 Mar 3. pii: S0735-1097(18)33483-1. doi: 10.1016/j.jacc.2018.03.002. [Epub ahead of print]
Pablo Avanzas, Consultant in Interventional Cardiology, Hospital Universitario Central de Asturias
The authors tested the hypothesis that canakinumab, an IL-1β 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) ≥2 mg/L to placebo or canakinumab at doses of 50mg, 150mg, or 300mg subcutaneously once every three months. The investigators 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. 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.
This randomized, double blind, placebo controlled trial of IL-1β inhibition affirmed that baseline concentrations of hsCRP and IL-6 predict incident diabetes, and found that canakinumab has similar efficacy for major cardiovascular events in patients with and without diabetes. However, contrary to the protocol pre-specified hypothesis, IL-1β inhibition over a 5- year period did not limit the development of new onset diabetes. Canakinumab reduced HbA1c over the first 6-9 months, an effect that attenuated over time such that there was no difference in HbA1c at 48 months. In contrast to the previous publication for atherosclerosis and cancer, where the authors saw greater risk reductions with higher doses of canakinumab, they saw no dose response effect of IL-1β inhibition for incident diabetes.
These data have several important implications for both clinical practice and pathophysiology. First, the neutral data for incident diabetes indicate that previously reported benefits on major cardiovascular events in CANTOS as a whole do not relate to the prevention of diabetes or to changes in glucose metabolism.
Second, while canakinumab did not reduce the risk of new onset type 2 diabetes in CANTOS, nor did IL-1β neutralization increase the risk of diabetes. These analyses reassure that current strategies to treat atherosclerosis through inflammation inhibition do not appear to hasten the onset of diabetes in those already at risk.
Third, careful interpretation of these results is warranted given the a priori strength of the hypothesis relating inflammation and diabetes. In this study, over the first 6 to 9 months, canakinumab led to small decreases in HbA1c in the first 6-9 months that were similar in magnitude to prior work in patients with type 2 diabetes. However, this effect was attenuated over time. The reason for this attenuation is not clear, but may be due to the design of the study, which allowed lifestyle interventions and alterations in other anti-diabetic therapies. Indeed, in other cardiovascular outcome studies using “classical” antidiabetic drugs (dipeptidyl peptidase 4 and sodium–glucose cotransporter 2 inhibitors), similar patterns and magnitude of effects were observed.
In conclusion, random allocation to canakinumab had similar efficacy for cardiovascular events in patients with and without diabetes at study entry. Yet, IL-1β inhibition did not reduce the risk of new onset diabetes in spite of significant reductions in hsCRP and IL-6, a transient improvement of HbA1c, nor did it have long-lasting effects on glycemia among those with diabetes.