IL-1β inhibitor does not prevent new onset type 2 diabetes
Anti-Inflammatory Therapy with Canakinumab and Incident Type 2 Diabetes: A Pre-Specified Key Secondary Endpoint of the CANTOS Trial
News - Mar. 12, 2018Introduction and methods
Data suggest a pathologic role for subclinical inflammation in peripheral insulin resistance, impaired insulin secretion and the development of type 2 diabetes (T2DM). This may in part be mediated by induction of the NLRP3 inflammasome and activation of IL-1β. Treatment with anakinra, an IL-1 receptor antagonist, showed improvements in beta cell function, peripheral glucose sensitivity, reductions in HbA1c in 70 T2DM patients [1].
The monoclonal antibody targeting IL-1β canakinumab, was evaluated in post-MI patients for the reduction of CV events. In the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), stable post-MI patients with hsCRP ≥2 mg/mL were randomized to placebo or one of three doses (50, 150, 300 mg) canakinumab. Canakinumab reduced the primary endpoint, a composite of non-fatal MI, non-fatal stroke, and CV death (MACE).
In this sub-analysis of CANTOS, the effect of canakinumab on the risk of new onset T2DM was evaluated. Participants were monitored for the development of newly diagnosed T2DM, defined as two measures within 6 weeks of either HbA1c ≥6.5% or fasting plasma glucose ≥126 mg/dL, or by the institution of antihyperglycemic therapy.
Main results
- There was no difference of the effect of canakinumab on MACE or MACEplus between those with and without T2DM and pre-diabetes at baseline.
- Baseline hsCRP and IL-6 levels were associated with the rate of incident T2DM (log-rank P=0.0002 and P<0.0001, respectively).
- Treatment with canakinumab reduced HbA1c from baseline to 9-12 months in participants with pre-diabetes, but effects attenuated over time after this period.
- There was no effect of canakinumab on the rate of new onset diabetes in those with pre-diabetes at baseline compared to placebo (adjudicated diabetes: HR 1.01; 95%CI:0.87-1.18, P=0.86, all physician reported diabetes: HR 1.01 95%CI:0.88-1.17, P=0.89).
Conclusion
Treatment with the IL-1β inhibitor canakinumab did not prevent the progression from pre-diabetes to diabetes in post-MI patients with hsCRP ≥2 mg/mL.
In a press release the study’s lead author dr. Everett said: “The results were surprising, because we demonstrated there was an effect on blood glucose that didn’t translate into a reduced rate of type 2 diabetes diagnosis. It suggests that alternative inflammatory pathways may be more critical to the development of diabetes than inhibition of interleukin-1 beta, which was the specific mechanism we tested in this study.”
References
1. Larsen CM, Faulenbach M, Vaag A, et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med. 2007;356:1517-26.
Disclosures
Our coverage of ACC.18 is based on the information provided during the congress.
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