Anti-Inflammatory Therapy With Canakinumab for the Prevention and Management of Diabetes
Key result
Canakinumab fails to reduce new-onset diabetes compared to placebo in post-MI patients.
Why the study?
Subclinical inflammation mediated by IL-1β contributes to insulin resistance and impaired insulin secretion, motivating testing of canakinumab to reduce incident diabetes.
Does canakinumab reduce incident diabetes and major cardiovascular events in patients with prior myocardial infarction and elevated hsCRP?
Study Design
Type
RCT (n=10,061)
Randomization
randomized
Structured PICO
Does canakinumab reduce incident diabetes and major cardiovascular events in patients with prior myocardial infarction and elevated hsCRP?
P
Population
10,061 patients with prior myocardial infarction and hsCRP ≥2 mg/l, followed for a median of 3.7 years.
I
Intervention
Canakinumab 50 mg, 150 mg, or 300 mg subcutaneously once every 3 months
C
Comparator
Placebo
O
Outcome
Major cardiovascular events across glycemic strata; adjudicated cases of new-onset type 2 diabetes among those with protocol-defined pre-diabetes at trial entrycomposite
Main Result
Hazard Ratio: 1.02 (95% CI 0.87–1.19)
p-value: p=0.82
In patients with prior myocardial infarction and elevated hsCRP, IL-1β inhibition with canakinumab reduces cardiovascular risk irrespective of baseline glycemic status, but does not prevent incident diabetes.
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Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“When we designed the main trial, we knew we were going after atherosclerosis and we knew we were going after cancer.”
“We find that among heart attack survivors with diabetes or pre-diabetes, canakinumab is effective at reducing risk of cardiovascular events. Our data also suggest that as cardiovascular disease and diabetes take root, the inflammatory pathways underlying them may diverge.”
“There's this idea that the pancreas kind of gives out at some point in type 2 diabetes, that it just goes kaput, and inflammation may play an important role in the islet cells giving out. We thought, maybe, by interrupting that [with canakinumab] we could prolong islet cell longevity, improve peripheral glucose sensitivity, and prevent diabetes.”
Implication
IL-1β inhibition offers no diabetes prevention benefit post-MI; challenges IL-1β as a modifiable driver of incident diabetes.
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 (HbA 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 HbA 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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Cite This Study
Donath et al. (2018) conducted an RCT in Prior myocardial infarction and elevated hsCRP (n=10,061). Canakinumab vs. Placebo was evaluated on New-onset type 2 diabetes (HR 1.02, 95% CI 0.87-1.19, p=0.82). Canakinumab did not reduce the incidence of new-onset diabetes compared to placebo among patients with prior myocardial infarction and elevated hsCRP.