Author + information
- Received February 14, 2018
- Revision received February 28, 2018
- Accepted March 1, 2018
- Published online May 21, 2018.
- Brendan M. Everett, MD, MPHa,b,∗ (, )@_brendan_,
- Marc Y. Donath, MDc,
- Aruna D. Pradhan, MD, MPHa,d,
- Tom Thuren, MDe,
- Prem Pais, MDf,
- Jose C. Nicolau, MDg,
- Robert J. Glynn, ScDa,
- Peter Libby, MDb and
- Paul M Ridker, MD, MPHa,b
- aCenter for Cardiovascular Disease Prevention, Harvard Medical School, Boston, Massachusetts
- bDivision of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
- cEndocrinology, Diabetes & Metabolism, University Hospital Basel, Basel, Switzerland
- dDivision of Cardiovascular Medicine, Department of Medicine, VA Boston Medical Center, West Roxbury, Massachusetts
- eNovartis Pharmaceutical Corporation, East Hanover, New Jersey, and Basel, Switzerland
- fSt. John’s Research Institute, Bangalore, India
- gInstituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil
- ↵∗Address for correspondence:
Dr. Brendan M. Everett, Brigham and Women’s Hospital, Divisions of Preventive and Cardiovascular Medicine, 900 Commonwealth Avenue, Boston, Massachusetts 02215.
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)
Substantial data support a pathological role for subclinical inflammation in both insulin sensitivity and impaired insulin production from pancreatic beta cells that promotes initiation and progression of type 2 diabetes (1–3). Cellular and animal experiments suggest prolonged hyperglycemia and the deposition of amyloid polyprotein in pancreatic islet cells lead to induction of the NOD-like receptor pyrin-3 (NLRP3) inflammasome, followed by activation of interleukin (IL)-1β and local autoinduction of IL-1 in pancreatic islets (4–6). Macrophage recruitment and local inflammation could then lead to impaired insulin secretion and beta cell death, a critical step in progression from pre-diabetes to type 2 diabetes (2,4,7). Clinically, a randomized trial of anakinra, an IL-1 receptor antagonist, showed improvements in beta cell function and peripheral glucose sensitivity, and reductions in glycosylated hemoglobin (HbA1c), in patients with established type 2 diabetes (8). Longer-term follow-up of these patients revealed persistence of these beneficial effects (9). Other small studies with IL-1 inhibitors have shown modest reductions in HbA1c (10,11). Yet, although these data support the inflammation hypothesis of diabetes, no data inform whether IL-1 inhibition can prevent incident type 2 diabetes in a pre-diabetic population. A pre-specified secondary endpoint of the recently reported CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) specifically addressed this hypothesis (12). In addition, the CANTOS trial structure included many patients with pre-existing diabetes, and thus afforded the additional opportunity to evaluate whether IL-1β inhibition slows the progression of type 2 diabetes as assessed by HbA1c and fasting plasma glucose.
Study design and participants
The randomized, double-blind, placebo-controlled CANTOS trial compared 3 doses of canakinumab (50, 150, or 300 mg) to placebo that enrolled 10,061 patients with prior myocardial infarction and high-sensitivity C-reactive protein (hsCRP) ≥2 mg/l (12). The study protocol pre-specified that the occurrence of type 2 diabetes among those with pre-diabetes at baseline was a key secondary endpoint of the trial.
Before randomization, participants were assessed for the presence of either diabetes (type 1 or 2) as well as protocol-defined pre-diabetes. The assessment of the effect of canakinumab on the occurrence of type 2 diabetes included only those without diabetes at baseline, and the primary analysis was the protocol pre-specified effect of canakinumab among those with pre-diabetes at baseline. The definition of diabetes at baseline included any patient with a medical history of type 2 diabetes, or any patient currently on an antidiabetic medication, or any patient with an HbA1c ≥6.5% at screening and randomization; or a fasting plasma glucose of ≥126 mg/dl at screening and randomization; or a combination of fasting plasma glucose ≥126 mg/dl and a HbA1c ≥6.5% at screening or randomization; or any patient subsequently determined by the clinical endpoints committee to have developed type 2 diabetes with a date of onset equal to or prior to the date of randomization. Pre-diabetes was defined by an HbA1c of 5.7% to <6.5% at screening or randomization; a fasting plasma glucose of 100 to 125 mg/dl (5.6 to 6.9 mmol/l) at screening or randomization; a fasting plasma glucose ≥126 mg/dl at either screening or randomization, but not both; or an HbA1c ≥6.5% at either screening or randomization, but not both (13). Patients with an HbA1c <5.7% and a fasting plasma glucose <100 mg/dl at screening and randomization were defined as normoglycemic.
Patients enrolled in the CANTOS trial had blood collected for assessment of fasting plasma glucose and HbA1c at screening and randomization, and then again at months 1.5, 3, 6, 9, 12, and every 12 months thereafter. Patients were asked about a new diagnosis of type 2 diabetes and medications were assessed for the addition of any new antidiabetic medications at in-person visits every 3 months. Baseline and 3-month concentrations of hsCRP and IL-6 assessed inflammation inhibition with canakinumab for individual participants.
To determine whether any effect of canakinumab on the development of type 2 diabetes was maintained after study drug discontinuation, patients with pre-diabetes at baseline and at the time of trial completion had blood collected for HbA1c and fasting plasma glucose 6 months after study drug discontinuation. Other trial participants entered an open-label extension period.
The CANTOS trial primary cardiovascular endpoint was the composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. The CANTOS trial secondary cardiovascular endpoint was the primary endpoint plus hospitalization for unstable angina with unplanned coronary revascularization. Both endpoints were assessed by a clinical endpoint committee composed of cardiologists and neurologists blinded to study drug allocation. New-onset type 2 diabetes was adjudicated by an endpoints committee of endocrinologists who were blinded to study drug allocation. The definition of type 2 diabetes used by the adjudication committee required an HbA1c ≥6.5% or a fasting plasma glucose ≥126 mg/dl, or the combination, on 2 blood draws within 6 weeks of one another, or a new prescription of an antidiabetic medication. The date of onset was the date of the first laboratory abnormality if the diagnosis was made using laboratory parameters, or the date of antidiabetic medication prescription. In a sensitivity analysis, we expanded the definition of type 2 diabetes to include physician-diagnosed type 2 diabetes, even if the diagnosis did not meet the definition used by the clinical endpoints committee. Results for the primary and key secondary cardiovascular endpoints were previously published (12), whereas results for the other key secondary endpoint of incident diabetes in participants with pre-diabetes are presented here so as to include results from the washout period.
We first identified the effect of canakinumab on the occurrence of the trial primary and secondary cardiovascular endpoints in patients with and without baseline diabetes. Kaplan-Meier graphs and unadjusted log-rank p values were used to evaluate differences between groups. Evidence for heterogeneity of treatment across baseline diabetes strata was tested by means of a likelihood ratio test by adding multiplicative interaction terms for randomized treatment (all canakinumab doses combined vs. placebo) × baseline pre-diabetes, diabetes, or normoglycemia status to a proportional hazards model.
We then attempted to replicate previously reported associations between baseline tertiles of hsCRP and IL-6, and new-onset type 2 diabetes among the CANTOS trial patients without diabetes at study entry (1). We used Kaplan-Meier graphs, unadjusted log-rank p values, and adjusted Cox proportional hazards models to compare the rates of new-onset type 2 diabetes by tertile of baseline hsCRP or IL-6. Of the 6,004 patients without diabetes at entry, baseline hsCRP and IL-6 measures were available in 6,001 and 2,928, respectively. Consistent with prior work, models were adjusted for age, sex, race, body mass index, family history of diabetes, smoking, physical activity, alcohol use, and randomized treatment allocation (1).
On a protocol pre-specified basis, we compared unadjusted incidence rates of adjudicator-determined type 2 diabetes in the placebo and canakinumab 50 mg, 150 mg, and 300 mg treatment groups among patients with pre-diabetes at baseline. Kaplan-Meier graphs and unadjusted log-rank p values evaluated differences between randomly allocated treatment groups, and Cox proportional hazards were used to calculate the risk of new-onset type 2 diabetes among those randomly allocated to each of the canakinumab doses versus placebo, as well as for all canakinumab doses combined versus placebo. We tested the adequacy of the proportional hazards assumption in Cox regression models using methods derived from the cumulative sums of martingale residuals over follow-up times. A nominal violation of the proportional hazards assumption (P<0.05) led us to examine that risk for new-onset diabetes with randomly allocated canakinumab therapy for events that occurred prior to or after the median study event time of 2.5 years. We evaluated the effect of canakinumab versus placebo on HbA1c and fasting plasma glucose over the course of the trial in patients with baseline pre-diabetes, established diabetes, and normoglycemia using linear regression mixed models with percent change from baseline as the outcome and adjusted for baseline measure.
Among patients with diabetes at study entry, a protocol pre-specified analysis compared HbA1c by treatment group over the course of the study. In a sensitivity analysis, we analyzed changes in HbA1c among participants with baseline diabetes and an HbA1c ≥8.0%. A second protocol pre-specified analysis compared the time to failure of glycemic control, defined as the time to an HbA1c ≥7.5% for those with baseline diabetes and an HbA1c <7%. We compared the mean number of classes of diabetes medications by treatment group, and the proportion of patients who initiated insulin among those with baseline diabetes in the placebo versus canakinumab groups. The diabetes medication classes were insulin, thiazolidinediones, metformin/biguanides, sulfonylureas, alpha-glucosidase inhibitors, meglitinides, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose co-transporter 2 inhibitors.
Of the 10,061 patients randomized in the CANTOS trial, 4,057 had diabetes at baseline, 4,960 had protocol-defined pre-diabetes, and 1,044 had normal glucose levels. Compared with placebo, canakinumab had similar efficacy in preventing major cardiovascular events among those with and without diabetes at trial entry. The estimated risk of the CANTOS primary cardiovascular endpoint for patients randomly allocated to all doses of canakinumab versus placebo was 0.90 (95% confidence interval [CI]: 0.77 to 1.05) among those with baseline diabetes, and 0.86 (95% CI: 0.73 to 1.01) with baseline pre-diabetes, and 0.81 (95% CI: 0.56 to 1.19) among those with normal glucose at baseline (p-heterogeneity = 0.86) (Online Table 1). Comparable estimates for the secondary cardiovascular endpoint were 0.90 (95% CI: 0.78 to 1.04) for patients with diabetes, 0.81 (95% CI: 0.70 to 0.95) for patients with pre-diabetes, and 0.77 (95% CI: 0.54 to 1.11) for those with normal glucose at baseline (p for heterogeneity = 0.56) (Online Table 2). Compared with placebo, randomly allocated canakinumab was associated with a similar reduction in the absolute risk of the primary cardiovascular endpoint in patients with baseline diabetes (0.55), pre-diabetes (0.55), and normoglycemia (0.64).
Baseline concentrations of hsCRP and IL-6 significantly predicted new-onset type 2 diabetes among those without diabetes at study entry (Figure 1). In models adjusted for age, sex, race, and study drug allocation, relative risks in the lowest to highest tertile of hsCRP were 1.00 (referent), 1.29 (1.08 to 1.56), and 1.36 (1.13 to 1.63), p for trend <0.001. Comparable tertile data for IL-6 were 1.00 (referent), 1.42 (1.09 to 1.84), and 1.93 (1.50 to 2.48), p for trend <0.001. These results were modestly attenuated but remained statistically significant after adjustment for body mass index, family history of diabetes, smoking, exercise, alcohol use, and randomly allocated therapy. They were attenuated and no longer statistically significant for hsCRP, but remained significant for IL-6 after the addition of baseline HbA1c to the model (Online Table 3).
The baseline characteristics of the 4,960 patients with protocol-defined pre-diabetes at study entry were well balanced across randomized treatment assignment (Online Table 4).
Similar to observations made in the CANTOS trial as a whole, the median percent reduction (interquartile range [IQR]) in hsCRP after the first dose of canakinumab, compared with placebo, among those with protocol-specified pre-diabetes in the 50, 150, and 300 mg groups were −49.2 (IQR: −20.0 to −67.2), −61.5 (IQR: −33.3 to −75.8), and −67.1 (IQR: −43.2 to −80.6), respectively. Comparable data for IL-6 were −25.7 (IQR: 0.7 to −46.6), −37.4 (IQR: −9.1 to −54.9), and −43.4 (IQR: −21.0 to −60.0). Among those with diabetes at baseline, a similar pattern was seen (Online Table 5).
Despite these significant, dose-dependent reductions in inflammation with canakinumab, IL-1β inhibition did not reduce rates of new-onset diabetes, a major pre-specified secondary endpoint of the CANTOS trial. The incidence rates of adjudicated cases of new-onset diabetes were 4.20, 4.24, 4.35, and 4.12 in the placebo, 50 mg, 150 mg, and 300 mg canakinumab groups, respectively (Table 1) (all p values ≥0.70). When all canakinumab doses were combined and compared with placebo, the hazard ratio (HR) was 1.02 (95% CI: 0.87 to 1.18; p = 0.85) (Figure 2). The use of physician-reported diabetes as an endpoint yielded similar neutral results (Table 1, Online Figure 1). We repeated these analyses in the subgroup of patients with normal glucose at study entry (Online Table 6) and saw no benefit of canakinumab on rates of new-onset diabetes. We also found no evidence that, compared with placebo, canakinumab reduced the risk of new-onset diabetes among those who achieved hsCRP <2 mg/l or an IL-6 level less than the median (1.54 ng/l).
The suggestion of a time-varying effect on new onset diabetes observed in Figure 2A and 2B was supported by statistically significant evidence of a violation of the proportional hazards assumption. When we analyzed events that occurred prior to the median event time of 2.5 years separately from those that occurred after the median event time, we observed a reduced risk of new-onset diabetes with randomly allocated canakinumab therapy for the early events, followed by the suggestion of an increased risk for the later events (Online Table 7).
Participants with protocol-defined pre-diabetes randomized to active canakinumab demonstrated modest, but statistically significant, reductions in HbA1c over the first 6 to 9 months, an effect that attenuated over time such that there was no difference in HbA1c at 48 months (Figures 3A and 3B, Online Table 8). A similar pattern was observed among those with diabetes (Figures 3C and 3D, Online Table 8) or normoglycemia at trial entry (Figures 3E and 3F, Online Table 8). No consistent effects were observed for fasting plasma glucose (Online Figure 2, Online Table 9). In a sensitivity analysis conducted among 1,224 patients with baseline diabetes and HbA1c ≥8.0%, we observed an initial fall in HbA1c and fasting plasma glucose in all 4 treatment groups for the first 6 months of the study, reflecting regression to the mean or more aggressive treatment, and similar HbA1c and fasting glucose levels for the remainder of the study (Online Figure 3, Online Table 10). There were no significant differences in the time to HbA1c ≥7.5% among patients with baseline diabetes and a baseline HbA1c <7% (Online Figure 4). Among patients with baseline diabetes, the mean number of diabetes medication classes did not differ between active and placebo treatment groups (Online Table 11), and a similar proportion of patients with type 2 diabetes randomly allocated to placebo (11.4%) and canakinumab (11.8%) initiated insulin during the trial (p = 0.40).
The baseline characteristics of the 1,770 patients enrolled in the washout period were well balanced across treatment groups (Online Table 12). At the beginning of the washout period, the median (IQR) HbA1c for placebo and 50 mg, 150 mg, and 300 mg treatment groups were 5.9% (IQR: 5.7% to 6.2%), 5.9 (IQR: 5.7% to 6.2%), 5.9% (IQR: 5.7% to 6.1%), and 5.9% (IQR: 5.7% to 6.1%), respectively. No clinically substantive changes in HbA1c or fasting plasma glucose were observed 6 months after discontinuation of canakinumab (Table 2).
Irrespective of drug allocation, rates of serious infections were higher among patients with diabetes than without diabetes (incidence rate per 100 person-years 3.94 vs. 2.49; HR: 1.58; 95% CI: 1.41 to 1.78; p < 0.0001), as were rates of fatal infections (incidence rate per 100 person-years 0.41 vs. 0.17; HR: 2.42; 95% CI: 1.62 to 3.62; p < 0.0001). Among patients with diabetes, canakinumab as compared with placebo was not associated with an increased risk of infection (HR: 1.05; 95% CI: 0.88 to 1.25; p = 0.63) but was associated with a significant increase in fatal infection (HR: 1.86; 95% CI: 1.01 to 3.43) as was seen in the trial as a whole.
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 our 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 to 9 months, an effect that attenuated over time such that there was no difference in HbA1c at 48 months. In contrast to our prior publications for atherosclerosis and cancer, where we saw greater risk reductions with higher doses of canakinumab, we saw no dose-response effect of IL-1β inhibition for incident diabetes (12,14).
These data have several important implications for both clinical practice and pathophysiology. First, our neutral data for incident diabetes indicate that previously reported benefits on major cardiovascular events in the CANTOS trial as a whole do not relate to the prevention of diabetes or to changes in glucose metabolism. These data add to prior evidence from the CANTOS trial that showed no effect of canakinumab on low-density lipoprotein cholesterol levels, and thus reinforce that the benefits of IL-1β antagonism on atherosclerosis appear due to inflammation inhibition alone (Central Illustration) (12,15).
Second, although canakinumab did not reduce the risk of new-onset type 2 diabetes in the CANTOS trial, 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 (16).
Third, careful interpretation of these results is warranted given the a priori strength of the hypothesis relating inflammation and diabetes. In our study, canakinumab led to small decreases in HbA1c in the first 6 to 9 months that were similar in magnitude to prior work in patients with type 2 diabetes (8,10,11,17). 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 antidiabetic 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 (18,19).
Our data do not address the possibility that cytokines beyond IL-1 may drive the progression from pre-diabetes to type 2 diabetes. Adipose tissue can elaborate tumor necrosis factor, a cytokine that causes insulin resistance in mouse models of type 2 diabetes (20). However, the role of tumor necrosis factor in humans with type 2 diabetes or metabolic syndrome remains to be tested in well-designed studies (21–23). Salicylate, a less targeted anti-inflammatory agent that is thought to inhibit nuclear factor kappa-B (NF-κB) activity by activating adenosine monophosphate-activated protein kinase, modestly lowered HbA1c and inflammatory mediators in patients with type 2 diabetes (24). NF-κB integrates and amplifies the inflammatory signals transmitted by key chemokines and cytokines known to associate with type 2 diabetes and insulin resistance, including IL-1β and IL-6, 2 key cytokines directly affected by canakinumab administration (25). Agents with less targeted anti-inflammatory actions that nonetheless alter NF-κB activity, such as salicylate, may be more likely to alter the key inflammatory pathways contributing to insulin resistance and progression from pre-diabetes to type 2 diabetes (3). The ongoing CIRT (Cardiovascular Inflammation Reduction Trial) of low-dose methotrexate in patients with established coronary artery disease and diabetes or the metabolic syndrome is tracking incident type 2 diabetes (26). Just as anti-inflammatory agents targeting alternative, non–IL-1β pathways failed to show a benefit on major cardiovascular events before the CANTOS trial (27,28), drugs targeting alternative inflammatory pathways may yet show benefit in diabetes prevention.
More than 20 years ago, the “common soil” hypothesis postulated that a shared antecedent exists for both type 2 diabetes and cardiovascular disease (29). Whereas inflammation remains important for both disorders, data from the CANTOS trial suggest divergence of inflammatory pathways in cardiovascular disease and diabetes.
The CANTOS trial included >9,000 patients with pre-diabetes and diabetes within a randomized, double-blind, placebo-controlled trial. Nonetheless, the CANTOS eligibility criteria limit the generalizability of our findings to those with prior myocardial infarction and an hsCRP ≥2 mg/l. As shown here, these criteria selected for a population with a remarkably high prevalence of abnormal glucose tolerance (90% of all participants), emphasizing the utility of hsCRP, a measure of subclinical inflammation, in identifying patients with abnormalities in glucose metabolism (30). CANTOS was not designed specifically to test the effect of canakinumab among patients with established diabetes, so the results of glucose control in that population should be considered hypothesis-generating.
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.
COMPETENCY IN MEDICAL KNOWLEDGE: Although elevated hsCRP and IL-6, markers of subclinical inflammation, predict development of type 2 diabetes mellitus, and canakinumab reduces these levels and lowers cardiovascular event rates in patients with diabetes, pre-diabetes, and normoglycemia, it does not prevent diabetes among patients with pre-diabetes.
TRANSLATIONAL OUTLOOK: Further studies are needed to assess the efficacy of other anti-inflammatory therapies on insulin production, insulin sensitivity, and cardiovascular outcomes.
Funded by Novartis, Basel, Switzerland. The sponsor of the CANTOS trial, Novartis Pharmaceuticals, was involved in the design of the trial protocol and the collection of trial data. Dr. Everett has served as a consultant to and received grant support from Novartis for work unrelated to the CANTOS trial. Dr. Thuren is an employee of and holds stock in Novartis Pharmaceuticals. Dr. Pais has received research grant support from Novartis Pharmaceuticals to conduct the CANTOS trial. Dr. Nicolau has received research grant support from Novartis Pharmaceuticals to conduct the CANTOS trial; and has received research grants and/or personal fees from Amgen, Novartis, AstraZeneca, Bayer, Dalcor, Merck, Pfizer, and Sanofi. Dr. Glynn has received research grant support from Novartis Pharmaceuticals to conduct the CANTOS trial; and has been an unpaid consultant to Novartis. Dr. Libby has served as a consultant to Novartis. Dr. Ridker has received research grant support from Novartis Pharmaceuticals to conduct the CANTOS trial, and from Pfizer and Kowa Pharmaceuticals; has served as a consultant to Novartis; and is listed as a coinventor on patents held by the Brigham and Women’s Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease and diabetes that have been licensed to AstraZeneca and Siemens. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- confidence interval
- glycosylated hemoglobin
- hazard ratio
- high-sensitivity C-reactive protein
- interquartile range
- nuclear factor kappa-B
- NOD-like receptor pyrin-3
- Received February 14, 2018.
- Revision received February 28, 2018.
- Accepted March 1, 2018.
- 2018 American College of Cardiology Foundation
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