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CANTOS: Canakinumab reduces CV events in CKD, diabetes
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ORLANDO, Fla. — Canakinumab demonstrated efficacy in two patient groups with high CV risk and unmet medical need: those with chronic kidney disease and those with diabetes, according to new data from the CANTOS trial presented at the American College of Cardiology Scientific Session.
As previously reported by Cardiology Today, the CANTOS trial found that canakinumab (Novartis) reduces the rates of recurrent CV events in patients with a history of MI and an elevated high-sensitivity C-reactive protein level. In other data from the CANTOS trial also reported by Cardiology Today, researchers were able to identify which patients would yield the greatest benefits from continued treatment with canakinumab.
Canakinumab in CKD
“Canakinumab, an [interleukin 1-beta] inhibitor, obviously works as a new class of therapy for atherosclerotic disease that lowers CRP with no effect on lipid levels and importantly for the renal discussion, no hemodynamic effects” Paul M. Ridker, MD, MPH, director of the Center for Cardiovascular Disease Prevention and the Eugene Braunwald Professor of Medicine at Brigham and Women’s Hospital, said during the presentation. “Current data demonstrate that anti-inflammatory therapy, at least with canakinumab, has considerable cardiovascular efficacy in high-risk patients with moderate to severe CKD.”
Researchers compared 1,875 patients with moderate chronic kidney disease (CKD; mean age, 68 years) and 8,184 patients with normal renal function (mean age, 60 years) who were assigned canakinumab or placebo. Moderate CKD was defined as an estimated glomerular filtration rate between 30 mL/min/1.73 m2 and 60 mL/min/1.73 m2.
Both groups had equally balanced baseline characteristics. Patients with moderate CKD were more likely to have diabetes, hypertension, high CRP levels and worse renal indices.
The moderate CKD group had an increased risk for major CV events, all-cause mortality and CVD death compared with the normal renal function group (P for all < .0001).
“These are very high-risk patients with considerable unmet needs,” Ridker said in the presentation.
The rates of major adverse CV events plus unstable angina that required urgent revascularization were 7.89 per 100 person-years in patients with moderate CKD who were assigned placebo vs. 4.55 per 100 person-years in patients with normal kidney function who were assigned placebo. In all doses of canakinumab, these rates were lower in patients with moderate CKD (6.46 per 100 person-years; HR = 0.82; 95% CI, 0.68-1; P for trend = .045) and normal kidney function (3.92 per 100 person-years; HR = 0.86; 95% CI, 0.77-0.97; P for trend = .018).
After adjusting for sex, age, hypertension, smoking, BMI, diabetes, baseline LDL and baseline high-sensitivity CRP, HRs in patients with moderate CKD who were treated with canakinumab and had a high-sensitivity CRP greater than 2 mg/L were 0.81 for major adverse CV events plus unstable angina that required urgent revascularization (95% CI, 0.64-1.04), 0.96 for CV mortality (95%, 0.68-1.35) and 0.99 for total mortality (95% CI, 0.76-1.29).
In patients who had a robust response with canakinumab, HRs improved for CV mortality (HR = 0.66; 95% CI, 0.46-0.94), total mortality (HR = 0.76; 95% CI, 0.57-1) and major adverse CV events plus unstable angina that required urgent revascularization (HR = 0.69; 95% CI, 0.54-0.89).
The data were neutral regarding the effect of canakinumab on renal function and on urine albumin-to-creatinine ratio greater than 3 mg/mmol. There was also no difference in the most severe estimated glomerular filtration rate and postrandomization progression to dialysis across all doses.
“Moving forward, for investigators, it will be very important to try to extend these data and test the efficacy of canakinumab in patients with end-stage renal failure and/or those undergoing dialysis,” Ridker said. “In that setting, CRP and IL-6 are powerful predictors of risk, while LDL cholesterol is not, and that’s the only setting where statin therapy has not proved terribly effective, so there’s a reason to think that inflammation is particularly important.”
Canakinumab in diabetes
In a separate analysis, Brendan M. Everett, MD, director of general cardiology inpatient services and assistant professor of medicine at Brigham and Women’s Hospital and Harvard Medical School, and colleagues stratified the CANTOS cohort by diabetes status: 4,507 patients had baseline diabetes, 4,960 patients had baseline prediabetes and 1,044 patients had normal glucose at baseline.
Baseline prediabetes was defined as an HbA1c between 5.7% and 6.5% or a fasting plasma glucose of 100 mg/dL to 125 mg/dL.
The prespecified secondary endpoint was new-onset diabetes in patients with prediabetes at baseline. New-onset diabetes was defined as fasting plasma glucose greater than 126 mg/dL, HbA1c greater than 6.5%, a combination of both of those factors or a new prescription for an antidiabetic medication.
The effects of canakinumab on major adverse CV events with and without diabetes were consistent in all groups with no statistically significant evidence of heterogeneity, Everett said.
High-sensitivity CRP (log-rank P = .0002) and IL-6 (log-rank P < .0001) were significant predictors of the development of new-onset diabetes in patients who did not have it at baseline, and the effects remained after multivariable adjustment for diabetes risk factors. After adjusting for baseline HbA1c, IL-6 remained a significant predictor.
In patients with prediabetes at baseline, high-sensitivity CRP substantially reduced in those assigned 50 mg (–49.2%), 150 mg (–61.5%) and 300 mg canakinumab (–67.1%). This was also seen in IL-6 (–25.7%, –37.4% and –43.4%, respectively). The reductions were similar to those seen in the overall CANTOS cohort, Everett said.
In patients with prediabetes, there was a significant reduction in HbA1c that was mostly evident for the first 9 to 12 months of the trial, when then weakened for the duration of the study. This was also seen in patients with diabetes, but it was nonsignificant. The 150-mg and 300-mg doses of canakinumab had a significant effect on HbA1c in patients with normal glucose at baseline.
Regarding the key secondary endpoint, canakinumab had no effect vs. placebo on prevention of new-onset diabetes in patients with prediabetes at baseline. This was also seen when all doses of canakinumab were combined.
“We note that canakinumab has a similar efficacy in preventing major cardiovascular events in patients with and without diabetes at trial entry,” Everett said. “However, in n spite of the combination of reductions in both inflammatory biomarkers and HbA1c, it appears that canakinumab does not prevent the progression from prediabetes to diabetes among patients with prior myocardial infarction and an hsCRP of 2 mg/L or higher,” Everett said. – by Darlene Dobkowski
References:
Everett BM, et al. ACC/NEJM Late-Breaking Clinical Trials.
Ridker PM, et al. Featured Interventional Clinical Research II. Both presented at: American College of Cardiology Scientific Session; March 10-12, 2018; Orlando, Fla.
Everett BM, et al. J Am Coll Cardiol. 2018;doi:10.1016/j.jacc.2018.03.002.
Disclosures: CANTOS was funded by Novartis. Ridker reports he receives consultant fees/honoraria from AstraZeneca, CSL Behring, Pfizer, Sanofi and Teva; has ownership interest/partnership/principal with Brigham and Women's Hospital; and receives research grants from Kowa Pharmaceuticals, Novartis and Pfizer. Everett reports no relevant financial disclosures.
Perspective
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Robert Rosenson, MD
I was surprised based on some of the earlier studies that there was not a sustained decrease in incident diabetes. There had been studies to show that inflammation is one of the mechanisms involved in causing diabetes, but in the CANTOS study, they included many people with diabetes. They showed short-term improvement in the HbA1c, but it was not sustained.
My conclusions are that the prevention of diabetes through selected inhibition of one inflammatory pathway is still an unresolved issue. There is more work that needs to be done to understand the inflammatory basis of diabetes and how best to inhibit these pathways.
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