CANTOS: Canakinumab Fails to Prevent New-Onset Diabetes

Patrice Wendling

March 14, 2018

ORLANDO — New CANTOS trial results show canakinumab is equally effective in reducing major cardiovascular (CV) events among high-risk patients with atherosclerosis with or without chronic kidney disease (CKD) or diabetes.

A key secondary finding, however, dashed hopes that reducing systemic inflammation with the interleukin (IL)-1β inhibitor would prevent the progression of prediabetes to diabetes.

Among patients with baseline prediabetes in the trial, incidence rates of adjudicated new-onset diabetes per 100 person-years were similar between canakinumab 50 mg, 150 mg, and 300 mg and placebo (4.24, 4.35, 4.12, and 4.20, respectively; all P values at least .70).

Interestingly, patients with prediabetes treated with canakinumab (Ilaris, Novartis) had significant declines in hemoglobin A1c (HbA1c) levels for the first 6 to 9 months, but the reduction attenuated over time. A similar pattern, albeit nonsignificant, was seen in patients with baseline diabetes.

"It's a bit of a mystery why that occurred," but this pattern is also  seen with other types of diabetes therapies, including metformin plus exercise in the Diabetes Prevention Program, lead author, Brendan Everett, MD, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, said at the American College of Cardiology (ACC) Annual 2018 Scientific Session.

"It makes me think that there's some other broader biological process that is multifactorial that continues to gain a head of steam as time goes on. We've been able to delay the process briefly, at least in terms of hemoglobin A1c levels, but ultimately it's not enough to prevent further progression and development of the disease," he said.

Last year, results from CANTOS made headlines after showing that canakinumab, which is already approved for rare autoimmune diseases, significantly reduced CV events without any effect on lipids and reduced cancer mortality by up to 51% among 10,061 high-risk patients who had a prior myocardial infarction (MI) and persistently elevated high-sensitivity C-reactive protein (hs-CRP).

"You've opened a whole new window to the world with this class of therapies. I know you're disappointed that you were not able to prevent diabetes, but you've got cardiovascular disease and lung cancer already under your belt," panelist Kim Eagle, MD, director of the Frankel Cardiovascular Center at the University of Michigan, Ann Arbor, said to a round of laughter in the late-breaking trial session.

Eagle asked whether patients with diabetes treated with canakinumab might be at higher risk for the life-threatening side effect of sepsis. Everett said they did not have a significant increased risk for "garden-variety" infections but did for fatal infections, as seen in the overall trial. The corresponding hazard ratios (HRs) were 1.05 (95% CI, 0.88 - 1.25) and 1.86 (95% CI, 1.01 - 3.43).

The new analysis, simultaneously published in the Journal of the American College of Cardiology, involved 4057 patients with baseline diabetes, 4960 with prediabetes, and 1044 with normal baseline glucose.

Risk for the primary CV endpoint, a composite of nonfatal MI, nonfatal stroke, or CV death, was similar for all doses of canakinumab vs placebo among patients with diabetes, prediabetes, and normal glucose at baseline (HRs, 0.90, 0.86, and 0.81, respectively), with no significant evidence of heterogeneity (P  = .86), Everett said.

Baseline concentrations of the inflammatory biomarkers, hs-CRP and IL-6, significantly predicted new-onset diabetes among those without diabetes at study entry, even after multivariable adjustment. After further adjusting for baseline HbA1c, IL-6 remained a significant predictor.

Patients with prediabetes had significant dose-dependent reductions after the first dose of canakinumab 50 mg, 150 mg, and 300 mg, in hsCRP (–49.2%, –61.5%, and –67.1%, respectively) and IL-6 (–25.7%, –37.4%, and –43.4%, respectively).

Despite this and the early HbA1c reductions, a sensitivity analysis of all physician-reported diabetes also found no statistically significant evidence that canakinumab prevents the development of diabetes in patients with baseline prediabetes, he said.

Commenting for | Medscape Cardiology, session co-chair John A Jarcho, MD, also from Brigham and Women's Hospital, said canakinumab seemed "like a good bet" to prevent prediabetes progression because there is supportive evidence.

"It's puzzling in a way that the result was negative and it either means there's a different inflammatory pathway that contributes to diabetes other than the one targeted by canakinumab or inflammation is not causative, it's an epiphenomenon," he said.

Canakinumab in CKD

A separate subanalysis focused on patients with moderate CKD, a group that experiences accelerated atherosclerosis and is at greater risk for poor outcomes. Yet the mechanism for this risk remains uncertain, and as a result, therapies to reduce MI and CV death in the CKD population are limited, CANTOS principal investigator, Paul Ridker, MD, Brigham and Women's Hospital, explained during a featured clinical research session.

"In our current armamentarium with very aggressive care these are very high-risk patients with considerable unmet need," he said, noting that in the overall trial, patients with CKD had almost three times the rate of CV death and nearly twice the rate of all-cause mortality as those with normal renal function.

The researchers hypothesized that canakinumab may be beneficial in patients with CKD in light of research suggesting that processes related to renal injury and repair induce changes in innate and adaptive immunity, including enhanced NLRP3 inflammasome function resulting in activation of IL-1β.

The subanalysis involved 1875 patients with moderate CKD (stage 3, estimated glomerular filtration rate [eGFR] of 30 - 60 mL/min/1.73 m2) and 8184 patients with normal renal function. Patients with CKD were older; more likely to be women; and more likely to have diabetes, hypertension, and higher hsCRP levels.

Major adverse CV events were reduced by 18% with canakinumab in patients with moderate CKD (HR, 0.82; 95% CI, 0.68 - 1.00; P   = .05) and by 14% in those with normal renal function (HR, 0.86; 95% CI, 0.77 - 0.97; P = .015), with no significant evidence of heterogeneity, Ridker said.

Robust responders who had an on-treatment hsCRP less than 2 mg/L, however, had a 31% reduction in major CV events (P = .004), a 34% reduction in CV mortality (P = .02), and a 24% reduction in all-cause mortality (P = .05).

Canakinumab had no clinically meaningful benefits or substantive harms with respect to adverse renal events, such as microalbuminuria progression, decline in eGFR, or need for dialysis, but the trial did not enroll patients with an eGFR between 15 and 30 mL/min/1.73 m2, Ridker noted.

"Moving forward, it will be important to extend these data and test the efficacy of canakinumab in patients with end-stage renal failure and or those undergoing dialysis," he said. "In that setting, hsCRP and IL-6 are powerful predictors of risk while LDL [low-density lipoprotein] cholesterol is not, and dialysis is one of the few settings where LDL reduction with statins has not been highly effective."

CANTOS was funded by Novartis. Everett reports no relevant conflicts of interest. Ridker reports research grants from Novartis to conduct CANTOS; consulting for Novartis; and being a co-inventor on patents held by 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. Jarcho reported no relevant disclosures.

American College of Cardiology (ACC) 2018 Annual Scientific Session. Presentation 408-10. Presented March 12, 2018.

J Am Coll Cardiol. Published online March 12, 2018. Abstract

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