Lipoprotein(a) levels in a global population with established atherosclerotic cardiovascular disease.

OBJECTIVE: Lipoprotein(a) (Lp(a)) is an important genetically determined risk factor for atherosclerotic vascular disease (ASCVD). With the development of Lp(a)-lowering therapies, this study sought to characterise patterns of Lp(a) levels in a global ASCVD population and identify racial, ethnic, regional and gender differences. METHODS: A multicentre cross-sectional epidemiological study to estimate the prevalence of elevated Lp(a) in patients with a history of myocardial infarction, ischaemic stroke or peripheral artery disease conducted at 949 sites in 48 countries in North America, Europe, Asia, South America, South Africa and Australia between April 2019 and July 2021. Low-density lipoprotein cholesterol (LDL-C) and Lp(a) levels were measured either as mass (mg/dL) or molar concentration (nmol/L). RESULTS: Of 48 135 enrolled patients, 13.9% had prior measurements of Lp(a). Mean age was 62.6 (SD 10.1) years and 25.9% were female. Median Lp(a) was 18.0 mg/dL (IQR 7.9-57.1) or 42.0 nmol/L (IQR 15.0-155.4). Median LDL-C was 77 mg/dL (IQR 58.4-101.0). Lp(a) in women was higher, 22.8 (IQR 9.0-73.0) mg/dL, than in men, 17.0 (IQR 7.1-52.2) mg/dL, p<0.001. Black patients had Lp(a) levels approximately threefold higher than white, Hispanic or Asian patients. Younger patients also had higher levels. 27.9% of patients had Lp(a) levels >50 mg/dL, 20.7% had levels >70 mg/dL, 12.9% were >90 mg/dL and 26.0% of patients exceeded 150 nmol/L. CONCLUSIONS: Globally, Lp(a) is measured in a small minority of patients with ASCVD and is highest in black, younger and female patients. More than 25% of patients had levels exceeding the established threshold for increased cardiovascular risk, approximately 50 mg/dL or 125 nmol/L.

Inhibition of Interleukin-1ß and Reduction in Atherothrombotic Cardiovascular Events in the CANTOS Trial.

BACKGROUND: Inflammation reduction with the interleukin (IL)-1ß inhibitor canakinumab significantly reduces the first major adverse cardiovascular event in patients with prior myocardial infarction (MI) and residual inflammatory risk (high-sensitivity C-reactive protein ≥ 2 mg/l). However, the effect of canakinumab on the total number of cardiovascular events, including recurrent events collected after a first event, is unknown. OBJECTIVES: This study sought to determine whether randomly allocated canakinumab would reduce the total burden of serious cardiovascular events. METHODS: We randomized 10,061 patients to placebo or canakinumab 50 mg, 150 mg, or 300 mg once every 3 months and compared the rates of the composite of all serious cardiovascular events (MI, stroke, coronary revascularization, and cardiovascular death) in active versus placebo groups. We used negative binomial regression to account for correlations among repeated events in the same person and to estimate rate ratios and 95% confidence intervals. RESULTS: During a median of 3.7 years of follow-up, 3,417 total serious cardiovascular events occurred in 2,003 individuals among the 10,061 unique patients randomized. Canakinumab reduced the rates of total serious cardiovascular events, with rates per 100 person-years in the placebo, 50 mg, 150 mg, and 300 mg canakinumab groups of 10.4, 8.4, 8.3, and 8.2, respectively. The corresponding rate ratios (95% confidence intervals) compared with placebo were 0.80 (0.69 to 0.93) for 50 mg, 0.79 (0.68 to 0.92) for 150 mg, and 0.78 (0.67 to 0.91) for 300 mg. CONCLUSIONS: Anti-inflammatory therapy with canakinumab significantly reduced the total number of cardiovascular events in patients with prior MI and evidence of residual inflammatory risk. (Cardiovascular Risk Reduction Study [Reduction in Recurrent Major CV Disease Events] (CANTOS); NCT01327846.

Effects of Interleukin-1ß Inhibition on Incident Hip and Knee Replacement : Exploratory Analyses From a Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Osteoarthritis is a common inflammatory disorder with no disease-modifying therapies. Whether inhibition of interleukin-1ß (IL-1ß) can reduce the consequences of large joint osteoarthritis is unclear. OBJECTIVE: To determine whether IL-1ß inhibition with canakinumab reduces incident total hip or knee replacement (THR/TKR). DESIGN: Exploratory analysis of a randomized trial. (ClinicalTrials.gov: NCT01327846). SETTING: 1091 clinical sites in 39 countries. PARTICIPANTS: 10 061 CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) participants. INTERVENTION: Random allocation to placebo or canakinumab (50, 150, or 300 mg) subcutaneously once every 3 months. MEASUREMENTS: The primary and secondary outcomes were time to first incident THR/TKR and time to first occurrence of an osteoarthritis-related adverse event (AE). Data were obtained through blinded ascertainment of trial clinical and safety databases. RESULTS: Median follow-up was 3.7 years. For the individual canakinumab dose groups, compared with placebo, hazard ratios (HRs) for incident THR/TKR during follow-up were 0.60 (95% CI, 0.38 to 0.95) for the 50-mg group, 0.53 (CI, 0.33 to 0.84) for the 150-mg group, and 0.60 (CI, 0.38 to 0.93) for the 300-mg group. Thus, in the pooled canakinumab groups, compared with the placebo group, incidence rates for THR/TKR were 0.31 and 0.54 events per 100 person-years (HR, 0.58 [CI, 0.42 to 0.80]; P = 0.001), respectively. The HR for the secondary end point of osteoarthritis-related AEs was 0.73 (CI, 0.61 to 0.87). Similar findings were observed in analyses restricted to participants with a history of osteoarthritis. LIMITATION: Because the parent trial was not designed to examine the efficacy of IL-1ß inhibitors in osteoarthritis, information on structural joint outcomes was not collected. CONCLUSION: Findings from this exploratory analysis of a randomized controlled trial support further investigation of IL-1ß inhibition for treatment of large joint osteoarthritis. PRIMARY FUNDING SOURCE: Novartis Pharmaceuticals.

Effects of Interleukin-1ß Inhibition on Incident Anemia: Exploratory Analyses From a Randomized Trial.

Background: Inflammatory cytokines, such as interleukin (IL)-1ß, alter iron homeostasis and erythropoiesis, resulting in anemia, but whether inhibition of IL-1ß can reverse these effects is unclear. Objective: To determine whether IL-1ß inhibition with canakinumab reduces incident anemia and improves hemoglobin levels among those with prevalent anemia. Design: Exploratory analysis of a randomized controlled trial. (ClinicalTrials.gov: NCT01327846). Setting: Many clinical sites in 39 countries. Participants: 8683 CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) participants without anemia at trial entry and 1303 with prevalent anemia at trial entry. Intervention: Random assignment to receive placebo or canakinumab (50, 150, or 300 mg) subcutaneously once every 3 months. Measurements: Primary outcome was incident anemia (hemoglobin level <130 g/L in men or <120 g/L in women). Results: Anemia incidence increased with rising baseline levels of high-sensitivity C-reactive protein (hsCRP), and both hsCRP and IL-6 decreased among participants receiving canakinumab compared with the placebo group. During a median follow-up of 3.7 years, participants without baseline anemia who received canakinumab at any dosage had significantly less incident anemia than those who received placebo (hazard ratio, 0.84 [95% CI, 0.77 to 0.93]; P < 0.001). Compared with placebo, the greatest benefits of IL-1ß inhibition on incident anemia were observed among participants with the most robust anti-inflammatory response, an effect corroborated in formal mediation analyses. Among those with baseline anemia, canakinumab increased mean hemoglobin levels by 11.3 g/L (P < 0.001) compared with placebo after 2 years of treatment. Canakinumab increased the risk for infection and was associated with mild cases of thrombocytopenia and neutropenia, none of which was grade 3 or higher. Limitation: CANTOS was not designed to assess the cause of anemia in individual trial participants. Conclusion: These exploratory analyses of randomized trial data provide proof of principle that inflammation inhibition, at least through the IL-1ß/IL-6 signaling pathway, reduces the incidence of anemia and improves hemoglobin levels in patients with anemia. Primary Funding Source: Novartis Pharmaceuticals.

Effects of Interleukin-1ß Inhibition on Blood Pressure, Incident Hypertension, and Residual Inflammatory Risk: A Secondary Analysis of CANTOS.

While hypertension and inflammation are physiologically inter-related, the effect of therapies that specifically target inflammation on blood pressure is uncertain. The recent CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) afforded the opportunity to test whether IL (interleukin)-1ß inhibition would reduce blood pressure, prevent incident hypertension, and modify relationships between hypertension and cardiovascular events. CANTOS randomized 10 061 patients with prior myocardial infarction and hsCRP (high sensitivity C-reactive protein) ≥2 mg/L to canakinumab 50 mg, 150 mg, 300 mg, or placebo. A total of 9549 trial participants had blood pressure recordings during follow-up; of these, 80% had a preexisting diagnosis of hypertension. In patients without baseline hypertension, rates of incident hypertension were 23.4, 26.6, and 28.1 per 100-person years for the lowest to highest baseline tertiles of hsCRP (P>0.2). In all participants random allocation to canakinumab did not reduce blood pressure (P>0.2) or incident hypertension during the follow-up period (hazard ratio, 0.96 [0.85-1.08], P>0.2). IL-1ß inhibition with canakinumab reduces major adverse cardiovascular event rates. These analyses suggest that the mechanisms underlying this benefit are not related to changes in blood pressure or incident hypertension. Clinical Trial Registration- URL: https://clinicaltrials.gov. Unique identifier: NCT01327846.

Residual inflammatory risk associated with interleukin-18 and interleukin-6 after successful interleukin-1ß inhibition with canakinumab: further rationale for the development of targeted anti-cytokine therapies for the treatment of atherothrombosis.

AIMS: The Canakinumab Antiinflammatory Thrombosis Outcomes Study (CANTOS) established that targeting inflammation with interleukin-1ß (IL-1ß) inhibition can significantly reduce cardiovascular (CV) event rates in the absence of any beneficial effects on cholesterol. Yet, CANTOS participants treated with both high-intensity statins and canakinumab remain at considerable risk for recurrent CV events. Both interleukin-18 (IL-18, which like IL-1ß requires the NLRP3 inflammasome for activation) and interleukin-6 (IL-6, a pro-inflammatory cytokine downstream of IL-1) may contribute to the recurrent events that occur even on canakinumab therapy, and thus represent novel targets for treating atherothrombosis. METHODS AND RESULTS: Plasma samples from 4848 stable post-myocardial infarction patients who were assigned to active IL-1ß inhibition or placebo within CANTOS underwent measurement of IL-18 and IL-6 both before and after initiation of canakinumab using validated ELISA. All participants were followed over a median 3.7-year period (maximum 5 years) for recurrent major adverse cardiovascular events (MACE) and for all-cause mortality. Compared to placebo, canakinumab significantly reduced IL-6 levels in a dose-dependent manner yielding placebo-subtracted median percent reductions in IL-6 at 3 months of 24.8%, 36.3%, and 43.2% for the 50, 150, and 300 mg doses, respectively (all P-values <0.001). By contrast, no dose of canakinumab significantly altered IL-18 levels measured at 3 months (all effects <1%, all P-values > 0.05). Yet, despite these differential plasma effects, either baseline and on-treatment levels of IL-18 or IL-6 associated with rates of future CV events. For example, for MACE, each tertile increase in IL-18 measured 3 months after canakinumab initiation associated with a 15% increase in risk [95% confidence interval (CI) 3-29%, P = 0.016], while each tertile increase in IL-6 measured 3 months after canakinumab initiation associated with a 42% increase in risk (95% CI 26-59%, P < 0.0001). Similar effects were observed for MACE-plus, CV death, all-cause mortality, and the for the combination endpoint of all vascular events inclusive of revascularization procedures and hospitalization for congestive heart failure. In baseline as well as on-treatment analyses, risks were highest among those with the highest levels of both IL-18 and IL-6. CONCLUSION: There remains substantial residual inflammatory risk related to both IL-18 and IL-6 after IL-1ß inhibition with canakinumab These data support further pharmacologic development of therapies for atherothrombosis that target IL-18 or IL-6 signalling, or that can simultaneously inhibit both IL-1ß and IL-18 (such as NLRP3 inflammasome inhibitors). CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01327846.

Anti-Inflammatory Therapy With Canakinumab for the Prevention of Hospitalization for Heart Failure.

BACKGROUND: Subclinical inflammation is associated with an increased risk of heart failure and with adverse prognosis in patients with established heart failure. Yet, treatments specifically directed at reducing inflammation in patients with heart failure have not yet shown improved clinical outcomes. We tested the hypothesis that the interleukin-1ß inhibitor canakinumab would prevent hospitalization for heart failure (HHF) and the composite of HHF or heart failure-related mortality. METHODS: We randomized 10 061 patients with prior myocardial infarction and high-sensitivity C-reactive protein ≥2 mg/L to canakinumab 50, 150, or 300 mg or placebo, given subcutaneously once every 3 months. In total, 2173 (22%) reported a history of heart failure at baseline. We tested the hypothesis that canakinumab prevents prospectively collected HHF events and the composite of HHF or heart failure-related mortality. RESULTS: A total of 385 patients had an HHF event during a median follow-up of 3.7 years. Patients who had HHF were older, had higher body mass index, and were more likely to have diabetes mellitus, hypertension, and prior coronary bypass surgery. As anticipated, median (quartile 1, 3) baseline concentrations of high-sensitivity C-reactive protein were higher among those who had HHF during follow-up than those who did not (5.7 [3.5, 9.9] mg/L versus 4.2 [2.8, 6.9] mg/L, respectively; P<0.0001). The unadjusted hazard ratios for HHF with each dose of canakinumab compared with placebo were 1.04 (95% CI, 0.79-1.36) for 50 mg, 0.86 (95% CI, 0.65-1.13) for 150 mg, and 0.76 (95% CI, 0.57-1.01) for 300 mg ( P for trend=0.025). The composite of HHF or heart failure-related mortality was also reduced by canakinumab, with unadjusted hazard ratios of 1.00 (95% CI, 0.78-1.29) for 50 mg, 0.88 (95% CI, 0.68-1.13) for 150 mg, and 0.78 (95% CI, 0.60-1.02) for 300 mg ( P for trend=0.042). CONCLUSIONS: These randomized double-blind placebo-controlled data suggest that therapy with canakinumab, an interleukin-1ß inhibitor, is related to a dose-dependent reduction in HHF and the composite of HHF or heart failure-related mortality in a population of patients with prior myocardial infarction and elevations in high-sensitivity C-reactive protein. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01327846.

Relationship of Interleukin-1ß Blockade With Incident Gout and Serum Uric Acid Levels: Exploratory Analysis of a Randomized Controlled Trial.

Background: Although studies have shown that interleukin-1ß (IL-1ß) inhibitors can shorten gout attacks, whether they can prevent gout attacks is unclear. Objective: To examine the relationship among canakinumab, a monoclonal antibody targeting IL-1ß; serum uric acid levels; and the incidence of gout attacks. Design: Secondary exploratory analysis of a randomized controlled trial. (ClinicalTrials.gov: NCT01327846). Setting: Many clinical sites in 39 countries. Participants: 10 059 patients with a prior myocardial infarction and a high-sensitivity C-reactive protein (hsCRP) level of at least 19.1 nmol/L. Intervention: Random allocation to canakinumab (50 mg, 150 mg, or 300 mg) versus placebo, administered subcutaneously every 3 months. Measurements: Rates of gout attacks were compared across patients with different baseline concentrations of serum uric acid (≤404.5 µmol/L, 404.6 to 535.3 µmol/L, and ≥535.4 µmol/L) and in different intervention groups in Cox proportional hazards regression models. Results: The median baseline concentration of serum uric acid was 362.9 µmol/L (interquartile range, 309.3 to 428.3 µmol/L), and median follow-up was 3.7 years. Among participants receiving placebo, incidence rates of gout attacks for serum uric acid concentrations of 404.5 µmol/L or lower, 404.6 to 535.3 µmol/L, and 535.4 µmol/L or higher were 0.28, 1.36, and 5.94, respectively, per 100 person-years. Canakinumab did not affect serum uric acid levels over time yet significantly reduced rates of gout attacks at all baseline concentrations of serum uric acid: Hazard ratios were 0.40 (95% CI, 0.22 to 0.73) for concentrations of 404.5 µmol/L or lower, 0.48 (CI, 0.31 to 0.74) for those between 404.6 and 535.3 µmol/L, and 0.45 (CI, 0.28 to 0.72) for those of 535.4 µmol/L or higher. Limitation: No adjudication of gout attacks. Conclusion: Quarterly canakinumab administration was associated with significantly reduced risk for gout attacks without any change in serum uric acid levels. These data have relevance for the development of agents for gout that target the IL-1ß pathway of innate immunity. Primary Funding Source: Novartis.

Modulation of the interleukin-6 signalling pathway and incidence rates of atherosclerotic events and all-cause mortality: analyses from the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS).

Aims: Canakinumab, a monoclonal antibody targeting interleukin (IL)-1ß, reduces rates of recurrent cardiovascular events without lowering lipids. It is uncertain, however, to what extent these beneficial cardiovascular outcomes are mediated through interleukin-6 (IL-6) signalling, an issue with substantial pathophysiologic consequences and therapeutic implications. Methods and results: A total of 4833 stable atherosclerosis patients in the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) had IL-6 levels measured before randomization and after treatment with placebo or one of three doses of canakinumab (50 mg, 150 mg, or 300 mg) given subcutaneously once every 3 months. Participants were followed for up to 5 years (median follow-up 3.7 years). Compared with those allocated to placebo, CANTOS participants receiving canakinumab who achieved on-treatment IL-6 levels below the study median value of 1.65 ng/L experienced a 32% reduction in major adverse cardiovascular events [MACE, multivariable adjusted hazard ratio (HRadj) 0.68, 95% confidence interval (CI) 0.56-0.82; P < 0.0001], a 30% reduction in MACE plus the additional endpoint of hospitalization for unstable angina requiring urgent revascularization (MACE+, HRadj 0.70, 95% CI 0.59-0.84; P < 0.0001), a 52% reduction in cardiovascular mortality (HRadj 0.48, 95% CI 0.34-0.68; P < 0.0001), and a 48% reduction in all-cause mortality (HRadj 0.52, 95% CI 0.40-0.68; P < 0.0001) with prolonged treatment. In contrast, those with on-treatment IL-6 levels equal to or above 1.65 ng/L after taking the first dose of canakinumab had no significant benefit for any of these endpoints. These differential findings based on the magnitude of IL-6 response were seen in analyses alternatively based on tertiles of on-treatment IL-6 levels, and in analyses using a statistical inference approach to estimate the effect of treatment among individuals who would achieve a targeted IL-6 level. Conclusion: CANTOS provides proof of concept evidence in humans that modulation of the IL-6 signalling pathway, at least with canakinumab, associates with reduced cardiovascular event rates, independent of lipid lowering. Clinical trial registration: ClinicalTrials.gov NCT01327846.

Inhibition of Interleukin-1ß by Canakinumab and Cardiovascular Outcomes in Patients With Chronic Kidney Disease.

BACKGROUND: Inflammation contributes to chronic kidney disease (CKD), in part mediated through activation of interleukin (IL)-1ß by the NLRP3 inflammasome within the kidney. This process also likely contributes to the accelerated atherosclerosis associated with nephropathy. OBJECTIVES: The authors hypothesized that canakinumab, a human monoclonal antibody targeting IL-1ß, might reduce cardiovascular event rates and improve renal function among post-myocardial infarction patients with CKD. METHODS: Stable post-myocardial infarction patients with high-sensitivity C-reactive protein (hsCRP) ≥ 2mg/l were randomly allocated to placebo or to 1 of 3 doses of canakinumab (50, 150, or 300 mg) given subcutaneously once every 3 months. Participants were followed for incident myocardial infarction, stroke, hospitalization for unstable angina requiring urgent revascularization, cardiovascular death, or death from any cause over a median follow-up period of 3.7 years (maximum 5 years). All patients additionally had serial monitoring of estimated glomerular filtration rate (eGFR), creatinine, the urine albumin to creatinine ratio (uACR), and were monitored for adverse renal and urinary events. RESULTS: Of 10,061 participants, 1,875 (18.6%) had baseline eGFR <60 ml/min/1.73 m2. These moderate CKD patients had higher incidence rates for major adverse vascular events compared with those with eGFR ≥60 ml/min/1.73 m2 (6.92 vs. 4.13 per 100 person-years; p < 0.0001). Random allocation to canakinumab reduced the risk of major adverse cardiovascular events among those with CKD (hazard ratio: 0.82; 95% confidence interval: 0.68 to 1.00; p = 0.05) with the largest cardiovascular benefits accruing among those who achieved on-treatment hsCRP levels below 2 mg/l measured after taking the first dose (hazard ratio: 0.68; 95% confidence interval: 0.53 to 0.86; p = 0.0015). Comparable effects were observed among those with baseline albuminuria or diabetes. Canakinumab had neither clinically meaningful benefits nor substantive harms with respect to serial measures of eGFR, creatinine, the uACR, or reported adverse renal events during trial follow-up. CONCLUSIONS: IL-1ß inhibition with canakinumab reduces major adverse cardiovascular event rates among high-risk atherosclerosis patients with CKD, particularly among those with a robust anti-inflammatory response to initial treatment. These cardiovascular benefits accrued with no adverse clinical renal events. (Canakinumab Anti-inflammatory Thrombosis Outcomes Study [CANTOS]; NCT01327846).

Anti-Inflammatory Therapy With Canakinumab for the Prevention and Management of Diabetes.

BACKGROUND: Subclinical inflammation mediated in part by interleukin (IL)-1ß participates in peripheral insulin resistance and impaired pancreatic insulin secretion. OBJECTIVES: The authors tested the hypothesis that the IL-1ß 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-1ß 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).

New strategies for the development of lipid-lowering therapies to reduce cardiovascular risk.

The very high occurrence of cardiovascular events presents a major public health issue, because treatment remains suboptimal. Lowering LDL cholesterol (LDL-C) with statins or ezetimibe in combination with a statin reduces major adverse cardiovascular events. The cardiovascular risk reduction in relation to the absolute LDL-C reduction is linear for most interventions without evidence of attenuation or increase in risk at low LDL-C levels. Opportunities for innovation in dyslipidaemia treatment should address the substantial risk of lipid-associated cardiovascular events among patients optimally treated per guidelines but who cannot achieve LDL-C goals and who could benefit from additional LDL-C-lowering therapy or experience side effects of statins. Fresh approaches are needed to identify promising drug targets early and develop them efficiently. The Cardiovascular Round Table of the European Society of Cardiology (ESC) convened a workshop to discuss new lipid-lowering strategies for cardiovascular risk reduction. Opportunities to improve treatment approaches and the efficient study of new therapies were explored. Circulating biomarkers may not be fully reliable proxy indicators of the relationship between treatment effect and clinical outcome. Mendelian randomization studies may better inform development strategies and refine treatment targets before Phase 3. Trials should match the drug to appropriate lipid and patient profile, and guidelines may move towards a precision-based approach to individual patient management. Stakeholder collaboration is needed to ensure continued innovation and better international coordination of both regulatory aspects and guidelines. It should be noted that risk may also be addressed through increased attention to other risk factors such as smoking, hypertension, overweight, and inactivity.

Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial.

BACKGROUND: Canakinumab, a monoclonal antibody targeting interleukin-1ß, reduces inflammation and cardiovascular event rates with no effect on lipid concentrations. However, it is uncertain which patient groups benefit the most from treatment and whether reductions in the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) correlate with clinical benefits for individual patients. METHODS: The Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) used computer-generated codes to randomly allocate 10 061 men and women with a history of myocardial infarction to placebo or one of three doses of canakinumab (50 mg, 150 mg, or 300 mg) given subcutaneously once every 3 months. In a prespecified secondary analysis designed to address the relationship of hsCRP reduction to event reduction in CANTOS, we evaluated the effects of canakinumab on rates of major adverse cardiovascular events, cardiovascular mortality, and all-cause mortality according to on-treatment concentrations of hsCRP. We used multivariable modelling to adjust for baseline factors associated with achieved hsCRP and multiple sensitivity analyses to address the magnitude of residual confounding. The median follow-up was 3·7 years. The trial is registered with ClinicalTrials.gov, number NCT01327846. FINDINGS: Baseline clinical characteristics did not define patient groups with greater or lesser cardiovascular benefits when treated with canakinumab. However, trial participants allocated to canakinumab who achieved hsCRP concentrations less than 2 mg/L had a 25% reduction in major adverse cardiovascular events (multivariable adjusted hazard ratio [HRadj]=0·75, 95% CI 0·66-0·85, p<0·0001), whereas no significant benefit was observed among those with on-treatment hsCRP concentrations of 2 mg/L or above (HRadj=0·90, 0·79-1·02, p=0·11). For those treated with canakinumab who achieved on-treatment hsCRP concentrations less than 2 mg/L, cardiovascular mortality (HRadj=0·69, 95% CI 0·56-0·85, p=0·0004) and all-cause mortality (HRadj=0·69, 0·58-0·81, p<0·0001) were both reduced by 31%, whereas no significant reduction in these endpoints was observed among those treated with canakinumab who achieved hsCRP concentrations of 2 mg/L or above. Similar differential effects were found in analyses of the trial prespecified secondary cardiovascular endpoint (which additionally included hospitalisation for unstable angina requiring unplanned revascularisation) and in sensitivity analyses alternatively based on median reductions in hsCRP, on 50% or greater reductions in hsCRP, on the median percent reduction in hsCRP, in dose-specific analyses, and in analyses using a causal inference approach to estimate the effect of treatment among individuals who would achieve a targeted hsCRP concentration. INTERPRETATION: The magnitude of hsCRP reduction following a single dose of canakinumab might provide a simple clinical method to identify individuals most likely to accrue the largest benefit from continued treatment. These data further suggest that lower is better for inflammation reduction with canakinumab. FUNDING: Novartis Pharmaceuticals.

Effect of interleukin-1ß inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Inflammation in the tumour microenvironment mediated by interleukin 1ß is hypothesised to have a major role in cancer invasiveness, progression, and metastases. We did an additional analysis in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), a randomised trial of the role of interleukin-1ß inhibition in atherosclerosis, with the aim of establishing whether inhibition of a major product of the Nod-like receptor protein 3 (NLRP3) inflammasome with canakinumab might alter cancer incidence. METHODS: We did a randomised, double-blind, placebo-controlled trial of canakinumab in 10 061 patients with atherosclerosis who had had a myocardial infarction, were free of previously diagnosed cancer, and had concentrations of high-sensitivity C-reactive protein (hsCRP) of 2 mg/L or greater. To assess dose-response effects, patients were randomly assigned by computer-generated codes to three canakinumab doses (50 mg, 150 mg, and 300 mg, subcutaneously every 3 months) or placebo. Participants were followed up for incident cancer diagnoses, which were adjudicated by an oncology endpoint committee masked to drug or dose allocation. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, NCT01327846. The trial is closed (the last patient visit was in June, 2017). FINDINGS: Baseline concentrations of hsCRP (median 6·0 mg/L vs 4·2 mg/L; p<0·0001) and interleukin 6 (3·2 vs 2·6 ng/L; p<0·0001) were significantly higher among participants subsequently diagnosed with lung cancer than among those not diagnosed with cancer. During median follow-up of 3·7 years, compared with placebo, canakinumab was associated with dose-dependent reductions in concentrations of hsCRP of 26-41% and of interleukin 6 of 25-43% (p<0·0001 for all comparisons). Total cancer mortality (n=196) was significantly lower in the pooled canakinumab group than in the placebo group (p=0·0007 for trend across groups), but was significantly lower than placebo only in the 300 mg group individually (hazard ratio [HR] 0·49 [95% CI 0·31-0·75]; p=0·0009). Incident lung cancer (n=129) was significantly less frequent in the 150 mg (HR 0·61 [95% CI 0·39-0·97]; p=0·034) and 300 mg groups (HR 0·33 [95% CI 0·18-0·59]; p<0·0001; p<0·0001 for trend across groups). Lung cancer mortality was significantly less common in the canakinumab 300 mg group than in the placebo group (HR 0·23 [95% CI 0·10-0·54]; p=0·0002) and in the pooled canakinumab population than in the placebo group (p=0·0002 for trend across groups). Fatal infections or sepsis were significantly more common in the canakinumab groups than in the placebo group. All-cause mortality did not differ significantly between the canakinumab and placebo groups (HR 0·94 [95% CI 0·83-1·06]; p=0·31). INTERPRETATION: Our hypothesis-generating data suggest the possibility that anti-inflammatory therapy with canakinumab targeting the interleukin-1ß innate immunity pathway could significantly reduce incident lung cancer and lung cancer mortality. Replication of these data in formal settings of cancer screening and treatment is required. FUNDING: Novartis Pharmaceuticals.

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease.

BACKGROUND: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. METHODS: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1ß, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P=0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P=0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P=0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P=0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P=0.31). CONCLUSIONS: Antiinflammatory therapy targeting the interleukin-1ß innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846 .).

Pharmacokinetic and pharmacodynamic characteristics of single-dose Canakinumab in patients with type 2 diabetes mellitus.

PURPOSE: Interleukin (IL)-1ß, an inflammatory molecule, contributes to the development of atherothrombosis and worsening of islet ß-cell function. Canakinumab, a human monoclonal antibody, targets IL-1ß-dependent inflammation and reduces the vascular inflammatory biomarker, high-sensitivity C-reactive protein (hsCRP), and other inflammatory cardiovascular biomarkers. Here, we aimed to assess the pharmacokinetic (PK) and pharmacodynamic characteristics, including the effect on hsCRP, of canakinumab in patients with type 2 diabetes mellitus (T2DM) after a 2-hour single-dose intravenous infusion. METHODS: This multicenter, randomized, double-blind, placebo-controlled, dose-escalation study was conducted in patients with T2DM (diagnosed ≥6 months before screening) on a stable daily dose of metformin. Patients were randomly assigned to receive a single intravenous dose of canakinumab 0.03, 0.1, 0.3, 1.5, or 10 mg/kg or placebo. The study was initially designed with 1 small cohort (15 patients, 0.3 mg/kg) on a stable dose of metformin ≥500 mg/d for an initial tolerability evaluation; all other patients were on a stable dose of ≥850 mg/d of metformin. The PK profile was assessed at 0 and 2 hours and at days 2, 14, 28, 56, 84, and 168. Changes in hsCRP and hemoglobin (Hb) A1c levels were assessed at weeks 4, 8, 12, and 24. FINDINGS: Of the 231 enrolled patients, 222 completed the study. Median hsCRP values at screening ranged from 1.8 to 3.2 mg/L, and the median daily dose of metformin ranged from 1000 to 2000 mg. Exposure to canakinumab was dose proportional. The mean half-life ranged from 17 to 26 days, and mean systemic clearance ranged from 0.094 to 0.128 mL/h/kg. Dose-related reductions in hsCRP were significantly greater with canakinumab compared with those with placebo at week 4 (-0.2 mg/L, -0.5 mg/L, -1.5 mg/L, and -1.7 mg/L with the 0.1-, 0.3-, 1.5-, and 10-mg/kg doses, respectively; all, P < 0.05). Significant reductions in hsCRP were maintained up to week 12 with the 2 highest doses of canakinumab (-0.8 mg/L with 1.5 mg/kg and -1.3 mg/L with 10 mg/kg; both, P < 0.05). A placebo-adjusted decrease in HbA1c of 0.31% at week 12 was reported with canakinumab 10 mg/kg (P = 0.038), and a reduction of 0.23% at week 4 was found with canakinumab 1.5 mg/kg (P = 0.011). IMPLICATIONS: The findings from this study suggest that IL-1ß blockade after single-dose administration of canakinumab at 1.5 and 10 mg/kg provided sustained suppression of hsCRP levels for 12 weeks in patients with T2DM. ClinicalTrials.gov identifier: NCT00900146.

Safety and tolerability of canakinumab, an IL-1ß inhibitor, in type 2 diabetes mellitus patients: a pooled analysis of three randomised double-blind studies.

BACKGROUND: We aimed to assess the safety and tolerability of different doses of canakinumab versus placebo in patients with type 2 diabetes mellitus (T2DM). METHODS: Data were pooled from three studies in 1026 T2DM patients with different routes of administration, treatment regimens and follow-up duration. Canakinumab groups were categorised as low (0.03 mg/kg i.v. once; N = 20), intermediate (0.1 and 0.3 mg/kg i.v. once, 5 and 15 mg s.c. monthly; N = 247), medium (1.5 mg/kg i.v. once, 50 mg s.c. monthly and 150 mg s.c. once; N = 268), and high doses (10 mg/kg i.v. once and 150 mg s.c. monthly; N = 137) and compared with placebo (N = 354). Incidences of adverse events (AEs), serious AEs (SAEs), discontinuations due to AEs, deaths, AEs of special interest related to interleukin-1ß inhibition and T2DM disease, and laboratory abnormalities related to haematology and biochemistry parameters were reported. Safety was also analysed by age (<65, ≥65) and gender. RESULTS: Average exposure across all groups was ≈ 6 months (maximum ~17 months). No dose response in AEs was observed but a trend towards more patients having at least one AE across canakinumab groups relative to placebo (P = 0.0152) was observed. SAEs were few and the incidence rate for most canakinumab groups was lower than that of placebo group except for the high-dose group (0.94% versus 0.58% per month in placebo). A total of five patients discontinued treatment due to AEs across treatment groups. No death was reported in any of the three studies. A small, non-significant increase in the incidence rate of infection AEs was observed on canakinumab groups relative to placebo. Canakinumab was associated with mostly mild decreases in WBC, neutrophils and platelet counts. Additionally, mild increases in SGPT, SGOT and bilirubin were reported. Overall, despite small differences, no clinically relevant findings were observed with respect to laboratory values and vital signs. CONCLUSIONS: This pooled analysis demonstrated that canakinumab was safe and well tolerated over a treatment period up to 1.4 years at the four pooled doses evaluated, in agreement with safety findings reported in the individual studies.

Effects of interleukin-1ß inhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen: a phase IIb randomized, placebo-controlled trial.

BACKGROUND: To test formally the inflammatory hypothesis of atherothrombosis, an agent is needed that reduces inflammatory biomarkers such as C-reactive protein, interleukin-6, and fibrinogen but that does not have major effects on lipid pathways associated with disease progression. METHODS AND RESULTS: We conducted a double-blind, multinational phase IIb trial of 556 men and women with well-controlled diabetes mellitus and high cardiovascular risk who were randomly allocated to subcutaneous placebo or to subcutaneous canakinumab at doses of 5, 15, 50, or 150 mg monthly and followed over 4 months. Compared with placebo, canakinumab had modest but nonsignificant effects on the change in hemoglobin A1c, glucose, and insulin levels. No effects were seen for low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or non-high-density lipoprotein cholesterol, although triglyceride levels increased ≈10% in the 50-mg (P=0.02) and 150-mg (P=0.03) groups. By contrast, the median reductions in C-reactive protein at 4 months were 36.4%, 53.0%, 64.6%, and 58.7% for the 5-, 15-, 50-, and 150-mg canakinumab doses, respectively, compared with 4.7% for placebo (all P values ≤0.02). Similarly, the median reductions in interleukin-6 at 4 months across the canakinumab dose range tested were 23.9%, 32.5%, 47.9%, and 44.5%, respectively, compared with 2.9% for placebo (all P≤0.008), and the median reductions in fibrinogen at 4 months were 4.9%, 11.7%, 18.5%, and 14.8%, respectively, compared with 0.4% for placebo (all P values ≤0.0001). Effects were observed in women and men. Clinical adverse events were similar in the canakinumab and placebo groups. CONCLUSIONS: Canakinumab, a human monoclonal antibody that neutralizes interleukin-1ß, significantly reduces inflammation without major effect on low-density lipoprotein cholesterol or high-density lipoprotein cholesterol. These phase II trial data support the use of canakinumab as a potential therapeutic method to test directly the inflammatory hypothesis of atherosclerosis.

Interleukin-1ß inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS).

BACKGROUND: Inflammation contributes to all phases of the atherothrombotic process, and patients with elevated inflammatory biomarkers such as high-sensitivity C-reactive protein (hsCRP) have increased vascular risk. Yet, it remains unknown whether direct inhibition of inflammation will reduce cardiovascular event rates. DESIGN: The CANTOS will evaluate whether interleukin-1ß (IL-1ß) inhibition as compared with placebo can reduce rates of recurrent myocardial infarction, stroke, and cardiovascular death among stable patients with coronary artery disease who remain at high vascular risk due to persistent elevations of hsCRP (>2 mg/L) despite contemporary secondary prevention strategies. Canakinumab is a human monoclonal antibody that selectively neutralizes IL-1ß, a proinflammatory cytokine that plays multiple roles in the atherothrombotic process and that undergoes activation by the nucleotide-binding leucine-rich repeat-containing pyrin receptor 3 inflammasome, a process promoted by cholesterol crystals. Canakinumab significantly reduces systemic C-reactive protein and other inflammatory biomarker levels, is generally well tolerated, and is currently indicated for the treatment of inherited IL-1ß driven inflammatory diseases such as the Muckle-Wells syndrome. In a multinational collaborative effort using an event-driven intention-to-treat protocol, CANTOS will randomly allocate 17,200 stable postmyocardial infarction patients with persistent elevation of hsCRP to either placebo or to canakinumab at doses of 50, 150, or 300 mg every 3 months, administered subcutaneously. All participants will be followed up over an estimated period of up to 4 years for the trial primary end point (nonfatal myocardial infarction, nonfatal stroke, cardiovascular death) as well as for other vascular events, total mortality, adverse events, and specific clinical end points associated with inflammation including new onset diabetes, venous thrombosis, and atrial fibrillation. SUMMARY: If positive, CANTOS would confirm the inflammatory hypothesis of atherothrombosis and provide a novel cytokine-based therapy for the secondary prevention of cardiovascular disease and new-onset diabetes.

Inhibition of CETP by torcetrapib attenuates the atherogenicity of postprandial TG-rich lipoproteins in type IIB hyperlipidemia.

OBJECTIVE: The purpose of this study was to evaluate the impact of torcetrapib on atherogenic TG-rich lipoprotein subfractions in the postprandial phase in Type IIB hyperlipidemia. METHODS AND RESULTS: The quantitative and qualitative features of the postprandial profile of TG-rich lipoproteins were determined at baseline, after treatment for 6 weeks with 10 mg/d atorvastatin, and subsequently with an atorvastatin/torcetrapib combination (10/60 mg/d) in Type IIB patients (n=18). After ingestion of a standardized mixed meal, TG-rich lipoprotein subfractions were evaluated over 8 hours after each experimental period. On a background of atorvastatin, torcetrapib significantly attenuated the incremental postprandial area under the curve (iAUC 0 to 8 hours) for VLDL-1 (-40%), and the AUC 0 to 8 hours for VLDL-2 (-53%), with minor effect on chylomicron iAUC (-24%); concomitantly, the CE/TG ratio in both VLDL-1 and VLDL-2 was significantly reduced (-27% to -42%). Such reduction was attributable to torcetrapib-mediated attenuation of postprandial CE transfer to Chylomicrons (-17%) and VLDL-1 (-33%). Marked reduction in postprandial VLDL-1 levels was associated with apoE enrichment. CONCLUSIONS: On a background of atorvastatin, torcetrapib attenuated the quantitative and qualitative features of the atherogenic postprandial profile of chylomicrons, VLDL-1 and VLDL-2. Such changes reflect the sum of torcetrapib-mediated effects on TG-rich lipoprotein production, intravascular remodeling, and catabolism.