The 2026 ACC/AHA/Multisociety Guideline on the Management of Dyslipidemia identified low-density lipoprotein cholesterol (LDL-C) as the primary lipoprotein for therapeutic targeting.¹ Similarly, lipoprotein(a) [Lp(a)] and high-sensitivity C-reactive protein (hs-CRP) also have long-standing independent associations with the development of atherosclerotic cardiovascular disease (ASCVD).

Atherosclerosis historically had been viewed as passive lipid accumulation, but there are active inflammatory and immunologic processes. Interleukin-6 (IL-6) plays a central role in the atherogenic inflammatory cascade, sitting downstream of the NLRP3 inflammasome and IL-1β and upstream of hepatic CRP production. It promotes atherogenesis through endothelial activation, monocyte recruitment, lipoprotein oxidation, stimulation of acute-phase reactants (serum amyloid A, fibrinogen, CRP), and release of prothrombotic mediators.² Notably, most IL-6-associated vascular inflammation is driven by trans-signaling via the soluble IL-6 receptor rather than the classical membrane-bound receptor.

There has been growing interest in understanding the magnitude of IL-6's role in ASCVD. The Physicians' Health Study demonstrated a 2.3-fold increase in CVD in men of the highest IL-6 quartile.³ Mendelian randomization provided the strongest evidence of IL-6 causality. The IL6R MR (Interleukin-6 Receptor Mendelian Randomization Analysis) Consortium study (n = 133,449) demonstrated that the IL6R p.Asp358Ala variant, which reduces IL-6 receptor signaling and CRP levels by 8% per allele, was associated with reduced coronary artery disease (odds ratio, 0.95 per allele; 95% confidence interval [CI], 0.93-0.97; p = 1.53 × 10^-5).⁴

Additionally, McParland et al.⁵ reported that IL-6 demonstrated the strongest independent association with ASCVD independent of LDL-C, Lp(a), and hs-CRP when mutually adjusted in both the United Kingdom (UK) Biobank and the MESA (Multi-Ethnic Study of Atherosclerosis). The hazard ratios (HRs) comparing the highest to the lowest quartile were 1.67 (95% CI, 1.44-1.93) and 1.60 (95% CI, 1.24-2.07), respectively. In practice, hs-CRP has been used to characterize residual inflammatory risk with levels ≥2 mg/L as an entry criterion for multiple trials. However, IL-6 is more specific and predictive, although it lacks a clinically validated cutpoint.

The central unresolved question is whether pharmacologic inhibition of the NLRP3→IL-1β→IL-6→CRP immune axis will reduce cardiovascular events. The CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study) trial,⁶ which randomized 10,061 patients post–myocardial infarction (MI) with hs-CRP ≥2 mg/L to either canakinumab (an IL-1β antibody) or placebo over a 3.7-year follow-up period, provided clinical proof of the role of inflammation in atherosclerosis. Canakinumab 150 mg dosing reduced nonfatal MI and stroke or cardiovascular death by 15% (HR, 0.85; 95% CI, 0.74-0.98; p = 0.021) and urgent revascularization by 17% (HR, 0.83; 95% CI, 0.73-0.95; p = 0.005) with no effect on LDL-C levels. However, all-cause mortality was neutral, and the significant increase in fatal infection, along with the drug cost, was why canakinumab was never pursued for cardiovascular indication, prompting targeting other points in the inflammatory cascade. Nonetheless, an exploratory CANTOS genomic substudy revealed a 62% major adverse cardiovascular event (MACE) reduction with canakinumab (HR, 0.38; 95% CI, 0.15-0.96) in patients with TET2 clonal hematopoiesis of indeterminate potential (CHIP).⁷

Ziltivekimab is a human monoclonal antibody targeting IL-6 ligand, blocking both the classic and trans-signaling pathways and preserving gp130-mediated signaling independently of IL-6. Unlike other IL-6 receptor blocking agents, it does not cause a paradoxical increase in IL-6 or significant lipid perturbations. The phase 2 RESCUE (IL-6 Inhibition With Ziltivekimab in Patients at High Atherosclerotic Risk) trial randomized 264 patients with chronic kidney disease,² and hs-CRP ≥2 mg/L demonstrated 77%, 88%, and 92% hs-CRP reduction at 7.5, 15, and 30 mg doses, respectively, versus 4% with placebo (all p < 0.0001) with nearly twice the suppression than that of canakinumab in the CANTOS trial. This was in addition to a dose-dependent reduction in fibrinogen, serum amyloid A, haptoglobin, secretory phospholipase A₂, and Lp(a) (16-25% reduction); the agent was well tolerated with no serious events. The RESCUE-2 (Trial to Evaluate Reduction in Inflammation in Patients With Advanced Chronic Renal Disease Utilizing Antibody Mediated IL-6 Inhibition in Japan) trial reproduced those results in Japan.⁸ However, these trials are short biomarker trials and not focused on outcomes. A biomarker effect does not guarantee event reduction. Outcomes data are not yet available for direct IL-6 inhibition. It is unclear whether CRP reduction with ziltivekimab will translate to event reduction greater than canakinumab.

The ZEUS (Ziltivekimab Cardiovascular Outcomes Trial) phase 3 trial randomized 6,376 patients with ASCVD, chronic kidney disease, and hs-CRP ≥2 mg/L to ziltivekimab 15 mg monthly or placebo, with a MACE primary endpoint and a composite kidney secondary endpoint.⁹ Other ongoing trials include ARTEMIS (Effects of Ziltivekimab Versus Placebo on Cardiovascular Outcomes in Patients With Acute Myocardial Infarction; ~10,000 patients with a history of MI), HERMES (Effects of Ziltivekimab Versus Placebo on Morbidity and Mortality in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction and Systemic Inflammation; n = 4,900), and ATHENA (Effects of Ziltivekimab Versus Placebo on Heart Failure Symptoms and Physical Function in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction and Systemic Inflammation; n = 673) in patients with a history of heart failure (Table 1).

Table 1: Anti-Inflammatory Agents in Clinical Development for CV Prevention: Targets, Phase, Clinical Trials, and Indications Under Investigation

ASCVD = atherosclerotic cardiovascular disease; CAD = coronary artery disease; CCTA = coronary computed tomography angiography; CHIP = clonal hematopoiesis of indeterminate potential; CKD = chronic kidney disease; CV = cardiovascular; DM = diabetes mellitus; ESKD = end-stage kidney disease; FDA = Food and Drug Administration; HF = heart failure; HFmrEF = heart failure with mildly reduced ejection fraction; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; hs-CRP = high-sensitivity C-reactive protein; IL-6 = interleukin-6; LDL = low-density lipoprotein; MI = myocardial infarction; NYHA = New York Heart Association; RCT = randomized controlled trial.

The Inflammation and Cardiovascular Disease: 2025 ACC Scientific Statement suggests that although IL-6 is associated with risk, it does not provide incremental predictive value to hs-CRP ≥2 mg/L.¹⁰ IL-6 testing has significant intermethod variability, prominent circadian variability with no established cutoff levels, and high costs. Nonetheless, the high in-person variability is problematic because a single measurement captures only up to 35-41% of the true long-term average, prompting at least two serial measurements. Currently, its measurement will not change management because it does not trigger a therapeutic action.

IL-6 is a promising target point in the inflammatory cascade; however, hs-CRP remains the central inflammatory biomarker tested for cardiovascular risk stratification. There are still multiple remaining points to be addressed, including large, randomized trials to test anti-inflammatory therapies in primary ASCVD prevention, when to start anti-inflammatory therapies, biomarker-guided population selection, and long-term safety of IL-6 inhibitors, such as infection risk, wound healing, and immune surveillance. Moreover, CHIP stratified therapy represents a high-potential precision medicine opportunity requiring dedicated trials. The phase 3 ZEUS trial results will be the key inflection point in which positive outcomes would shift the calculus, creating IL-6 as a therapeutic measurement and target point in preventing ASCVDs.

References

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