This review followed the PRISMA 2020 framework to ensure transparency and rigour. Study selection was performed independently by 2 reviewers. An internal protocol guided the process and was updated as needed. PROSPERO registration was not pursued due to scope and time constraints, but the protocol was archived. Ethical approval was not required, and all procedures met research integrity standards.

We included peer-reviewed, English-language studies of adults (≥18 years) with ASCVD or major risk factors, including chronic inflammatory conditions. Eligible studies evaluated inflammatory biomarkers or immune-modulatory therapies and reported at least 1 cardiovascular or surrogate outcome. Non-human, single-arm, and non-peer-reviewed studies were excluded.

We searched PubMed, Embase, Scopus, Web of Science, ScienceDirect, and Google Scholar in February 2025, with an update in April. Reference lists, ClinicalTrials.gov, and trial bibliographies were also reviewed. The strategy, developed with an information specialist, targeted studies from 2000 onward on atherosclerosis and inflammation, limited to English. Database-specific terms and forward citation tracking were used. Full details are in Table 2 .

Two reviewers independently screened all titles and abstracts, excluding clearly irrelevant items such as case reports and editorials. Full texts of potentially eligible studies were then reviewed in duplicate using predefined criteria, with disagreements resolved by discussion or adjudication. A PRISMA flow diagram documented the selection process ( Figure 2 ). For overlapping publications from the same cohort, the most complete version was included unless others provided distinct data.

PRISMA flow diagram. The PRISMA 2020 flow diagram illustrates the systematic process of study identification, screening, eligibility assessment and final inclusion. It reflects the comprehensive search across 6 databases, detailing exclusions at each stage and the final inclusion of 57 studies for qualitative synthesis.

Data were extracted using a structured form capturing study design, population, interventions, comparators, outcomes, and key results. Two reviewers worked independently and resolved discrepancies by consensus. Extracted data included effect estimates, follow-up duration, and biomarker associations. Missing values were supplemented using additional sources when needed. All data were tabulated in Excel and summarized in Supplementary Table S1 .

Risk of bias was assessed using RoB 2 for trials and the Newcastle–Ottawa Scale for observational studies. Most RCTs, including CANTOS, COLCOT and LoDoCo2, were low risk; minor concerns arose in unblinded or abstract-only reports. Observational studies generally scored 8–9 stars, with 1 rated moderate due to confounding. Publication bias was assessed qualitatively. No studies were excluded for quality alone, but higher-quality evidence was prioritized. Full assessments are in Tables 3 and 4 .

Due to intervention and outcome heterogeneity, we performed a qualitative synthesis. Studies were grouped by intervention type and compared for consistency and effect size, focusing on major adverse cardiovascular events (MACE) and myocardial infarction (MI). GRADE ratings were applied; colchicine evidence was high, IL-6 data limited. Mechanistic links like hs-CRP reduction were considered. No new meta-analyses were done, but key ones were cited. Subgroup effects and both positive and neutral results were included.

We assessed overall evidence certainty using GRADE, considering strength, consistency and clinical relevance. IL-1β inhibition was rated moderate to high, based on 1 large RCT with some limitations, while IL-6 therapies remain low-certainty pending Phase III trials. Key uncertainties and ongoing studies were noted. All analyses were qualitative; no meta-analysis software was used.

A total of 8,974 records were identified through database searches. After duplicate removal and screening, 962 full-text articles were assessed for eligibility. Ultimately, 57 studies met inclusion criteria and were retained for qualitative synthesis. The selection process followed PRISMA 2020 guidelines and is detailed in the Supplementary Flow Diagram.

Fifty-seven studies published between 2000 and 2025 were included and categorized into 7 thematic groups: IL-1β inhibitors (n = 4), colchicine trials (n = 5), other anti-inflammatory agents (n = 6), narrative reviews (n = 10), epidemiologic studies (n = 6), mechanistic/experimental studies (n = 4), and supplementary or post hoc analyses (n = 6). Additionally, 13 studies were grouped under observational biomarker studies and 3 under genetic analyses. Study sizes ranged from small cohorts to large trials, involving high-risk and general populations. Interventions included pharmacologic, genetic and observational approaches, with outcomes focused on cardiovascular events, mortality and inflammatory markers. Study details are summarized in Supplementary Table S1 .

Risk of bias was assessed using the Cochrane RoB 2 tool for 19 randomized controlled trials and the Newcastle–Ottawa Scale for 15 observational studies. Most trials demonstrated low risk across all domains, including randomization, adherence to protocol, outcome completeness, and reporting. A few trials showed some concerns, notably the open-label LoDoCo trial and an abstract-only anakinra report. All other trials, including CANTOS, COLCOT, and LoDoCo2, were judged low risk overall. Among observational studies, NOS scores were high in most cases, indicating low risk. One study (Roubille et al. ) was rated moderate risk due to confounding and methodological heterogeneity. Risk of bias for each study is summarized in Table 3 (RCTs) and Table 4 (observational studies).

Elevated levels of hs-CRP, IL-6 and IL-18 were consistently associated with increased cardiovascular risk in both healthy and diseased populations. ^, The Emerging Risk Factors Collaboration showed a log-linear association between hs-CRP and CHD risk. IL-6 and IL-18 were independently predictive of events, particularly cardiovascular mortality in CAD patients. Mendelian studies found that IL6R variants conferred reduced CHD risk, while CRP variants did not, supporting causality for IL-6 but not CRP.

Observational studies in rheumatoid arthritis and psoriasis populations demonstrated excess cardiovascular risk, which was reduced among users of TNF inhibitors or MTX. MTX-treated rheumatoid arthritis (RA) patients had lower cardiovascular mortality, while biologics in psoriasis were linked to decreased coronary inflammation and plaque burden.

Anti-inflammatory therapies showed mixed results. IL-1β inhibition in CANTOS clearly reduced recurrent events without altering lipid levels. In contrast, MTX in CIRT showed no benefit, likely due to its broad action and minimal impact on IL-6 or CRP. Colchicine consistently reduced MACE in chronic and post-MI patients by modulating neutrophil activity and inflammasome function. Other agents showed less promise. Lp-PLA₂ and sPLA₂ inhibitors, though mechanistically linked to plaque inflammation, did not translate into improved clinical outcomes in large-scale trials. Similarly, p38 MAPK inhibition with losmapimod reduced CRP transiently but failed to reduce cardiovascular events after MI. IL-6–targeting therapies like tocilizumab and ziltivekimab strongly suppressed biomarkers; outcome trials are underway to assess clinical benefit. Emerging biologics targeting IL-12, IL-17, and IL-23 have demonstrated potential benefits primarily in autoimmune diseases such as psoriasis, indirectly suggesting possible cardiovascular protection by reducing systemic inflammation. Preliminary data on IL-17 and IL-23 inhibitors indicate potential reduction in coronary inflammation; however, dedicated cardiovascular trials remain limited. The JAK-STAT signaling pathway, known for its central role in cytokine signaling, also represents a novel therapeutic target currently under investigation for cardiovascular inflammation management, although clinical outcome data in atherosclerosis remain preliminary. Recent interleukin-targeted therapies demonstrate significant potential in reducing cardiovascular events through targeted cytokine modulation. Moreover, JAK-STAT signaling pathways have emerged as promising therapeutic targets for managing cardiovascular inflammation, expanding potential treatment options beyond conventional cytokine pathways. Overall, anti-inflammatory efficacy in ASCVD depends on targeting the right pathway, reducing inflammation sufficiently, and treating patients with high baseline inflammatory burden.

Chronic inflammation is a core mechanism in atherosclerosis. Elevated inflammatory biomarkers, especially CRP, IL-6 and IL-18, predict cardiovascular risk independently of traditional factors. ^, However, while CRP reflects inflammatory activity, it is not a causal factor; Mendelian randomization studies confirm causality for IL-6 signalling but not for CRP.

Genetic and clinical trial evidence identify IL-1β and IL-6 pathways as central in atherothrombosis. Canakinumab significantly reduced MACE in patients with prior MI and elevated hsCRP, with greater benefit seen in those achieving on-treatment CRP <2 mg/L. IL-6 inhibition, supported by Mendelian data and early clinical findings, also holds promise; ziltivekimab showed robust biomarker reductions in high-risk patients (RESCUE trial), and tocilizumab improved myocardial salvage in STEMI.

Not all interventions are effective. MTX, despite benefits in RA, failed in CIRT to reduce events or inflammatory markers. Similarly, Lp-PLA₂ and p38 MAPK inhibitors (darapladib and losmapimod) showed no cardiovascular benefit in large RCTs, suggesting these targets may be insufficient or bypassed in human disease.

Targeted therapies like canakinumab and colchicine proved more effective than broad immunosuppression. ^, while MTX and steroids have shown neutral or adverse effects. This underscores the importance of selectively modulating key inflammatory nodes, particularly the IL-1/IL-6 axis.

Patients with controlled lipids but high CRP, as in CANTOS and COLCOT, showed greater benefit from anti-inflammatory therapy. ^, Patients with CRP <2 mg/L on canakinumab saw 31% lower mortality; in COLCOT, those with higher CRP had greater benefit from colchicine. This supports inflammation-guided, precision therapy.

In terms of absolute benefit, anti-inflammatory therapies compare favourably to moderate-intensity lipid-lowering. Colchicine achieved ∼25–30% MACE reduction, ^, and canakinumab ∼15%. In JUPITER, rosuvastatin lowered LDL by 50%, CRP by 37%, and events by 44%. This dual-pathway benefit suggests that optimal ASCVD prevention should address both lipid and inflammatory risk.

Safety is an important consideration. Canakinumab increased infection risk and remains costly. Colchicine was generally well-tolerated, though mild GI symptoms and rare drug interactions (e.g. with statins in renal impairment) require attention. MTX in CIRT caused elevated liver enzymes and cytopenias, while IL-6 inhibitors can cause neutropenia and lipid shifts, though these were manageable in short trials.

Finally, therapy should be targeted. Anti-inflammatory drugs should not be used universally in ASCVD but rather in patients with high inflammatory burden, measurable by biomarkers or associated conditions (e.g. RA, psoriasis). This mirrors lipid management, where therapies like PCSK9 inhibitors are reserved for patients with high residual LDL. A similar, biomarker-based approach to residual inflammatory risk may help optimise cardiovascular prevention strategies moving forward.

The Summary of Findings ( Table 1 ) distills the primary outcomes of major interventions with our GRADE assessment of confidence.

Table 3

RoB 2 risk of bias assessment for included RCTs (low, some concerns, or high risk)

References	Rand.	Dev.	Missing	Outcome	Reporting	Overall RoB
Ridker et al. (CANTOS)	Low	Low	Low	Low	Low	Low
Abbate et al. (VCU-ART pilot)	Low	Low	Low	Low	Low	Low
Abbate et al. (VCU-ART1&2 pooled)	Low	Low	Low	Low	Low	Low
Morton et al. (MRC-ILA Heart)	Low	Low	Low	Low	Low	Low
Van Tassell et al. (VCU-ART abstract)	Low	Low	Low	Low	Some Concerns	Some Concerns
Nidorf et al. (LoDoCo)	Low	Some Concerns	Some Concerns	Some Concerns	Low	Some Concerns
Tardif et al. (COLCOT)	Low	Low	Low	Low	Low	Low
Nidorf et al. (LoDoCo2)	Low	Low	Low	Low	Low	Low
Tong et al. (COPS)	Low	Low	Low	Low	Low	Low
Deftereos et al. (Colchicine-AMI)	Low	Low	Low	Low	Low	Low
Ridker et al. (CIRT)	Low	Low	Low	Low	Low	Low
Broch et al. (ASSAIL-MI)	Low	Low	Low	Low	Low	Low
Kleveland et al. (Tocilizumab NSTEMI)	Low	Low	Low	Low	Low	Low
O’Donoghue et al. (SOLID-TIMI 52)	Low	Low	Low	Low	Low	Low
O’Donoghue et al. (LATITUDE-TIMI 60)	Low	Low	Low	Low	Low	Low
White et al. (STABILITY)	Low	Low	Low	Low	Low	Low
Nicholls et al. (VISTA-16)	Low	Low	Low	Low	Low	Low
Ridker et al. (JUPITER)	Low	Low	Low	Low	Low	Low
Mehta et al. (Psoriasis study)	Low	Low	Low	Low	Low	Low

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