R3i Editorials

R3i editorials, created by members of the R3i board, focus on addressing the persistent challenges of residual cardiovascular risk. These editorials serve to educate healthcare professionals about emerging insights and therapeutic strategies related to lipid-related risk factors, such as triglyceride-rich lipoproteins and lipoprotein(a).

Latest Editorial

February 2026
Is personalized residual risk the future?
Prof. Peter Libby, Prof. Michel Hermans, Prof. Pierre Amarenco, Prof. Lale Tokgözoglu 

Despite advances in interventional strategies and pharmacological treatments, residual cardiovascular risk remains a major clinical challenge. Novel insights reinforce the interplay of multiple contributing pathways, and the need for a personalized approach to management beyond traditional risk factors.

Lipids remain a key focus for targeting residual risk. Lipoprotein(a) [Lp(a)], a genetically determined, independent, and causal risk factor that is not controlled effectively by lifestyle or current standard lipid-lowering therapies, has gained increasing attention due to the advent of novel therapeutics that lower Lp(a) substantially (1). RNA-based therapies that specifically target Lp(a) include the antisense oligonucleotide pelacarsen and siRNAs such as olpasiran, lepodisiran, and zerlasiran, offer potent and durable reduction in Lp(a) (2). Definitive evidence for a role for Lp(a) lowering in residual risk awaits the findings from ongoing cardiovascular outcomes studies, such as HORIZON and OCEAN(a) (3,4). Lp(a) may also play a role in early-onset myocardial infarction (5) and participates causally in aortic stenosis, suggesting other conditions that would derive benefit from specific Lp(a)-lowering therapy. Furthermore, remnant cholesterol, the cholesterol contained in triglyceride-rich lipoproteins, remains in contention, with novel therapies targeting apolipoprotein CIII (APOC3) or ANGPLTL3 under investigation for their impact on cardiovascular outcomes (6,7).

Beyond lipids, there is conclusive evidence for residual inflammatory risk, often measured by high-sensitivity C-reactive protein (hsCRP). Studies such as CANTOS, testing an anti-inflammatory agent acting downstream of the NLRP3 inflammasome, and COLCOT and the LoDoCo2 trial with colchicine, showed reduction in cardiovascular events (8-10). More recently, ziltivekimab, an interleukin-6 inhibitor, reduced hsCRP by up to 92% in individuals with elevated hsCRP and chronic kidney disease (11); the ZEUS trial will evaluate whether lowering hsCRP with this agent reduces major adverse cardiovascular events (12).

While optimal management of lipid- and inflammatory residual risk is crucial, it does not eliminate the risk of recurrent cardiovascular events. Genetic studies been pivotal to identifying the junctional protein associated with coronary artery disease (JCAD) as a risk locus for coronary artery disease (13,14), with subsequent mechanistic studies implicating this protein as a potential biomarker of thrombotic residual risk given its dual mechanistic involvement in atherosclerosis and thrombosis (15). This month’s Focus report discusses evidence from two prospective cohorts of patients with acute coronary syndrome (ACS) (16), which showed that higher JCAD plasma levels linked independently and consistently to

increased risk of recurrent major adverse cardiovascular events. This association was present irrespective of residual lipid or inflammatory risk. Furthermore, the study also showed that high plasma levels of JCAD were independently associated with higher levels of biomarkers of pro-thrombotic mediators and impaired endogenous fibrinolysis in ACS patients. Taken together these findings support JCAD as a biomarker of thrombotic risk, suggesting a potential target for addressing residual risk that persists amongst ACS patients against a background of guideline-recommended preventive strategies.

 

As shown by the JCAD example, an in-depth understanding of the mechanisms and synergy of pathways is crucial to identify novel targets for residual risk. The use of integrated predictive models of the severity and extent of coronary artery disease, aided by artificial intelligence, offers the possibility of precise stratification of ACS patients to identify optimal therapeutic preventive astrategies. A personalized approach to the management of multifaceted residual risk beckons for the future.

References

      1. Kronenberg F, Borén J, Ray KK. 2025 focused update of the 2019 ESC/EAS guidelines for the management of dyslipidemias – Advancing evidence-based care through innovation. Atherosclerosis. 2025; doi: 10.1016/j.atherosclerosis.2025.120487.
      2. Pirillo A, Catapano AL. Lipoprotein (a): A new target for pharmacological research and an option for treatment. Eur J Intern Med 2025;139:106425.
      3. Cho L, Nicholls SJ, Nordestgaard BG, et al. Design and rationale of Lp(a)HORIZON Trial: assessing the effect of lipoprotein(a) lowering with pelacarsen on major cardiovascular events in patients with CVD and elevated Lp(a). Am Heart J 2025;287:1-9.
      4. Olpasiran Trials of Cardiovascular Events and Lipoprotein(a) Reduction (OCEAN(a)) – Outcomes Trial. NCT05581303.
      5. Ardissino A, Roberts A, Maglietta G et al. Genetic predisposition to elevated lipoprotein(a) in early-onset myocardial infarction. Eur J Prev Cardiol 2026; doi: 10.1093/eurjpc/zwag056.
      6. Ginsberg HN, Packard CJ, Chapman MJ, et al. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European atherosclerosis society. Eur Heart J 2021;42:4791–806.
      7. Li X, Li ZF, Wu NQ. Remnant cholesterol and residual risk of atherosclerotic cardiovascular disease. Rev Cardiovasc Med 2025; doi: 10.31083/RCM25985.
      8. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119–31.
      9. Nidorf SM, Fiolet ATLL, Mosterd A, et al. Colchicine in patients with chronic coronary disease. N Engl J Med 2020;383:1–10.
      10. Tardif J-C, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med 2019;381: 2497–505.
      11. Ridker PM, Devalaraja M, Baeres FMM, et al. IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 2021;397:2060-9.
      12. Ridker PM, Baeres FMM, Hveplund A, et al. Rationale, design, and baseline clinical characteristics of the Ziltivekimab Cardiovascular Outcomes Trial: Interleukin-6 inhibition and atherosclerotic event rate reduction. JAMA Cardiol 2025; doi: 10.1001/jamacardio.2025.4491.
      13. Erdmann J, Willenborg C, Nahrstaedt J, et al. Genome-wide association study identifies a new locus for coronary artery disease on chromosome 10p11.23. Eur Heart J 2011;32:158–68.
      14. Coronary Artery Disease (C4D) Genetics Consortium. A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease. Nat Genet 2011;43:339–44.
      15. Liberale L, Puspitasari YM, Ministrini S, et al. JCAD promotes arterial thrombosis through PI3K/Akt modulation: a translational study. Eur Heart J 2023;44:1818–33.
      16. Kraler S, Liberale L, Tirandi A, et al. The junctional protein associated with coronary artery disease predicts adverse cardiovascular events in patients with acute coronary syndromes at high residual risk. Eur Heart J 2025; doi.org/10.1093/eurheartj/ehaf979.

       

      Key words: Residual risk; Residual lipid risk; Residual inflammatory risk; Thrombotic risk; JCAD