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

August 2025
Update to the 2019 ESC/EAS guidelines clarifies lipid management
Prof. Peter Libby, Prof. Michel Hermans, Prof. Pierre Amarenco

Guidelines are not static but evolve as evidence dictates. Thus, it is not surprising that updated guidance to the 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines has been recently published (1,2). This update has been mandated by new evidence from major randomized controlled trials and meta-analyses which have evaluated different lipid-modifying interventions in high cardiovascular risk patients.

Given indisputable evidence that elevated low-density lipoprotein cholesterol (LDL-C) increases cardiovascular risk (3), updates to strategies for LDL-C lowering are a key focus. The 2019 ESC/EAS guidelines recognized the need for combination therapy to achieve LDL-C goals in high cardiovascular risk patients (1). This new guidance extends the recommended options available to clinicians. These now include bempedoic acid, based on evidence from the CLEAR Outcomes study in high-risk statin-intolerant patients (4), as well as inclisiran, which given twice yearly, represents an alternative to proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody therapy (5). Definitive evidence from ongoing cardiovascular outcomes trials (NCT03705234, NCT05030428) is awaited for class I recommendations regarding inclisiran in future iterations of the guidelines.

There are new recommendations for lipid lowering therapy in key patient groups. The ANGPTL3 (angiopoietin-like protein 3) inhibitor evinacumab is recommended in homozygous familial hypercholesterolemia (6,7), allowing the possibility of attaining LDL-C goal, which would be inconceivable with current LDL-lowering combination therapy. Ezetimibe is recommended in older patients, supported by evidence from EWTOPIA 75 (Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older) in people aged ≥75 years without a history of coronary artery disease (8).

The guidance also advocates early, intensive LDL-C lowering in patients with an acute coronary syndrome, with a statin initially, adding additional LDL-C lowering treatment with proven cardiovascular benefit according to the magnitude of additional LDL-C lowering required. This recommendation is supported by accumulating evidence, extending from the IMPROVE-IT with ezetimibe/statin fixed-dose dual therapy (9), to more recent studies with PCSK9 monoclonal antibody therapy, notably HUYGENS (High-Resolution Assessment of Coronary Plaques in a Global Evolocumab Randomized Study) (10) and PACMAN-AMI (Effects of the PCSK9 Antibody Alirocumab on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction) (11). Statin therapy is also recommended in all people with HIV aged ≥40 years, supported by evidence from the REPRIEVE trial (12), and in cancer patients at high chemotherapy-related cardiovascular toxicity risk (13-15).

Triglyceride-lowering interventions have also received expert appraisal. The new guidance only recommends high-dose icosapent ethyl for high cardiovascular risk patients with hypertriglyceridemia despite statin therapy, based on the REDUCE-IT trial (16). However, this could change in the future, given intensive investigation of novel RNA therapeutic approaches, including those targeting apolipoprotein (apo) CIII, ANGPTL3 and ANGPTL4. For patients with severe hypertriglyceridemia due to familial chylomicronaemia syndrome, volanesorsen, an antisense oligonucleotide targeting hepatic apoC-III messenger RNA, is recommended.

Beyond these updates, the guidance reaffirms a major shift in cardiovascular risk assessment, from SCORE to SCORE2, SCORE2-Diabetes and SCORE2-OP algorithms (17, 18). Not only do these extend risk assessment to age 89 years, but the inclusion of both fatal and non-fatal cardiovascular events improves assessment of the potential cardiovascular burden.  There is also recognition of the impact of cardiovascular risk enhancers, notably lipoprotein(a), in risk assessment (19). Considering lifetime risk, the update aligns with the concept of personalized medicine as the next stage in the evolution of cardiovascular risk assessment. 

 This update to the 2019 ESC/EAS lipid guidelines will undoubtedly aid the treatment of lipid-related residual cardiovascular risk. We await results from ongoing trials for insights into the management non-LDL components of this risk.

 

References

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    2. Mach F, Koskinas KC, Roeters van Lennep JE, et al. Focused update of the 2019 ESC/EAS guidelines for the management of dyslipidaemias. Atherosclerosis 2025. https://doi.org/10.1016/j.atherosclerosis.2025.120479.
    3. Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017;38:2459-72.
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    8. Ouchi Y, Arai H, et al. Ezetimibe lipid-lowering trial on prevention of atherosclerotic cardiovascular disease in 75 or older (EWTOPIA 75): a randomized, controlled trial. Circulation 2019;140:992-1003.
    9. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-97.
    10. Nicholls SJ, Kataoka Y, Nissen SE, et al. Effect of evolocumab on coronary plaque phenotype and burden in statin-treated patients following myocardial infarction. JACC Cardiovasc Imag 2022;15:1308-21.
    11. Raber L, Ueki Y, Otsuka T, et al. Effect of alirocumab added to high-intensity statin therapy on coronary atherosclerosis in patients with acute myocardial infarction: the PACMAN-AMI randomized clinical trial. JAMA 2022; 27:1771-81.
    12. Grinspoon SK, Fitch KV, Zanni MV, et al. Pitavastatin to prevent cardiovascular disease in HIV infection. N Engl J Med 2023;389:687-99.
    13. Neilan TG, Quinaglia T, Onoue T, et al. Atorvastatin for anthracycline-associated cardiac dysfunction: the STOP-CA randomized clinical trial. JAMA 2023; 330:528-36.
    14. Nabati M, Janbabai G, Esmailian J, et al. Effect of rosuvastatin in preventing chemotherapy-induced cardiotoxicity in women with breast cancer: a randomized, single-blind, placebo-controlled trial. J Cardiovasc Pharmacol Ther 2019;24:233-41.
    15. Thavendiranathan P, Houbois C, Marwick TH, et al. Statins to prevent early cardiac dysfunction in cancer patients at increased cardiotoxicity risk receiving anthracyclines. Eur Heart J Cardiovasc Pharmacother 2023;9:515-25.
    16. Bhatt DL, Steg PG,∙Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.
    17. SCORE2 working group and ESC Cardiovascular risk collaboration. SCORE2 risk prediction algorithms: new models to estimate 10-year risk of cardiovascular disease in Europe. Eur Heart J 2021;42:2439–54.
    18. SCORE2-OP working group and ESC Cardiovascular risk collaboration; SCORE2-OP risk prediction algorithms: estimating incident cardiovascular event risk in older persons in four geographical risk regions. Eur Heart J 2021;42:2455–67.
    19. Kronenberg F, Mora S, Stroes ESG, et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur Heart J 2022;43:3925–46.

    Key words: Guidelines; lipid lowering; triglycerides; low-density lipoprotein cholesterol; cardiovascular risk assessment

    –62.
    14. Aboyans V, Criqui MH, Denenberg JO, et al. Risk factors for progression of peripheral arterial disease in large and small vessels. Circulation 2006;113:2623–9.

Key words: Lipoprotein(a); peripheral artery disease; ODYSSEY OUTCOMES; residual vascular risk