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).

April 2026
US and European guidelines on dyslipidemia align
Prof. Peter Libby, Prof. Michel Hermans, Prof. Pierre Amarenco, Prof. Lale Tokgözoglu 

This month heralded the long-awaited release of updated US guidelines for the management of dyslipidemia from the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines (1). Lipid research has evolved substantially since the 2018 guidelines (2), and in recognition, the guidelines have moved beyond cholesterol to encompass other key lipids, notably triglycerides and lipoprotein(a) [Lp(a)].

There are several key take home messages from these guidelines. One of these relates to risk assessment in individuals with dyslipidemia. The guidelines now recommend the use  of the contemporary American Heart Association PREVENT calculator rather than the Pooled Cohort Equations to guide lipid lowering therapy in primary prevention (1). Selective use of coronary artery calcium (CAC) may aid stratification of risk.

Second, there has been alignment with the European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) dyslipidemia guidelines on low-density lipoprotein cholesterol (LDL-C) targets (3,4). A new lower LDL-C goal of <55 mg/dL is recommended for secondary prevention, and other individuals at very high risk, including those with subclinical atherosclerosis and a high CAC score, or with chronic kidney disease stage 3 or higher (1). Both guideline groups coalesce in recommending the combination of non-statin options  (ezetimibe, bempedoic acid and/or a PCSK9 inhibitor) with maximally tolerated statin therapy to achieve this goal. Evidence from the Ez-PAVE (Effects of Ezetimibe Combination Therapy for Patients with Atherosclerotic Cardiovascular Disease — Randomized Comparison of LDL Cholesterol Targeting <70 mg per Deciliter vs. <55 mg per Deciliter) trial supports this approach. In this study, intensive lipid lowering to attain a median LDL-C of 56 mg/dL  significantly reduced the rate of major cardiovascular events by about one-third, compared with conventional lipid management targeting an LDL-C <70 mg/dL (5). The 2019 ESC/EAS guidelines do, however, go further in recommending a lower LDL-C target of 40 mg/dL (<1.0 mmol/L) for secondary prevention patients at extreme risk, such as those with recurrent cardiovascular events (3). In support, a recent study showed that attainment of this LDL-C goal mitigated the risk of subsequent cardiovascular events in patients with coronary artery disease (6).

The pace of lipid research, however, overtook guideline development. The significant cardiovascular benefits associated with more intensive lowering of LDL-C to <55 mg/dL in patients without previous myocardial infarction or stroke in VESALIUS-CV (7) blur

distinctions between ASCVD risk categories and LDL-C goals. Future guideline updates should take into account all patients with ASCVD (as well as those moderate atherosclerosis on imaging without prior cardiovascular events) with an optimal LDL-C goal of <55 mg/dL. In addition, evidence from the VESALIUS-CV substudy in diabetes patients without significant known atherosclerosis (8) warrant recommendations for more intensive LDL-C lowering in this high-risk population in future updates.

Another vector of alignment between European and US guidelines is the recommendation for measurement of Lp(a) in all patients (1,3,4). Monitoring CAC may allow for better risk stratification in patients with elevated Lp(a) (9). In the absence of specific Lp(a)-lowering therapies, optimal management of modifiable cardiovascular risk factors is recommended. In the secondary prevention setting, adding a PCSK9 inhibitor is recommended if LDL-C goal is not achieved (1).

Finally, the new guidelines incorporate recommendations for the management of hypertriglyceridemia. For secondary prevention patients with triglycerides of 150-999 mg/dL who fail to attain LDL-C goal on maximally tolerated statin therapy, intensive lipid lowering therapy is recommended (1).  Olezarsen, an antisense oligonucleotide to apolipoprotein CIII, is recommended for patients with familial chylomicronemia syndrome with triglycerides ≥1000 mg/dL as an adjunct to diet, supported by evidence from the CORE studies (10).

The pace of research in the lipid field continues to accelerate. Adapting LDL-C management across the continuum of primary and secondary prevention, supported by VESALIUS-CV, is anticipated. In the meantime, implementation of key recommendations from this guideline to routine clinical practice will be the major challenge.

References

    1. Blumenthal RS, Morris PB, Gaudino M, et al. 2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Dyslipidemia: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 2026:S0735-1097(25)10254-4.
    2. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;73:e285–e350.
    3. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111-88.
    4. Mach F, Koskinas KC, Roeters van Lennep JE, et al. ESC/EAS Scientific Document Group. 2025 Focused Update of the 2019 ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J 2025;46:4359-78.
    5. Lee YJ, Lee SJ, Kim JW, et al. Intensive LDL cholesterol targeting in atherosclerotic cardiovascular disease. N Engl J Med 2026; DOI: 10.1056/NEJMoa2600283.
    6. Kataoka Y, Nicholls SJ, Kitahara S, et al. Achieving LDL-C <1.0 mmol/L and cardiovascular outcomes in patients with coronary artery disease who received percutaneous coronary intervention. Atherosclerosis 2026; DOI: 10.1016/j.atherosclerosis.2026.120684
    7. Bohula EA, Marston NA, BhatiaAK, et al. Evolocumab in patients without a previous myocardial infarction or stroke. N Engl J Med 2026;394:117-27.
    8. Marston NA, Bohula EA, Bhatia AK , et al. Evolocumab to reduce first major cardiovascular events in patients without known significant atherosclerosis and with diabetes. Results from the VESALIUS-CV Trial. JAMA 2026; DOI:10.1001/jama.2026.3277.
    9. Bhatia HS, Fan Y, Dharmavaram G, et al. Use of coronary artery calcium scoring in individuals with elevated lipoprotein(a). J Am Coll Cardiol 2026; DOI: 10.1016/j.jacc.2026.02.5067.
    10. Marston NA, Bergmark BA, Alexander VJ, et al. Olezarsen for managing severe hypertriglyceridemia and pancreatitis risk. N Engl J Med 2026;394:429-41.

    Key words: 2026 Dyslipidemia guidelines; LDL-C targets; lipoprotein(a); coronary artery calcium; hypertriglyceridemia