2025 Focused Update of the 2019 ESC/EAS Guidelines for the Management of Dyslipidaemias

Authors, Journal, Affiliations, Type, DOI

• Chairs: François Mach (ESC, Geneva), Konstantinos C. Koskinas (ESC, Bern), Jeanine E. Roeters van Lennep (EAS, Rotterdam)
• Journal: European Heart Journal 2025;46:4359–4378 (co-published in Atherosclerosis)
• Type: ESC/EAS Focused Update (interim guideline update)
• DOI: https://doi.org/10.1093/eurheartj/ehaf190
• Based on: 2019 ESC/EAS Guidelines (DOI: 10.1093/eurheartj/ehz455); updates based on trials published ≤31 March 2025

Overview

This focused update to the 2019 ESC/EAS dyslipidaemia guidelines incorporates evidence from seven major randomised trials (CLEAR Outcomes, ELIPSE HoFH, APPROACH, REPRIEVE, STRENGTH, STOP-CA, SPORT, OMEMI) and revises recommendations across eight topic areas. The core LDL-C treatment targets are unchanged from 2019; the update primarily addresses which agents to use, in which clinical settings, and when to initiate. Key additions include bempedoic acid as first-line for statin-intolerant patients (COR I B), replacement of the SCORE algorithm with SCORE2/SCORE2-OP for CV risk estimation, initiation of combination statin+ezetimibe at ACS hospitalization, and new recommendations for HIV, cancer cardioprotection, and dietary supplements.

Keywords

Guidelines • Dyslipidaemia • Lipid-lowering drugs • Low-density lipoproteins • Lipoprotein(a) • Hypertriglyceridaemia • Cardiovascular risk • Familial hypercholesterolaemia • Acute coronary syndromes

Key Takeaways

Section 1: CV Risk Estimation — SCORE2 and SCORE2-OP Replace SCORE (Recommendation Table 1)

• SCORE2 (age 40–69 y) and SCORE2-OP (≥70 y) are now the recommended risk algorithms for persons without established ASCVD, DM, CKD, or genetic lipid/BP disorders: COR I B
  • Key improvements over SCORE: uses non-HDL-C (not total cholesterol); estimates 10-year fatal AND non-fatal events (not fatal only); valid to age 89; calibrated to 4 European country-cluster risk zones
  • SCORE2/SCORE2-OP thresholds replace SCORE thresholds with approximately ×2 multiplier (since total CVD events ~2–3× fatal CVD events)
• Risk categories (Table 3):

• CAC as risk modifier (new recommendation): presence of subclinical coronary atherosclerosis by imaging or elevated CAC score should be considered as a risk modifier in individuals at moderate risk or around treatment decision thresholds: COR IIa B
• Risk modifiers (Box 1) beyond SCORE2/SCORE2-OP: family history of premature CVD, high-risk ethnicity, psychosocial stressors, obesity, physical inactivity, chronic inflammatory disorders, psychiatric disorders, premature menopause, pre-eclampsia, HIV infection, obstructive sleep apnoea, elevated hsCRP >2 mg/L, elevated Lp(a) >50 mg/dL (>105 nmol/L)
• LDL-C treatment goals (Figure 1) and intervention thresholds (Table 4) are unchanged from 2019:
  • Very high risk: LDL-C <1.4 mmol/L (<55 mg/dL) AND ≥50% reduction from baseline (COR I A)
  • High risk: LDL-C <1.8 mmol/L (<70 mg/dL) (COR I A)
  • Moderate risk: LDL-C <2.6 mmol/L (<100 mg/dL) (COR IIa A)
  • Low risk: LDL-C <3.0 mmol/L (<116 mg/dL) (COR IIb A)
• Note: SCORE2/SCORE2-OP should not be used in patients with existing ASCVD or those currently on lipid-lowering therapy

Section 2: New LDL-C Lowering Therapies — Bempedoic Acid and Evinacumab (Recommendation Table 2)

• Bempedoic acid (ATP-citrate lyase inhibitor, oral 180 mg/day): prodrug activated only in liver (not skeletal muscle) → muscle-related adverse events similar to placebo
  • Reduces LDL-C ~23% monotherapy; ~18% added to statin; ~38% in fixed combination with ezetimibe
  • CLEAR Outcomes (n=13,970 statin-intolerant; median 40.6 months): 13% reduction in MACE (HR 0.87; 95%CI 0.79–0.96; P=.004); no effect on CV death alone
  • Adverse effects vs placebo: hepatic enzymes >2×ULN (4.5% vs 3.0%), renal impairment (11.5% vs 8.6%), hyperuricaemia (10.9% vs 5.6%), gout (3.1% vs 2.1%), cholelithiasis (2.2% vs 1.2%), raised platelet count (7.2% vs 0.8%)
  • COR I B: bempedoic acid recommended in patients unable to take statin therapy to achieve LDL-C goal
  • COR IIa C: addition of bempedoic acid to maximally tolerated statin ± ezetimibe should be considered in patients at high/very high risk
• Evinacumab (anti-ANGPTL3 mAb, LDL receptor-independent): ~49% LDL-C reduction in HoFH
  • COR IIa B: should be considered in HoFH patients aged ≥5 years not at LDL-C goal despite maximum lipid-lowering therapy
• Inclisiran (siRNA PCSK9 inhibitor, SC every 6 months): ~50% LDL-C reduction; two CV outcome trials ongoing (expected 2026–2027); no CV outcomes recommendation yet
• Average LDL-C reductions (Figure 2): monotherapy: ezetimibe ~20%, bempedoic acid ~23%, PCSK9 mAb ~60%; combinations: statin+ezetimibe ~60–65%, statin+ezetimibe+PCSK9 mAb ~75–80%

Section 3: Lipid-Lowering Therapy in ACS (Recommendation Table 3)

• "Sooner, lower, better" strategy: early ACS phase is highest vulnerability; stepwise approach may delay goal attainment by up to 12 weeks
• PACMAN-AMI and HUYGENS trials: very intensive LDL-C reduction at ACS improves coronary plaque composition (plaque size ↓, fibrous cap ↑)
• COR I C: intensification of lipid-lowering therapy during index ACS hospitalization is recommended for patients already on any lipid-lowering therapy
• COR IIa B: initiating combination therapy with high-intensity statin + ezetimibe during index ACS hospitalization should be considered in treatment-naïve patients not expected to reach LDL-C goal with statin alone (based on IMPROVE-IT: ezetimibe added within median 5 days post-ACS → modest but significant CV event reduction)
• Check LDL-C 4–6 weeks after initiation or intensification; lifelong treatment strongly recommended

Section 4: Lipoprotein(a) (Recommendation Table 4)

• Lp(a) risk is continuous: risk begins to increase above 30 mg/dL (62 nmol/L), becomes clinically relevant above 50 mg/dL (105 nmol/L), with higher levels conferring greater risk
• Figure 3: lifetime risk for major CV events rises steeply from Lp(a) ≥105 nmol/L (UK Biobank, n=415,274)
• COR IIa B (new): Lp(a) levels above 50 mg/dL (105 nmol/L) should be considered in all adults as a CV risk-enhancing factor, with higher Lp(a) levels associated with greater increase in risk
• Lp(a) as risk modifier to potentially reclassify moderate risk or borderline individuals to higher category (see Box 1)
• Statins have no effect on Lp(a) concentrations (individual-level data from 7 placebo-controlled statin trials)
• RNA-based therapies (ASO/siRNA targeting apo(a)): 80–98% Lp(a) reduction; phase 3 CVOTs ongoing
• Measurement: at least once in adult lifetime; nmol/L preferred; substantial inter-assay variability related to apo(a) KIV repeat structure

Section 5: Hypertriglyceridaemia (Recommendation Table 5)

• Statins remain first drug of choice for CVD risk reduction in high-risk patients with elevated TG
• Fibrates (fenofibrate, bezafibrate): moderate TG lowering but no MACE reduction on statin background; still COR IIb
• STRENGTH trial (omega-3 EPA+DHA combination, n=13,078): no MACE benefit — negative; contrasts with REDUCE-IT positive results
  • Discordance explained by: different active compounds (EPA+DHA vs pure icosapent ethyl), different placebo (corn oil vs mineral oil in REDUCE-IT), different mechanisms
• COR IIa B (revised): high-dose icosapent ethyl (IPE, 2×2 g/day) should be considered in combination with a statin in high-risk or very high-risk patients with elevated TG (fasting 135–499 mg/dL / 1.52–5.63 mmol/L) to reduce CV events
• COR IIa B (new): volanesorsen (300 mg/week SC, anti-ApoC-III ASO) should be considered in patients with severe hypertriglyceridaemia (>750 mg/dL / >8.5 mmol/L) due to familial chylomicronaemia syndrome (FCS), to lower TG and reduce pancreatitis risk
  • APPROACH trial (FCS, mean baseline TG 2209 mg/dL): 77% TG reduction, <750 mg/dL achieved in 77%; meta-analysis: significant reduction in acute pancreatitis
  • Adverse effects: thrombocytopenia (requires monitoring), injection-site reactions (60%)
  • EMA-approved only (not FDA-approved); available as adjunct to diet for genetically confirmed FCS at high pancreatitis risk

Section 6: HIV — Primary Prevention (Recommendation Table 6)

• People with HIV (PWH) have ~2-fold higher ASCVD risk; conventional risk tools underestimate risk in PWH
• REPRIEVE trial (n=7,769 PWH aged 40–75 y, primary prevention, low-to-moderate risk on ART): pitavastatin 4 mg/day vs placebo; stopped early for efficacy after median 5.1 years
  • 35% lower MACE incidence (HR 0.65; 95%CI 0.48–0.90; P=.002); NNT 106 at 5 years
  • Pitavastatin does not interact with antiretroviral drugs (minimal CYP3A4)
  • Higher rates of muscle symptoms (2.4% vs 1.3%) and new-onset diabetes (5.3% vs 4.0%)
• COR I B (new): statin therapy is recommended for PWH aged ≥40 years in primary prevention, irrespective of estimated CV risk and LDL-C levels; choice of statin based on drug interactions

Section 7: Cancer/Cardio-Oncology (Recommendation Table 7)

• Anthracycline-based chemotherapy: heart failure in up to 20% within 5 years depending on cumulative dose
• STOP-CA trial (atorvastatin 40 mg vs placebo in 300 lymphoma patients): primary endpoint (≥10% LVEF decline to <55% at 12 months) occurred in 22% placebo vs 9% atorvastatin (P=.002)
• Three smaller trials: mixed results (differences in population, CV risk, outcomes, follow-up)
• COR IIa B (new): statins should be considered in adult patients at high or very high risk of developing chemotherapy-related CV toxicity to reduce the risk of anthracycline-induced cardiac dysfunction
  • Risk stratification per 2022 ESC cardio-oncology guidelines

Section 8: Dietary Supplements (Recommendation Table 8)

• SPORT trial (n=199, ASCVD-free with elevated 10-year risk): rosuvastatin 5 mg > all supplements and placebo for LDL-C lowering at 28 days; none of the supplements (fish oil, cinnamon, garlic, turmeric, plant sterols, red yeast rice) showed significant LDL-C reduction vs placebo
• OMEMI trial: omega-3 (DHA+EPA) in elderly post-MI without elevated TG → no reduction in clinical events
• Phytosterols: ~10% LDL-C reduction at ≤2 g/day (no CV outcome benefit)
• European Parliament/Council ban (June 2022): food supplements containing ≥3 mg/day monacolins from red yeast rice prohibited
• COR III B (new): dietary supplements or vitamins without documented safety and significant LDL-C-lowering efficacy are NOT recommended to lower ASCVD risk

Limitations of the Document

• Focused update only — does not address all sections of the 2019 full guidelines; other 2019 recommendations remain valid
• CLEAR Outcomes included significant proportion on low-dose statin (23%) — bempedoic acid efficacy may differ in true statin-naïve vs partial statin users
• REDUCE-IT mineral oil placebo controversy unresolved: IPE benefit magnitude uncertain
• REPRIEVE: pitavastatin-specific trial in HIV; generalizability to other statins uncertain; NNT 106 over 5 years — moderate absolute benefit
• STOP-CA: single large trial with mixed smaller trial results; cardioprotective mechanism of statins for anthracycline toxicity is plausible but not definitively established
• Volanesorsen: only EMA-approved (not FDA); small phase III trial (n=66); thrombocytopenia risk limits use

Key Concepts Mentioned

• concepts/Dyslipidemia-Management — LDL-C targets, bempedoic acid, ACS strategy, dietary supplements
• concepts/ASCVD-Risk-Assessment — SCORE2/SCORE2-OP replacing SCORE; CAC as risk modifier; risk categories
• concepts/Lipoprotein-a — Lp(a) >105 nmol/L as risk-enhancing factor COR IIa B
• concepts/Familial-Hypercholesterolemia — evinacumab COR IIa B for HoFH ≥5 years

Key Entities Mentioned

• entities/Obstructive-Sleep-Apnea — listed as clinical risk modifier beyond SCORE2 (Box 1)

Wiki Pages Updated

• wiki/sources/lipid-esc-2025.md — created (this file)
• wiki/concepts/Dyslipidemia-Management.md — updated with ESC 2025 content and ESC vs ACC/AHA contradictions
• wiki/concepts/ASCVD-Risk-Assessment.md — updated with SCORE2/SCORE2-OP framework and ESC risk categories
• wiki/concepts/Lipoprotein-a.md — updated with ESC Lp(a) threshold (105 nmol/L) and contradiction with ACC/AHA (125 nmol/L)
• wiki/concepts/Familial-Hypercholesterolemia.md — updated with evinacumab ESC recommendation and age extension (≥5 y)
• wiki/sourceindex.md — updated
• wiki/wikiindex.md — no new concept pages added (all relevant pages already exist)