2025 ESC/EAS Dyslipidemia Update

Focused Update of the 2019 ESC/EAS Guidelines for the management of dyslipidaemias

Published: European Heart Journal (2025) 46, 4359–4378
Societies: European Society of Cardiology (ESC) / European Atherosclerosis Society (EAS)
DOI: 10.1093/eurheartj/ehaf190

View Full Guideline

What's Changed: 2025 vs 2019

1. SCORE2 & SCORE2-OP Adoption

The 2025 update replaces the SCORE algorithm with SCORE2 and SCORE2-OP for cardiovascular risk estimation. This represents a major shift in how clinicians stratify patient risk.

SCORE2: 10-year fatal and non-fatal CVD risk for age <70 years
SCORE2-OP: For age ≥70 years; accounts for different risk trajectories in older adults
Risk thresholds: Very high, high, moderate, low categories based on calculated 10-year risk
2x multiplier: Used to convert previous SCORE-based thresholds to SCORE2-based ones

2. Updated LDL-C Target Goals

Very High Risk (secondary prevention, HoFH):
<55 mg/dL (<1.4 mmol/L) with ≥50% reduction from baseline

High Risk (ASCVD, FH):
<70 mg/dL (<1.8 mmol/L)

Moderate Risk:
<100 mg/dL (<2.6 mmol/L)

Low Risk:
<116 mg/dL (<3.0 mmol/L)

3. New Evidence-Based Classes of Recommendations

Recommendations follow standardized classification:

Class I: Recommended or indicated (evidence and general agreement)
Class IIa: Should be considered (weight of evidence/opinion favors)
Class IIb: May be considered (usefulness/efficacy less established)
Class III: Not recommended (evidence suggests no benefit or potential harm)

4. Intensive Post-ACS LDL-Lowering

Strong new recommendation for early, intensive LDL-C lowering during acute coronary syndrome hospitalization:

Initiate high-intensity statin immediately in hospital
Add ezetimibe and/or PCSK9 inhibitor if LDL-C goal not approached in acute phase
Target <55 mg/dL (<1.4 mmol/L) with ≥50% reduction from baseline
Check LDL-C at 4-6 weeks post-discharge and adjust therapy

Cardiovascular Risk Categories & LDL Targets

Risk Category	SCORE2/OP 10-Yr Risk	LDL-C Target	LDL Reduction Goal	Example Populations
Very High	≥20% (fatal + nonfatal)	<55 mg/dL (<1.4 mmol/L)	≥50% from baseline	Documented ASCVD, ACS, HoFH, DM with target organ damage
High	10-19%	<70 mg/dL (<1.8 mmol/L)	≥50% if feasible	HeFH, significant single RF, CKD, severe DM
Moderate	5-9%	<100 mg/dL (<2.6 mmol/L)	≥30% if feasible	Multiple risk factors, young age, moderate CKD
Low	<5%	<116 mg/dL (<3.0 mmol/L)	Lifestyle + selective pharmacotherapy	Young, no RF, low individual risk

Key Point: Intensity of LDL-C lowering should be determined by both absolute CVD risk AND the baseline untreated LDL-C level. Higher baseline LDL often requires more aggressive multi-drug therapy.

New & Updated Pharmacotherapy

Bempedoic Acid (BA)

Mechanism: ATP-citrate lyase inhibitor; reduces LDL-C synthesis upstream of statins
Monotherapy LDL reduction: ~23%
+ Statin combination: ~38% additional LDL reduction
Class I, Level B: Recommended for patients unable to take statin therapy or who require additional LDL-C lowering at LDL-C goal

Trial: CLEAR Outcomes (13,970 patients, 40.6 months)
Safety: Gout history (elevated uric acid); muscle-related AEs similar to statin
Dosing: 120 mg daily

Inclisiran (PCSK9 siRNA)

Mechanism: Small interfering RNA targeting PCSK9 mRNA
LDL reduction: ~50% at 50% efficacy; sustained effect
Class I, Level B: For patients with HoFH; Class IIb for ASCVD or statin-intolerant

Trials: ORION-1, 2, 3 (Phase III)
Dosing: 284 mg SC at baseline, 12 weeks, then every 6 months
Advantage: Sustained LDL reduction with lower dosing frequency vs monoclonal antibodies

Lp(a)-Lowering Agents

Pelacarsen (antisense oligonucleotide targeting apolipoprotein(a))

Phase III trials: HORIZON, EARTH, OCEAN ongoing
Lp(a) reduction: ~50% observed in early trials
Class IIb (May be considered) for patients with elevated Lp(a) and CV risk

Obicetrapib

CETP inhibitor; modest additional LDL-C reduction with statin
Under investigation; potential for combination therapy

Updated Treatment Algorithm

Step-Wise LDL-C Lowering Approach

Step 1: Foundation Therapy

High-intensity statin (atorvastatin 40–80 mg or rosuvastatin 20–40 mg daily)
Expected LDL reduction: ~50% from baseline

Step 2: First Add-On (if LDL goal not reached)

Ezetimibe 10 mg daily
Additional LDL reduction: ~18–20% (cumulative ~60–70% with statin)

Step 3: Second Add-On (if still above target)

Option A: PCSK9 Monoclonal Antibody
Evolocumab 140 mg SC Q2W or alirocumab 75 mg SC Q2W
Additional LDL reduction: ~50%
(Cumulative: ~75–80%)

Option B: Inclisiran
284 mg SC at baseline, week 12, then Q6M
Additional LDL reduction: ~50%
(Cumulative: ~75–80%)

Step 4: Further Optimization (for very high-risk patients)

Add Bempedoic Acid 120 mg daily
Additional LDL reduction: ~20–25%
(Cumulative: ~80–85% with full triple therapy)

Special Circumstance: Post-ACS

Goal: Intensive LDL-C lowering to <55 mg/dL (<1.4 mmol/L) with ≥50% reduction from baseline

Timing: Initiate during index hospitalization

Approach:

Day 1–2: High-intensity statin + ezetimibe
Consider adding PCSK9i or inclisiran if LDL-C not approaching goal in acute phase
Check LDL-C at 4–6 weeks post-discharge; adjust therapy intensity based on absolute LDL achieved
Do not delay intensive therapy; early, lower LDL = lower recurrent event risk

Lipoprotein(a) Management

Epidemiology & Risk

Plasma Lp(a) genetically determined; ~25% of population >50 mg/dL (105 nmol/L)
Risk escalates above 50 mg/dL; becomes clinically relevant for CV outcome prediction
Independent risk factor for ASCVD, aortic valve disease, peripheral artery disease
Measurement: At least once in lifetime; particularly relevant in younger patients with FH or premature ASCVD

New Recommendations

Class IIa Level B Lp(a) ≥50 mg/dL (105 nmol/L) should be considered a cardiovascular risk modifier for individuals at moderate or higher risk for ASCVD.

Treatment Strategy

Principle: Lp(a) lowering works synergistically with aggressive LDL-C reduction. Do NOT substitute Lp(a) treatment for LDL-C management.

Statins: Minimal Lp(a) reduction (0–5%); do not rely on statin monotherapy
PCSK9 inhibitors: ~25–35% Lp(a) reduction; use in high-risk patients
Pelacarsen (antisense RNA): ~50% Lp(a) reduction; ongoing phase III trials

Hypertriglyceridemia Management

High-Dose Icosapent Ethyl (REDUCE-IT)

Class IIa Level B High-dose icosapent ethyl (2×2 g/day) should be considered in high-risk or very high-risk patients with elevated triglyceride levels (fasting 135–499 mg/dL; 1.52–5.63 mmol/L) on statin therapy.

Trial: REDUCE-IT (13,078 patients; 70% diabetes; 56% ASCVD)
LDL-C requirement: 41–100 mg/dL (1.0–2.6 mmol/L) on baseline statin
Efficacy: 25% relative risk reduction in major CV events; NNT ~106 over 5 years
Caution: Atrial fibrillation/flutter risk; monitor if on anticoagulation

Pemafibrate (PROMINENT) — Negative Result

Trial: PROMINENT (Phase III; diabetes, hypertriglyceridemia)
Result: Failed to reduce composite of CVD death, non-fatal MI, stroke, or hospitalization
Recommendation: Class IIb (May be considered) only for specific triglyceride management

Volasorsen (ApoC-III Inhibitor)

Antisense oligonucleotide targeting ApoC-III mRNA
Phase II: ~77% achieved triglycerides <750 mg/dL within 3 months
Under investigation; not yet approved for routine clinical use

Statin Intolerance: Updated Definition & Management

Updated Definition

Statin intolerance is NOT simply the absence of any statin therapy. True statin intolerance requires:

Documented class-confirmed muscle-related adverse reaction
Clear temporal relationship: symptom onset during use, resolution after discontinuation
Rechallenge with symptom recurrence (confirms causality)
Inability to tolerate ANY statin at any dose

Rechallenge Protocol

Step 1: Education & Rechallenge

Counsel patient on trial-and-error approach. ~80% of patients can tolerate a statin with rechallenge.

Step 2: Restart at Lowest Dose

Pravastatin 10 mg daily OR Rosuvastatin 5 mg daily
Baseline assessment: Measure creatine kinase if symptoms severe

Step 3: Slow Titration

Increase dose every 2–4 weeks if tolerated. Many patients tolerate low doses successfully.

Step 4: Intermittent Dosing

If continuous dosing not tolerated, try every-other-day or once-weekly statin dosing. Efficacy is ~50–75% of daily dosing.

Step 5: Alternative Statin

Switch to a different statin (e.g., pravastatin if atorvastatin not tolerated). Cross-reactivity is rare.

Step 6: Non-Statin Alternatives

If NO statin tolerated: Ezetimibe + PCSK9i + inclisiran + bempedoic acid combination may achieve LDL-C reduction comparable to statin monotherapy.

Special Populations & Contexts

Elderly (≥70 Years)

Risk estimation: Use SCORE2-OP algorithm (replaces SCORE)
CAC score: Can be considered as risk modifier to improve discrimination
LDL targets: High to very high risk still benefit from LDL-C lowering
Polypharmacy concern: Careful balance of medication burden

Chronic Kidney Disease (CKD)

Threshold: eGFR ≥30 mL/min/1.73 m² warrants statin therapy for CV risk reduction
Dose adjustment: Most statins safe in CKD; pravastatin preferred in severe renal disease
Non-statin agents: PCSK9i, inclisiran, ezetimibe, bempedoic acid all usable

Type 2 Diabetes Mellitus (T2DM)

Without ASCVD, LDL-C ≥1.8 mmol/L (70 mg/dL): Initiate statin therapy
With ASCVD or very high risk: LDL-C target <1.4 mmol/L (55 mg/dL) with ≥50% reduction
GLP-1 agonists: Independent CV benefit; synergistic with lipid-lowering therapy

Familial Hypercholesterolemia (FH)

Heterozygous FH (HeFH) — Prevalence ~1:250–500

LDL target: <70 mg/dL (1.8 mmol/L) at high risk; <55 mg/dL (1.4 mmol/L) at very high risk
Combination therapy required: High-intensity statin + ezetimibe + PCSK9i standard of care
Inclisiran option: Class I for HeFH patients; ~50% additional LDL reduction

Homozygous FH (HoFH) — Prevalence ~1:160,000–1,000,000

Very aggressive LDL target: <55 mg/dL (1.4 mmol/L); some recommend <39 mg/dL (1.0 mmol/L)
Multi-drug approach: Statin + ezetimibe + PCSK9i + inclisiran ± bempedoic acid often required
Lipoprotein apheresis: Consider if LDL-C goals unattainable with pharmacotherapy alone

Post-Acute Coronary Syndrome (ACS)

Early intensive therapy: During index hospitalization (Class I recommendation)
Target: <55 mg/dL (<1.4 mmol/L) with ≥50% reduction from baseline preferred
Timing of additional agents: Add PCSK9i or inclisiran if LDL-C not approaching goal in acute phase
Post-discharge monitoring: LDL-C check at 4–6 weeks; adjust therapy intensity based on achieved LDL-C

People with HIV (PWH)

CV risk: 2–3x higher than age-matched HIV-negative peers
Statin recommendation (Class I): For individuals ≥40 years in primary prevention
Preferred statins: Pravastatin or rosuvastatin (lower drug interaction risk with protease inhibitors)
PCSK9 inhibitors: Effective; evocumab demonstrated CV benefit in PWH

Key Recommendations Summary (Classes & Levels)

Cardiovascular Risk Estimation (New SCORE2/SCORE2-OP)

Recommendation	Class	Level
SCORE2 for <70-year-olds without ASCVD	I	B
SCORE2-OP for ≥70-year-olds	I	B
CAC score consideration as risk modifier	IIa	B

Pharmacological LDL-C Lowering

Agent / Situation	Class	Level	Key Points
High-intensity statin (primary prevention at high/very high risk)	I	A	Foundation therapy; proven CV benefit
Ezetimibe (high-risk patients not at goal on statin)	I	A	~18% additional LDL reduction; safe
PCSK9 inhibitors (HoFH)	I	A	Proven benefit; standard of care
Inclisiran (HoFH)	I	B	~50% LDL reduction; alternative to PCSK9i
Bempedoic acid (high/very high risk not at goal)	IIa	B	CLEAR Outcomes trial; additional ~20–25% LDL

Lipoprotein(a)

Recommendation	Class	Level
Lp(a) ≥50 mg/dL (105 nmol/L) as CV risk modifier	IIa	B
Pelacarsen for Lp(a) lowering (when available)	IIb	B

Triglyceridemia

Agent	Class	Level	Notes
High-dose icosapent ethyl (TG 135–499 mg/dL on statin)	IIa	B	REDUCE-IT trial; modest CV benefit
Pemafibrate (T2DM hypertriglyceridemia)	IIb	B	PROMINENT trial negative; limited use

Clinical Pearls: Do & Don't

✓ DO:

Use SCORE2/SCORE2-OP for cardiovascular risk estimation (replaces old SCORE)
Consider CAC score as risk modifier in intermediate-risk individuals
Initiate early, intensive LDL-lowering in post-ACS patients (during hospitalization)
Use combination therapy (statin + ezetimibe + PCSK9i/inclisiran) for very high-risk patients
Measure Lp(a) at least once in lifetime, especially in young FH or premature ASCVD
Monitor LDL-C 4–6 weeks after initiation/intensification of therapy
Consider rechallenge protocol for statin intolerance (intermittent dosing, alternative statins)
Use bempedoic acid for additional LDL reduction when LDL goal not achieved
Manage CVD risk in PWH aged ≥40 with statin therapy

✗ DON'T:

Use old SCORE algorithm thresholds; adopt SCORE2/SCORE2-OP instead
Delay statin therapy in high-risk primary prevention patients
Assume incomplete LDL-C reduction means intolerance (rechallenge often effective)
Treat elevated Lp(a) without concurrent aggressive LDL-C lowering
Prescribe fenofibrate or bezafibrate as monotherapy for triglyceride lowering
Ignore post-MI medication adherence; assess at 4–12 weeks post-discharge
Use unsupported supplements (omega-3, PUFAs) as sole treatment
Prescribe psyllium or plant sterols as primary dyslipidemia therapy
Delay intensive therapy in HoFH patients; early multi-drug approach optimal

Interactive Calculators & Risk Assessment Tools

The following risk assessment and treatment planning calculators are recommended and available:

SCORE2 Risk Calculator

10-year fatal and non-fatal cardiovascular disease risk for age <70 years

SCORE2-OP (Older Persons)

Cardiovascular risk for age ≥70 years

LDL-C Reduction Calculator

Calculate LDL reduction percentage from baseline to target with different therapies

Lp(a) & ASCVD Risk

Integrated Lp(a) level and ASCVD risk assessment tool

ASCVD Risk Estimator

Supplementary 10-year ASCVD risk calculator

PREVENT-ASCVD Calculator

Lifetime ASCVD risk prediction and 10-year risk estimation

Framingham Risk Score

Traditional 10-year cardiovascular risk model

Lifetime ASCVD Risk

Long-term lifetime risk of major cardiovascular events

MESA Risk Calculator

Multi-Ethnic Study of Atherosclerosis (MESA) risk model

Adult GFR Calculator

Estimated glomerular filtration rate and kidney function assessment

Creatinine Clearance

Cockcroft-Gault equation for renal function estimation

Publication & Disclaimer

Citation: Mach F, Baigent C, Catapano AL, et al. 2025 Focused Update of the 2019 ESC/EAS Guidelines for the management of dyslipidaemias. European Heart Journal. 2025;46(45):4359–4378. https://doi.org/10.1093/eurheartj/ehaf190

Disclaimer: This document represents the views of the ESC/EAS and was produced after careful consideration of scientific and medical evidence. Health professionals should use clinical judgment and patient-specific factors when applying recommendations.

Permissions: Content published for personal and educational use. No commercial use without written permission from ESC and EAS. For permissions: journals.permissions@oup.com

Last Updated: March 2026 | Quick Reference by: Satti MD