The 2025 Focused Update of the European Society of Cardiology and European Atherosclerosis Society (ESC/EAS) Guidelines for the management of lipid disorders marks a significant evolution in cardiovascular disease (CVD) prevention, reflecting contemporary evidence, advances in risk assessment, and the advent of novel therapeutic modalities. Dyslipidemia remains a primary modifiable risk for atherosclerotic cardiovascular disease, necessitating robust, evidence-driven strategies to optimize prevention. Notably, the update transitions from the traditional SCORE system to the more comprehensive SCORE2 and SCORE2-OP risk models for estimating 10-year atherosclerotic cardiovascular disease risk. These new models broaden applicability, encompassing both fatal and non-fatal cardiovascular events and extending risk calculation up to age 89, while recalibrating country-specific risk clusters and prioritizing non-HDL cholesterol over total cholesterol as a core indicator. The guidelines emphasize the intensification of therapy for individuals identified as being at higher risk, integrating recent clinical trial data and targeted drug selection, with a particular focus on individualized risk stratification. This focused update contrasts its recommendations against the 2019 standard, outlining the rationale for new strategies in both primary and secondary prevention through intensified lipid-lowering therapy. Comprehensive implementation of these recommendations is anticipated to drive further reductions in ASCVD events, aligning with global public health priorities. The 2025 guidelines thus serve as an essential tool for clinicians and researchers, supporting nuanced decision-making and reinforcing the central role of lipid management in contemporary cardiovascular risk reduction.
Dyslipidemia continues to be a primary modifiable risk factor for atherosclerotic cardiovascular disease (ASCVD). Following pivotal trial results and emerging therapies since 2019, the ESC/EAS has revised its recommendations regarding risk stratification, drug selection, and treatment intensity to maximize preventive benefit.
Cardiovascular Risk Stratification
Transition from SCORE to SCORE2: Redefining ASCVD risk assessment
The 2019 guidelines recommended estimation based on the SCORE (Systematic Coronary Risk Estimation) model, using total cholesterol, HDL, age, sex, and blood pressure; focused mainly on fatal CVD events and up to age 70.
The major revision is the adoption of SCORE2 and SCORE2-OP risk models, replacing the previous SCORE system for estimating the 10-year risk of ASCVD events. SCORE2 is recommended for adults aged 70 years or younger, while SCORE2-OP is applicable for those aged 70 to 89 years (Class I, Level B). While the SCORE algorithm assessed the 10-year risk of fatal CVD in persons aged up to 70 years, the SCORE2/SCORE2-OP algorithms (accessible at) can also estimate the 10-year risk for both fatal and non-fatal CV events, including those in apparently healthy people aged 70 years or older (up to 89 years). The models are calibrated for 4 country risk clusters and use non-HDL cholesterol as a risk input, rather than total cholesterol.
In this update, a 2× multiplier was applied to convert previous SCORE-based thresholds into SCORE2- or SCORE2-OP-based thresholds, defining different categories of total CVD risk.
Revised risk categories and modifiers for personalized care
Updated risk categories are provided for primary prevention, encompassing definitions of risk categories based on SCORE2/SCORE2-OP thresholds. Figure 1 lists risk modifiers, including demographic, clinical, and biomarker-based variables such as family history, high-risk ethnicity, chronic inflammatory diseases, elevated hs-CRP, and Lp(a) levels of 50 mg/dL or above (≥105 nmol/L). The detection of subclinical atherosclerosis by imaging or an elevated coronary artery calcium (CAC) score should be regarded as a risk modifier, particularly for those at moderate risk or those near treatment thresholds (Class IIa, Level B). CAC scoring–very high scores (>300) in apparently healthy people may reclassify risk to an equivalent of secondary prevention. In contrast, a score of zero indicates lower risk, even in the presence of traditional risk factors (with caveats for statin-treated patients as the therapy is known to enhance calcium deposition in plaques).
Risk modifiers for consideration beyond the risk estimation based on the SCORE2 and SCORE2-OP algorithms.
Abbreviations: CVD = cardiovascular disease; hs-CRP = high sensitivity C-reactive protein; Lp(a) = lipoprotein(a).
Premature menopause and hypertensive disorders of pregnancy (such as pre-eclampsia) as risk factors in the 2025 ESC/EAS lipid guidelines are supported by growing evidence that these conditions significantly increase a woman’s lifetime risk of ASCVD.
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Premature menopause is associated with adverse changes in lipid profiles and a higher risk of cardiovascular disease due to the loss of protective estrogen earlier in life. This hormonal change leads to increased levels of LDL cholesterol and triglycerides, as well as changes in lipoprotein subfractions, which accelerate atherosclerosis.
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Hypertensive disorders of pregnancy, including pre-eclampsia, are recognized as significant risk markers for future cardiovascular disease. These disorders reflect endothelial dysfunction and systemic vascular damage during pregnancy, which increases long-term risk for hypertension, ischemic heart disease, and stroke.
Because traditional risk prediction models like SCORE2 and SCORE2-OP do not fully recognize the increased cardiovascular risk associated with these female-specific conditions, the guidelines include them as risk modifiers to enhance the accuracy of cardiovascular risk assessment and support more personalized preventive strategies, including lipid-lowering therapy.
Risk assessment algorithm: Integrating biomarkers and imaging into risk calculations
Risk stratification now involves a more nuanced approach, integrating imaging and biomarker data alongside traditional risk factors to facilitate personalized management strategies. Calculation of risk with SCORE2/SCORE2-OP should not be performed in those with established ASCVD, diabetes mellitus, chronic kidney disease, or those already on lipid-lowering therapies.
LDL-Cholesterol Targets and Therapeutic Strategy: Reinforcing Targets and Intensifying Risk-Based LDL-C Lowering
The 2025 update reaffirms the risk-based approach to lowering LDL-C, with the same treatment targets as the 2019 guideline. It re-emphasizes the use of both SCORE2/SCORE2-OP and baseline LDL-C for decision-making, particularly in primary prevention for non-statin candidates.
The LDL-C targets for each risk group remain unchanged ( Table 1 ).
Table 1
LDL-C treatment goals by risk categories
| Risk category | LDL-C goal | Class |
|---|---|---|
| Low risk | <3.0 mmol/L (<116 mg/dL) | IIb |
| Moderate risk | <2.6 mmol/L (<100 mg/dL) and ≥50% reduction from baseline | IIa |
| High risk | <1.8 mmol/L (<70 mg/dL) and ≥50% reduction from baseline | I |
| Very high risk | <1.4 mmol/L (<55 mg/dL) and ≥50% reduction from baseline | Ia |
| Extreme risk | <1.0 mmol/L (<40 mg/dL) and ≥50% reduction from baseline | IIb |
The initiation of pharmacological therapy is stratified based on risk assessment and baseline LDL-C levels. However, recent updates emphasize the importance of achieving both absolute and percentage reductions, with a decrease of ≥50% from baseline remaining pivotal for patients classified as high- and very-high-risk. A stepwise approach, aligning LDL-C levels with overall cardiovascular risk, continues to underpin therapeutic decision-making.
Innovations In LDL-C Lowering Therapies: Bempedoic Acid, Inclisiran, Evinacumab, and Algorithmic Approaches
Both guidelines specify that statins are the primary treatment choice for the majority of patients.
In 2019, non-statin therapies, such as ezetimibe and PCSK9 inhibitors, were recommended for patients categorized as high or very high risk who are unable to tolerate statins or fail to achieve their target lipid levels. PCSK9 inhibitors were explicitly emphasized for those at very high risk, including individuals with a history of acute coronary syndrome (ACS) and familial hypercholesterolemia.
Bempedoic acid
ATP-citrate lyase inhibitor bempedoic acid is now recommended for patients unable to tolerate statin therapy (Class I, Level B) and as an add-on to maximally tolerated statins (with or without ezetimibe) for high- or very-high-risk patients who are unable to achieve their LDL-C goal (Class IIa, Level C). The CLEAR Outcomes study showed a 13% decrease in major adverse cardiovascular events (MACE) compared to placebo in a statin-intolerant group. Safety considerations include reversible increases in uric acid, a higher risk of gout, and potential hepatic enzyme elevations.
Evinacumab
For homozygous familial hypercholesterolemia (HoFH), evinacumab (an ANGPTL3 inhibitor) is recommended for patients aged 5 years or older who have not reached their LDL-C goal despite maximum conventional therapy (Class IIa, Level B).
Inclisiran and other agents
Inclisiran, a siRNA targeting PCSK9 synthesis, administered biannually, achieves ∼50% LDL-C lowering in Phase III trials; however, its routine use awaits the results of large cardiovascular outcome trials, expected in 2026 to 2027. PCSK9 monoclonal antibodies and ezetimibe remain integral to combination therapy for patients who do not achieve targets with statin monotherapy.
Algorithmic, early combination therapy in ACS is explicitly endorsed.
Intensive Lipid-Lowering in Acute Coronary Syndromes: “Strike Early and Strong”
Patients with acute coronary syndromes (ACS) face the highest risk for recurrent cardiovascular events in the early postevent period. Yet, real-world studies repeatedly reveal under-treatment and clinical inertia after hospital discharge.
The 2025 Update, strengthened by evidence from trials like IMPROVE-IT , HUYGENS , PACMAN-AMI , SWEDEHEART and AT-TARGET IT , recommends immediate, in-hospital initiation of intensive lipid-lowering therapy for all ACS patients, aiming for “the sooner, the lower, the better.”
Protocol
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For all ACS patients, high-intensity statin therapy should be initiated promptly during the hospital stay.
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For those unlikely to achieve LDL-C targets with a statin alone (particularly patients already on a statin at admission), add-on non-statin agents (primarily ezetimibe) should be initiated before discharge.
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These recommendations are classified as Class I (statin intensification) and Class IIa (statin plus ezetimibe combination for those not previously treated).
The proactive approach ensures maximum early benefit, counteracts prescription inertia, and aims to shrink the post-ACS “risk window.” The guidelines emphasize that aggressive LDL-C lowering is well tolerated and yields significant outcome benefits if initiated without delay.
The expert analysis emphasizes that systematized protocols, hospital-based lipid clinics, and robust discharge planning are essential to translating these recommendations into durable clinical benefits, thereby reducing the persistent care gap after ACS.
Lipoprotein(a): From Single Measurement to Pivotal Risk Modifier
The 2019 ESC/EAS guidelines recommended that Lp(a) levels should be measured at least once in a lifetime, if possible, to identify those with a significantly elevated inherited Lp(a) level of 180 mg/dL or more (430 nmol/L or more). These individuals have a significantly higher lifetime risk of ASCVD, similar to the risk linked to heterozygous familial hypercholesterolemia (HeFH).
The 2025 update recommends that lipoprotein(a) [Lp(a)] be measured at least once in all adults, especially those with familial hypercholesterolemia, premature atherosclerotic cardiovascular disease (ASCVD), or at moderate risk or treatment thresholds. An Lp(a) level of ≥50 mg/dL (≥105 nmol/L) is now recognized as a significant risk modifier that may warrant reclassification and more aggressive LDL-C lowering strategies (Class IIa, Level B) based on current epidemiological and genetic evidence indicating increased risks of ASCVD and aortic valve stenosis at these levels. Furthermore, emerging RNA-based therapies targeting Lp(a) are currently being studied. Measurement of Lp(a) is influenced by substantial structural heterogeneity in apolipoprotein(a) isoforms, particularly variability in Kringle-IV repeats, which may affect assay accuracy. Therefore, the use of apo(a) isoform-insensitive immunoassays calibrated against international reference standards is recommended to ensure reliable quantification and comparability across studies. The ESC/EAS 2025 update prefers reporting Lp(a) in nmol/L, as this reflects molar particle concentration and is less affected by isoform variability than mg/dL, which represents mass concentration; accordingly, routine conversion between units is discouraged due to assay-dependent variability. However, for clinical purposes, mg/dL remains acceptable and clinically interpretable when used with validated, standardized assays.
Hypertriglyceridemia: Targeted Therapies and Updated Indications-Icosapent Ethyl, Volanesorsen
Statins remain the first-choice drugs to reduce CV risk for those with high triglycerides.
Icosapent ethyl (2 g twice daily) is now uniquely recommended—when added to statin—in high or very high risk patients if TG 135 to 499 mg/dL persists, based on REDUCE-IT results (Class IIa, Level B).
Volanesorsen (antisense inhibitor of ApoC-III): Recommended for severe hypertriglyceridemia due to familial chylomicronemia syndrome (FCS) when refractory to standard therapy (EMA approval; not FDA approved) (Class IIa, Level B).
Fibrates and combined (eicosapentaenoic acid and docosahexaenoic acid) n-3 PUFA (omega-3 polyunsaturated fatty acids) supplements are not broadly recommended for CV event reduction, given negative or neutral outcome data since 2019 (Class IIb).
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