Focused update of the ESC guideline for the management of dyslipidemia

Atherosclerosis is caused by the progressive deposition of LDL-C and other apolipoprotein B-containing lipoproteins in the artery wall, triggering inflammatory reactions that lead to the formation and progression of atherosclerotic plaques. Over time, atherosclerotic plaques enlarge, increasing the risk of an acute atherosclerotic cardiovascular event. LDL-C is not only a risk factor but also a direct cause of atherosclerotic cardiovascular disease (ASCVD). Lowering LDL-C levels is therefore the main pillar for preventing cardiovascular events.

This focused update continues to support the concept of the 2019 ESC guideline of using the estimated 10-year risk of a cardiovascular event as a benchmark for the intensity of LDL-C reduction. A new recommendation is to use the SCORE2 and SCORE2-OP risk scores (instead of the SCORE algorithm) for individuals with CVD aged 40–89 years (in line with the 2021 ESC guidelines on CVD prevention in clinical practice⁴). SCORE2-OP enables a more accurate risk assessment in older individuals (70–89 years). The risk categories (based on SCORE2 and SCORE2-OP) have been redefined (see Fig. 1). Demographic factors, comorbidities, and biomarkers are risk modifiers that may justify classification into a higher risk category or serve as decision aids for LDL-C targets and lipid-lowering therapies.

• Demographic factors and comorbidity: Relatives with early CVD (<55 years in men and <60 years in women), high-risk ethnicity (South Asian), stress symptoms, loneliness, obesity, physical inactivity, chronic inflammation, mental illness, premature menopause, HIV infection, preeclampsia, or other hypertensive disorders in pregnancy
• Biomarkers: Persistently elevated hs-CRP (>2 mg/L) and elevated Lp(a) levels

The LDL-C targets and intervention strategies have not changed from the 2019 guideline (Fig. 1). The intensity of LDL-C reduction depends on the risk classification. The recommendations for starting LDL-C-lowering drug therapy also continue to apply depending on the risk and baseline LDL-C level. Risk assessment according to SCORE2 and SCORE2-OP is used exclusively for classification before starting lipid-lowering therapy, but not for re-evaluation during the course of therapy.

The recommendations for statins, ezetimibe, and PCSK9 antibodies remain unchanged. However, a new recommendation is the use of the oral small molecule bempedoic acid for LDL-C-lowering medication in individuals with statin intolerance (1B recommendation). In individuals at high or very high risk, bempedoic acid may be considered in addition to statins. Ezetimibe, PCSK9 antibodies, and bempedoic acid can be given either alone or in combination as an add-on to statins if the LDL-C target is not achieved despite the maximum tolerated dose of statins. The choice of substance depends on the need for LDL-C reduction (see Fig. 2). In individuals with homozygous familial hypercholesterolemia and insufficient efficacy of statins and PCSK9 inhibitors, evinacumab (monoclonal antibody against ANGPTL3) is an effective option. The PCSK9 siRNA drug inclisiran could be an alternative to PCSK9 antibodies in the future. However, we'll have to wait for the results of the ongoing ORION-4 and VICTORION-2P studies, which are expected in 2026 and 2027. 

The 2019 guideline recommendation that LDL-C levels should be checked again 4–6 weeks after starting or intensifying lipid-lowering therapy still applies.

Twenty years ago, the association between intensive lipid-lowering therapy and outcomes after ACS was clearly demonstrated, supporting the principle of “the lower, the better”. Both in the early setting and during the chronic stable phase, LDL-C reduction is a mainstay of management for individuals with ACS. However, the majority of LDL targets are not being achieved with the gradual dose increase recommended in 2019. The principle of “the faster and the lower, the better” has therefore been newly introduced, along with the following recommendations for patients with acute coronary syndrome with and without previous lipid-lowering therapy:

• Individuals undergoing lipid-lowering therapy: Intensification of LDL-C reduction already during ACS hospitalization.
• Treatment-naïve individuals: Start high-intensity statin therapy, possibly in combination with ezetimibe (if it is foreseeable that the LDL-C target cannot be achieved with statin monotherapy).

After starting or intensifying lipid-lowering therapy, LDL-C levels should be checked again within 4–6 weeks. Lifelong lipid-lowering therapy is strongly recommended.

Epidemiological and genetic studies indicate a causal and direct link between Lp(a) levels and the risk of ASCVD and aortic valve stenosis (AVS). The risk is considered clinically relevant at Lp(a) levels >50 mg/dL (affecting approximately 20% of the population) and continues to increase with rising Lp(a) levels. Lp(a) levels should be measured at least once in a lifetime, especially if there is a family history of early-onset ASCVD. An Lp(a) risk-benefit algorithm is available online here.

Several agents for lowering Lp(a) are currently undergoing clinical trials, such as antisense oligonucleotides or siRNA, which reduce Lp(a) levels by approximately 80–90%.

Triglyceride levels are associated with an increased CV risk, regardless of LDL-C levels. In high-risk individuals, statins are recommended as the treatment of choice for reducing CVD risk. The fibrates currently available have only moderate triglyceride-lowering effects. The recommendations of the 2019 guideline continue to apply to the use of fenofibrate and bezafibrate (class IIb recommendation). Fibrates are not indicated for lowering total cholesterol or LDL-C. Several new triglyceride-lowering agents (antisense oligonucleotides and siRNA) that target ApoC3 and achieve a triglyceride reduction of approximately 80% are currently in clinical development.

Further recommendations (class IIaB) are:

• High-dose icosapent ethyl (2 x 2 g/day) combined with a statin may be considered to reduce CVD risk in patients at high or very high risk with elevated triglyceride levels (fasting triglyceride level 135–499 mg/dL).
• Volanesorsen (300 mg/week) may be considered to reduce the risk of pancreatitis in patients with familial chylomicronemia syndrome (FCS) and severe hypertriglyceridemia (>750 mg/dL).

In people with HIV, the risk of ASCVD is doubled compared to the general population due to chronic inflammation, immune activation, and dyslipidemia caused by antiretroviral therapy. Based on recent study data, the recommendation for lipid-lowering therapy with statins has been strengthened compared to the 2019 guideline: Statins are recommended for primary prevention in individuals with HIV infection from the age of 40, regardless of cardiovascular risk and LDL-C levels. The choice of statin depends on potential drug interactions (Class 1B recommendation).

Anthracycline-based chemotherapy is a central component of many chemotherapy regimens for numerous tumor types (e.g., breast cancer or lymphoma). Depending on the cumulative dose, anthracycline-based chemotherapy is associated with the development of heart failure in up to 20% of patients within 5 years. Taking into account the various recent studies available, this update supports the following recommendation from the 2022 ESC Guidelines on Cardio-Oncology⁵: Statins may be considered in adults at high or very high risk of chemotherapy-related cardiovascular toxicity to reduce the risk of anthracycline-induced cardiac dysfunction (Class IIaB recommendation).

The importance of a healthy diet in reducing LDL-C levels and CVD risk was discussed extensively in the 2019 guidelines. A healthy diet is defined as low in saturated fats and rich in whole grains, vegetables, fruits, and fish. There is no convincing evidence that dietary supplements reduce CVD risk. Neither dietary supplements nor vitamins are recommended to reduce ASCD risk.

The focused update 2025 provides new recommendations for risk classification based on SCORE2 and SCORE2-OP. Risk modifiers can also serve as decision aids for lipid-lowering measures. A new recommendation is the use of bempedoic acid for drug-induced LDL-C reduction in individuals with statin intolerance. The combination of statins, ezetimibe, PCSK9 antibodies, and bempedoic acid allows for greater LDL-C reduction as needed. In cases of ACS hospitalization, lipid-lowering treatment should be started quickly or intensified (“the faster and the lower, the better”). Another new recommendation is the use of statins for individuals with HIV infections or cancer and a high risk of CVD due to chemotherapy. However, the use of dietary supplements or vitamins for lipid-lowering is not recommended.

These are not new guidelines, but rather an update based on clear ESC rules: only points for which relevant new study data had become available since 2019 were discussed. The text is a consensus reached after intensive discussions between approximately 20 authors from the EAS and ESC and approximately 100 additional reviewers from around the world.

The current study situation unanimously underscores the principle of LDL target values depending on individual risk. The recommendations have been adapted to the current risk calculators. New and clinically important are the risk modifiers that determine individual risk in addition to SCORE2 / SCORE2-OP. The recommendations place particular focus on elevated lipoprotein(a), HIV, and tumor patients. Important: the target values themselves were further supported by the new studies and did not need to be modified.

One “simple” recommendation based on the new studies was the inclusion of bempedoic acid as a third oral therapy option for lowering LDL-C. Fibrates are no longer indicated for lowering cholesterol. A niche indication for fenofibrate and bezafibrate remains in individual cases of hypertriglyceridemia, but not for the reduction of cardiovascular events or pancreatitis. High-dose (4 g) icosapent ethyl receives a IIaB recommendation for hypertriglyceridemia and ASCVD based on the clearly positive REDUCE-IT trial but is currently not reimbursed in Germany. For the extremely rare but serious familial chylomicronemia syndrome (FCS), the ApoC3 ASO volanesorsen is available, but it is likely to be replaced shortly by the pharmacologically superior siRNA olezarsen and then become obsolete.

The new study findings on acute coronary syndrome were summarized literally with the following terms: “the sooner, the lower, the better” and “strike early and strong”. The implementation of this clinically important principle is the use of LDL-lowering combination therapy. As a rule (IIaB), ACS should be treated immediately with a combination of atorvastatin or rosuvastatin and ezetimibe. Patients with ACS and existing lipid-lowering therapy benefit from its intensification.

From a cardiologist's perspective, many colleagues in the lipid sector traditionally find it difficult to rigorously evaluate the data on nutrition and dietary supplements. There was so much new neutral (or even negative) evidence from this area that—albeit with a somewhat vague recommendation—a clear Class III recommendation was issued for dietary supplements and vitamins for the first time: This means that these substances should not be used for the prevention of ASCVD.

To the overview page ESC Congress 2025

• Video: Prof. Ulrich Laufs summarizes the key points of the lipid updates briefly and concisely (31.08.2025).