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Reprinted from: wechat official Account of China Medical Forum

The LDL-C level has reached the standard, but it still can't prevent coronary heart disease? Most patients are unaware of these 5 points!

In addition to LDL-C, attention should also be paid to residual LDL-C, LDL particle levels and subtypes, oxidized LDL levels, cumulative LDL-C exposure, and LDL-C variability. Comprehensive management of lipid-related cardiovascular risks is not limited to a single LDL-C lipid-lowering treatment. Instead, it involves a comprehensive and holistic assessment and intervention of all lipid parameters and other coexisting risk factors related to cardiovascular risk.

Sometimes, plasma LDL-C does not accurately reflect the concentration of LDL particles

In clinical practice, the level of plasma low-density lipoprotein (LDL) is generally not directly measured but estimated based on its cholesterol content. Ldl-c is an indicator that measures the total amount of cholesterol contained in LDL particles.

In most cases, the concentration of LDL-C is highly correlated with the number of LDL particles; However, in some cases, such as hypertriglyceridemia (HTG), metabolic syndrome and diabetes, plasma LDL-C cannot accurately reflect the concentration of LDL particles.

With the deepening of research, while people are paying attention to LDL-C, they are also concerned about the correlation and management strategies of residual LDL-C, LDL particle levels and subtypes, oxidized LDL (ox-LDL) levels, cumulative exposure to LDL-C, LDL-C variability and cardiovascular risk related to it.

Ldl-c is the primary intervention target for the prevention and treatment of ASCVD

The homogeneous method is currently the main method for determining LDL-C in China. LDL-C can also be directly calculated using the Friedewald formula: LDL-C=TC-HDL-C-TG/2.2

Ldl-c is a pathogenic risk factor for ASCVD and the primary intervention target for the prevention and treatment of ASCVD. Genetic, epidemiological and clinical intervention studies have all confirmed that for every 1 mmol/L reduction in LDL-C, the risk of cardiovascular events can be reduced by 20% to 23%. Ldl-c management should be based on the recommendations of the "Chinese Lipid Management Guidelines (2023)", and the target value of LDL-C should be determined according to cardiovascular risk stratification.

However, the prevention and treatment of ASCVD is not limited to LCL-C1

The risk of LDL-C remains

Residual LDL-C risk is generally defined as the occurrence of cardiovascular events even when LDL-C is reduced to a lower level or has reached the target. In the era of statin treatment, even if ASCVD patients receive the most optimized statin treatment to lower LDL-C levels, there is still a 60% to 80% residual risk.

LDL particle levels and subtypes are associated with ASCVD risk

LDL contains a series of particles with different physicochemical properties, metabolisms and functions. Generally speaking, the level of LDL particles can be indirectly reflected by measuring the LDL-C level. However, in special populations such as HTG and diabetes, the levels of the two are not consistent.

In people with normal triglyceride (TG) levels, three common subtypes usually occur: large and light, intermediate, and small and dense LDL (sdLDL).

As plasma TG levels rise, the composition shifts from being dominated by large particles to more sdLDL. sdLDL has a strong oxidizing capacity, can induce inflammatory responses, is not easily cleared by low-density lipoprotein receptors (LDLR), and is more easily phagocytosed to form foam cells. It is considered to have a stronger atherosclerotic effect than other subtypes.

Therefore, if the above clinical conditions are combined, physicians need to pay attention to LDL-C while also combining apolipoprotein B (ApoB) to further assess the patient's risk and formulate management strategies.

Ox-ldl levels and ASCVD risk

Ox-ldl is regarded as an independent risk factor for the occurrence of atherosclerosis. Ox-ldl can further promote the occurrence and development of atherosclerotic lesions by triggering endothelial dysfunction, increasing inflammatory responses, etc. While LDL-C has reached the standard and other risk factors have been effectively managed, atherosclerotic lesions are still progressing. Ox-ldl can be considered as one of the factors for residual risk management.

Cumulative LDL-C exposure and ASCVD risk

With the accumulation of evidence-based evidence, the residual risk of LDL-C no longer only refers to the single or real-time measured LDL-C level, but is also related to the exposure time of cholesterol. That is, the absolute risk of ASCVD depends on the cumulative exposure of cholesterol (roughly estimated as LDL-C level × age), and its correlation with events is stronger than that of LDL-C level.

Cumulative cholesterol exposure is significantly associated with plaque burden threshold and the risk of acute coronary syndrome (ACS), suggesting that initiating lipid-lowering treatment as early as possible and adhering to it for a long time is an effective strategy for controlling cumulative cholesterol exposure, reducing plaque burden and event risk.

Ldl-c variability and ASCVD risk

Post hoc analysis of the New Target Therapy (TNT) study found that LDL-C variability is an independent risk factor for cardiovascular events. For every one standard deviation increase in LDL-C variation, the risk of coronary artery events significantly increases by 16%, which is not related to the efficacy of statins or LDL-C levels.

Ldl-c variability, as a part of cardiovascular residual risk, requires further attention in clinical practice. Improving patient compliance, adhering to long-term stable target attainment, and avoiding fluctuations in LDL-C levels can bring more benefits to patients.

Here are five major strategies for comprehensive management of LDL-C

Reduce LDL-C

Target values and intervention methods of LDL-C in patients with different risk stratifications

Ldl-c is the primary intervention target for the prevention and treatment of ASCVD and should be stratified and reached in accordance with the "Chinese Lipid Management Guidelines (2023)". Lifestyle intervention is the foundation. Moderate-intensity statins are recommended as the initial treatment. If the target is not met within 4 to 6 weeks, non-statins can be combined.

2. Selection of LDL-C lowering drugs

Statin drugs: The "Chinese Lipid Management Guidelines (2023)" recommend moderate-intensity statin therapy (i.e., a daily dose that can reduce LDL-C by 25% to 50%) as the preferred initial treatment for lowering cholesterol in the Chinese population.

② Cholesterol absorption inhibitors: Research has confirmed that adding cholesterol absorption inhibitors (ezetimibe or Hibotimibe) to statins can further reduce LDL-C levels by 15% to 20%.

③ PCSK9 inhibitors: On the basis of statins with or without ezetimibe, PCSK9 monoclonal antibodies can further reduce LDL-C levels by 50% to 70%.

④ Natural lipid-regulating drugs

⑤ Bile acid chelating agents: When used in combination with statins, they can significantly enhance the lipid-lowering effect. The options for lipid-lowering drugs for pregnant patients are very limited. For instance, for pregnant patients with ACS, bile acid chelating agents can be considered.

Reduce the risk of LDL-C retention

For specific groups of people who have already reached the LDL-C target, further lipid reduction can still be considered to lower the risk of remaining cardiovascular diseases: ① For those who have repeatedly experienced ASCVD events within 2 years or have recently developed ACS with a high risk of recurrence, it is recommended to reduce LDL-C to less than 1.0mmol/L. ② If LDL-C has reached the target but there is still progression or event of atherosclerosis (other risk factors have been controlled), individualized assessment is recommended. If necessary, the LDL-C level can be further reduced.

Reduce LDL particle levels and improve subtypes

All drugs that lower LDL-C levels can effectively reduce LDL particle levels. Some studies suggest that fibrates and high-purity omega-3 fatty acids can improve LDL particle subtypes, but there is no direct evidence of cardiovascular benefits.

Drugs that inhibit the formation of ox-LDL

Probucol affects lipoprotein metabolism by incorporating into the core of LDL particles, making LDL easier to be cleared through non-receptor pathways. At the same time, it can inhibit the oxidation of LDL and slow down the formation of foam cells in atherosclerotic plaques.

② High-purity omega-3 fatty acids: Studies have shown that both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have antioxidant effects, but EPA's effect is more lasting. Recent studies suggest that EPA may enhance cardiovascular protection by inhibiting the oxidation of Lp (a) and LDL, but there is currently no direct or quantitative evidence that high-purity omega-3 fatty acids can reduce cardiovascular events through antioxidant effects.

Reduce the cumulative exposure and variability of LDL-C

Improving the awareness rate, treatment rate and control rate of dyslipidemia among the public or patients is the core strategy for the primary and secondary prevention of ASCVD. Controlling LDL-C at an ideal level as early as possible can reduce or delay the occurrence of cardiovascular events. At the same time, the longer the lipid-lowering treatment lasts, the greater the benefits.

At present, LDL-C variability is regarded as an independent risk factor for CVD and is closely related to the progression and rupture risk of atherosclerotic plaques. Improving patients' compliance with lipid-lowering treatment and ensuring the long-term stability and compliance of lipid levels are the guarantees for patients' ultimate benefits and the maximization of benefits. Advocating the concept of "early screening, early diagnosis and early treatment" is precisely an important path to promote long-term control of blood lipids and achieve the goal of ASCVD prevention.

Expert Consensus on Comprehensive Management of Lipid-related Cardiovascular Risks (2025) Formulation Expert Group, Suzhou Industrial Park Oriental Huaxia Cardiovascular Health Research Institute. Expert Consensus on Comprehensive Management of Lipid-related Cardiovascular Risks (2025) [J/OL] Chinese Journal of Cardiovascular Diseases (Online Edition), 2025.