Dyslipidemias, particularly that of an increased low-density lipoprotein cholesterol (LDL-C) and/or triglycerides (TGs), are often known to significantly elevate the risk of atherosclerotic cardiovascular disease (ASCVD).¹ The 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines for dyslipidemias, the most up-to-date in the field, emphasize the need to lower LDL-C and TGs as much as possible, citing new evidence that a lower limit to LDL-C levels is absent.² The aims are to streamline treatment, especially for the high-risk and very high-risk patients, and make the time used by both clinicians and patients more effective.¹ The EAS has indeed issued a practical guidance document for commencing the statin-ezetimibe combination earlier in treatment for these patients.

The causality between high LDL-C levels and ASCVDs is well-established through evidence from the genetic studies, cohort studies and randomized trials.3 The TG levels reflect the concentration of circulating apolipoprotein B (ApoB)-containing TG-rich lipoproteins.² The pathological mechanism of ASCVDs which are caused by dyslipidemias is well-understood. That is, ApoB-containing lipoproteins smaller than 70nm in diameter are able to cross dysfunctional parts of endothelial barrier of the vasculature where they can be trapped after interaction with extracellular structures such as proteoglycans. The accumulation of such lipoproteins provokes a complex cascade that eventually leads to lipid deposition, initiation of an atheroma and formation of a plaque, whose contents may be detached from the wall, resulting in cardiovascular (CV) events such as unstable angina, myocardial infarction (MI), or death.² Hence, the reduction of LDL-C and TGs from upfront is important for prevention of such life-threatening outcomes.

For the high to very high-risk patients, the 2019 ESC/EAS guidelines currently stipulate that a minimum of 50% reduction in LDL-C levels is suggested, in order to substantially lower the CV risk.² The high-risk patients are defined with markedly elevated single risk factors, in particular the total cholesterol, the history of familial hypercholesterolemia, plus a calculated Systematic Coronary Risk Evaluation (SCORE) of greater than or equal to 5% and lower than 10% for the 10-year risk of fatal CV disease, amongst other criteria. The very high-risk patients are those who also carry an ASCVD or diabetes type 2 co-morbidity, or they may have a calculated SCORE ≥10%.² The guidelines acknowledge there is considerable variation between patients in terms of the extent of LDL-C reduction even with the same dose of statin, which has provided a basis for more personalized therapeutic plans.² On the other hand, the guidelines recommend the addition of a non-statin lipid-modifying agent to a maximally tolerated statin in patients who fail to tolerate the recommended intensity of a statin because of the adverse effects or those who fail to reach their goals.¹

As such, a related EAS task force has been set up and recently published a practical guidance document regarding the combination lipid-lowering therapy for high to very high-risk patients, which aims to alert clinicians the possibility of taking more aggressive lipid-reducing measures earlier for these selected groups of patients.¹

The overall management strategy of LDL-C levels can be summarized into 3 statements: “The lower the better”, “the earlier the better” and “the longer the better”.¹ Immediate commencement of ezetimibe, an inhibitor of intestinal cholesterol absorption, being paired with a statin, should be recommended when statin monotherapy is not sufficient in meeting the reduction targets, plus the patient is of high to very high CV risk or has a history of familial hypercholesterolemia.^1,4 The combination treatment has also shown to provide significant improvement with 15% reduction in the LDL-C levels in statin-naïve patients, potentially better than the statin monotherapy and doubling the statin dosage.² If not effective, a proprotein convertase subtilisin/ kexin type 9 (PCSK9) inhibitor should be added to the regimen.¹ As for controlling the TG levels, the guidelines also recommend the addition of fibrate or high-dose omega-3 fatty acids to the statin therapy for high and very high-risk patients with mild to moderately elevated TG levels.¹ By using the combination treatment, more advantages can be seen, such as avoiding repeated medical follow-ups, enabling patients to be on target as early as possible, and enjoying more favorable CV outcomes.¹