One year after the ESC/EAS guidelines on cholesterol control: New evidence and possible challenges

Key Takeaway

This review article summarizes the new evidence from clinical trials since ESC/EAS 2019 guideline release and outlines following points that should be considered during the development of next guidelines, and the possible challenges for the development of future guidelines (what’s missing).


  • Based on SCORE CV risk charts:
    • Older individuals have the highest CV risk
    • Though younger people may present a low 10-year risk, they might be at higher lifetime risk, due to a longer exposure time
    • Definitions based on genetics and cholesterol burden might help to mitigate this problem by allowing calculation of a lifetime risk regardless of age, linking the CV benefit only to the reduction of LDL-C*


  • Increasing HDL-C plasma levels would not be the correct way to achieve a benefit if this is not paralleled by an increase in the quality and functionality of HDL


  • Should non-HDL-C and apoB levels be evaluated in all individuals?
  • Non-HDL-C and apoB levels are associated with CV risk ApoB marker provides exactly the number of atherogenic particles, which offers more accurate estimate of the total concentration of atherogenic particles
  • Though younger people may present a low 10-year risk, they might be at higher lifetime risk, due to a longer exposure time
  • Non-HDL-C and apoB levels may be more appropriate for risk evaluation among patients having diabetes or hypertriglyceridemia, who may have LDL-C levels in the range of normality


  • Independent of LDL-C levels, elevated levels of Lp(a) represent a risk factor for CV disease
  • To obtain the same benefit seen with 1 mmol/L reduction in LDL-C (~ x223C 40 mg/dL), it is necessary to reduce Lp(a) by 70–90 mg/dL


  • New vs previous guidelines: More intensive reduction in LDL-C levels (LDL-C reduction of ≥50% from baseline and an LDL-C goal of <1.4 mmol/L or <1.8 mmol/L for very high-risk and high-risk patients, respectively)
  • In individuals with lower baseline values of LDL-C, going beyond the achievement of the LDL-C goal ensures a reduction in CV risk
    • Based on the observation: Lower the achieved LDL-C values, the lower the risk of future CV events, with no lower limits for LDL-C values


  • Study design plays a crucial role among the reasons that may explain the failure of a clinical trial
  • Patients with lower baseline LDL-C: No matter how effective a drug is, it will inevitably result in a lower risk reduction
  • Study duration: Drug benefit during the first year is lower vs subsequent years, which may significantly underestimate a potential effect if the follow-up is too short



  • According to guidelines, in patients who cannot achieve LDL-C goals with statin monotherapy, a combination therapy is ad- vised, with steps for the addition of drugs that is based on achievement of LDL-C goal
  • The most recent clinical trials showed that combination therapy always represents a step forward in the CV prevention
  • Question raised: Is it still acceptable to apply a stepwise approach in very-high/high risk patients instead of managing them as soon as possible with the most effective combination therapy?
  • This issue must be addressed shortly as it represents a challenge for the future


  • Although it is well established that adherence to lipid-lowering therapy increases the survival of patients, goal achievement among patients with established atherosclerotic cardiovascular disease is commonly suboptimal in the clinical practice
  • Many patients at high or very-high CV risk are still being treated inadequately (high percentage of patients on a moderate dose of statin, few on statin + ezetimibe, and an even fewer on a proprotein convertase subtilisin/kexin type 9 inhibitor)
  • Gaps still exist between guideline recommendations and clinical practice; current more stringent goals may further increase these gaps
  • Awareness of optimal therapy for CV benefit needs to be increased

Why This Matters

  • The recent ESC/EAS 2019 guidelines for the management of dyslipidemias have highlighted the importance of a powerful reduction in LDL-C levels to reduce the individual CV risk.
    • However, some challenges remain to be addressed in view of future guideline elaboration
  • New guidelines will have to address a fundamental challenge in medicine: Treat to prevent or treat when it is perhaps late?
    • As of now, we have positioned our attention on the latter, which may not be the best choice.

* Literature evidence: Mendelian randomization studies; early therapeutic intervention in familial hypercholesterolemia patients, can delay or even normalize the CV event curve
As suggested by the U-shaped association between HDL-C levels and cardiovascular and all-cause mortality
Based on results from Mendelian randomization studies

ABBREVIATIONS: apoB, apolipoprotein B; CV, cardiovascular; EAS, European Atherosclerosis Society; ESC, European Society of Cardiology; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; Lp(a); Lipoprotein(a).

    1. Averna M, Catapano AL. One year after the ESC/EAS guidelines on cholesterol control. What's the new evidence? What's missing? Eur J Intern Med. 2022;95:1–4. doi: 10.1016/j.ejim.2021.10.017. PMID: 34728127.