Invited editorial Evaluating statin effect on LDL-cholesterol: when predicted is not measured Maurizio Giuseppe Abrignani Low-density lipoprotein (LDL) cholesterol has a casual effect on atherosclerotic cardiovascular diseases, and multiple meta-analyses, as well as individual rando- mised controlled trials (RCTs), show a consistent, graded decrease in cardiovascular risk in response to its reduction. The 2018 American guidelines 1 advocate the use of statins reducing LDL-cholesterol by less than 50% (low-moderate intensity) or 50% or greater (high inten- sity) according to the global cardiovascular risk and suggest a LDL-cholesterol threshold only for consider- ing the addition of ezetimibe or PCSK-9 inhibitors. Very recently published European guidelines for the management of dyslipidaemias 2 retain, instead, a treat- ment goal approach (more intensive than in previous guidelines). They recommend a LDL-cholesterol goal of less than 1.4 mmol/L (<55 mg/dL) for patients at very high risk and less than 1.8 mmol/L (<70 mg/dL) for people at high risk. Despite these fixed LDL- cholesterol targets, there is also an indication on the attainment of a 50% or greater reduction in LDL-cholesterol, particularly in those patients who are close to the goal already. It seems appropriate, in fact, to reduce LDL-cholesterol to as low a level as possible, at least in patients at very high risk. Total cardiovascular risk reduction should be individualised, and this can be more specific in everyday clinical prac- tice if goals are defined. Among lipid-lowering drugs, statins are the most commonly used and will remain the gold standard, being safe, efficacious in lowering LDL-cholesterol and cost-effective in cardioprevention. Current avail- able evidence from meta-analyses suggests that their clinical benefit is largely a class effect, driven by the absolute LDL-cholesterol reduction, clearly related to the lipid-lowering intensity. 3 Therefore, prescribing a statin should reflect the treatment goals for a given patient, as the degree of LDL-cholesterol reduction is dose-dependent and varies between the different mol- ecules. It is recommended that a high-intensity statin is prescribed up to the highest tolerated dose to reach the goals (percentage and absolute value) set for the specific level of risk; if they are not achieved, additional treat- ment is recommended. 1,2 However, in the real world too many patients are still inadequately treated, and a large proportion of them are not achieving the treat- ment targets. 4 One reason may be the considerable interindividual variation in the magnitude of LDL- cholesterol reduction with a given dose of the same statin. This may reflect poor compliance, 5 unidentified changes in concomitant drug therapies, errors in drug administration or mistakes in blood sample handling or in laboratory assays. Feedback mechanisms in patterns of cholesterol synthesis/absorption or PCSK-9 expres- sion may be involved in this phenomenon, which may also be partly explained by genetic backgrounds, well documented in Mendelian randomisation-based stu- dies. Using genome-wide association screening, many single nucleotide polymorphisms within the CELSR2/ PSRC1/SORT1, CILP2/PBX4, ABCG2, LPA, CLMN, SLCO1B1, APOB, APOE/C1/C4, HMGCoA reduc- tase, LDL receptor and PCSK-9 genes have been identified as candidates potentially modifying the LDL-cholesterol response to statins. 6,7 These inherited polymorphisms are common in the general population, but their influence on individual patient response to statins is under debate. Predicting the effect of a given dose of a statin may have practical importance not only to know future LDL-cholesterol reductions, but also retrospectively. In fact, in daily practice many patients under lipid-low- ering therapy may be unaware of their pretreatment lipid levels. Thus, correction factors have been devel- oped from on-treatment LDL-cholesterol for the specific type and dose of the current statin to predict pre-treatment LDL-cholesterol. They are derived from Operative Unit of Cardiology, S. Antonio Abate Hospital, ASP Trapani, Italy Corresponding author: Maurizio Giuseppe Abrignani, Via F Crispi 6, 91025 Marsala, Italy. Email: maur.abri@alice.it European Journal of Preventive Cardiology 0(00) 1–3 ! The European Society of Cardiology 2019 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/2047487319882818 journals.sagepub.com/home/cpr