We read with interest the meta-analysis of APOE genotypes and the effect of statins on lipid outcomes by Assiimwe et al.1 The results suggested that APOE polymorphisms influence statin response giving thus a possibility to incorporate known APOE into personalized treatment of dyslipidaemia. More specifically, the meta-analysis showed that individuals carrying ε2 allele of APOE had better response with statin treatment than those carrying ε3 allele: Mean reduction in low-density cholesterol (LDL-C) was 2.98% (95% CI: −5.88 to −0.08). In contrast, individuals carrying ε4 allele showed smaller reductions than those carrying ε3 allele in LDL-C response during statin treatment (mean reduction 10.04%, 95% CI: −6.04% to −14.04%). We certainly agree with the conclusion of the authors that knowing APOE genotype gives a possibility to improve personalized hypercholesterolemia treatment. However, we think that the discussion has not fully addressed the mechanistic explanation for the different response according to APOE genotypes during statin treatment. More light might be shed by the closer analyses of two randomized statin trials: the Scandinavian Simvastatin Survival Study2 and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels.3 In the 4S, a subgroup analysis of 868 participants with coronary heart disease (CHD) provides an indirect clue to understand the effect of APOE for the response of statin treatment.2 In that analysis, baseline serum cholestanol/cholesterol ratio—negatively and positively related to cholesterol synthesis and absorption, respectively—was used to predict reduction of CHD events during the trial. It was shown that the risk of CHD events increased 2.2-fold (P < 0.01) from the lowest to the highest quarter of cholestanol/cholesterol. Consequently, patients with high baseline synthesis of cholesterol were responders, whereas those with low cholesterol synthesis had poorer response to statin treatment. Interestingly, this finding can be traced back to current meta-analysis by Asiimwe et al.1 because apoE phenotypes are differently associated with individual cholesterol absorption and synthesis.4 Accordingly, individuals with apoE4 (apoE3/4 or 4/4) absorb cholesterol effectively and those with apoE2 (apoE3/2 or 2/2) have increased cholesterol synthesis as compared to apoE3/3 individuals. With these data, the poor responses in LDL-C lowering among ε4 carriers in the meta-analysis are very much expected. It is utmost important to notice that it is not only the poor response of LDL-C among ε4 carriers but also higher risk of CHD events in statin-treated patients with high vs. low cholesterol absorption.2 Authors of the meta-analysis also found heterogeneity between analysed studies mainly due to individuals with familial hypercholesterolemia.1 It has been shown that the genetically determined apoE polymorphism contributes to cholesterol absorption efficiency in FH patients, but LDL-C levels are poorly related to APOE polymorphisms.5, 6 Asiimwe et al.1 had insufficient data to report clinical outcomes related to APOE. Interestingly, it has been shown that APOE2 is related to increased and APOE4 to decreased apoE concentrations in plasma.7 In the SPARCL trial, 80-mg atorvastatin daily was compared with placebo in patients with recent stroke or transient ischemic attack (TIA) and without a history of CHD.3 It was shown that low apoE concentrations were predictive of recurring CHD events in these patients. It is currently known that ε2 carriers enjoy cardioprotective effects related to less subclinical and clinical atherosclerosis; this effect is based on several mechanisms including anti-inflammatory effects, anticoagulation and complement activation.8 The current meta-analysis by Asiimwe et al.1 reminds us that unfortunately ε4 carriers who would need the highest CHD protection have the poorest statin response. If one reason would be higher cholesterol absorption with ε4 allele, a logical solution is to combine statin with ezetimibe, which lowers cholesterol absorption. The benefit of this combination has been proved, generic ezetimibe does not add much the cost of dyslipidaemia therapy and ezetimibe LDL-C lowering is not related to APOE genotype.9, 10 Both authors contributed to outline and write this document. A.V. has received consultancy fees from Amgen and Novartis and is a member of the Finnish dyslipidaemia guideline. T.K. has received consultancy fees and talks sponsored by Amarin, Amgen, CoroPrevention, Duodecim, Finnish Medical Journal, GlaxoSmithKline, Novartis, Nutricia, Orion Pharma, Sankyo and Valio and is the Chairperson of the Finnish dyslipidaemia guideline group. Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.
Vuorio et al. (Thu,) studied this question.