Cybulska Barbara, Gaciong Zbigniew, Hoffman Piotr, Jankowski Piotr, Kłosiewicz-Latoszek Longina, Kaźmierczak Jarosław, Mitręga Katarzyna, Opolski Grzegorz, Pająk Andrzej, Ponikowski Piotr, Rynkiewicz Andrzej, Stępińska Janina, Średniawa Beata, Kalarus Zbigniew
Instytut Żywności i Żywienia.
Kardiol Pol. 2016;74(4):394-8. doi: 10.5603/KP.2016.0051.
The severe hypercholesterolaemia can be recognised when low density lipoprotein cholesterol (LDL-C) serum levels are equal to or above 5 mmol/L (≥ 190 mg/dL). The prevalence of LDL-C ≥ 5 mmol/L is 3.8% in Polish population aged 18-79 years. Among these adults there are patients with familial hypercholesterolaemia (FH). According to meta-analysis of 6 Polish population surveys prevalence of heterozygous FH (HeFH) diagnosed using Dutch Lipid Clinic criteria is 0.4% (95% Cl 0.28-0.53%) in men and women aged 20-74 years, i.e. one in every 250 people. As HeFH is a wellknown cause of premature coronary heart disease the rigorous treatment targets for LDL-C have been established in clinical guidelines. Their achievements, even with a high dose of high efficacy statin therapy is difficult or even impossible. New strong hypolipidaemic drugs i.e. PCSK9 inhibitors have been initiated against this chalange. Both drugs, evolocumab and alirocumab, have been extensively studied in numerous phase 2 and phase 3 trials. Fewer studies with bococizumab are available until now. The PCSK9 inhibitors, as monotherapy as well in combination with statins were associated with mean LDL-C reduction about 60%. It means that the majority of patients (70-90%) with severe hypercholesterolaemia (including HeFH), treated with statins, after addition of PCSK9 inhibitors were able to achieve an LDL-C < 2.5 mmol/L (< 100 mg/dL) or < 1.8 mmol/L (< 70 mg/dL) level. Another group of patients who may benefit from PCSK9 inhibitors include those who need lipid lowering therapy, but who are statin intolerant, especially because of statin-associated muscle symptoms (SAMS). In our statement we have accepted the diagnosis of SAMS proposed recently by European Atherosclerosis Society. Today the longest clinical trial with evolocumab (11 months) was the open OSLER study, and with alirocumab ODYSSEY LONG TERM (78 weeks). In the first one the reduction of cardiovascular events by 53% (95% Cl 22-72%) was observed, and in the second one by 48% (10-69%). Neurocognitive events were reported more frequently with both drugs than with placebo. This adverse effect will be the subject of observation in ongoing studies. We still await the results of 4 ongoing large placebo controlled phase 3 trials investigating whether PCSK9 inhibitors on background of statin therapy reduce cardiovascular events. Meanwhile evolocumab, as well as alirocumab have been accepted to use in clinical practice by European Medicine Agency. In this situation the experts of Polish Society of Cardiology have prepared the statement on the use PCSK9 inhibitors with indication in the first place for HeFH patients, statin intolerant and those at high risk who are not able to reach LDL-C target level with a high potent high dose statin.
当血清低密度脂蛋白胆固醇（LDL-C）水平等于或高于5 mmol/L（≥190 mg/dL）时，可诊断为严重高胆固醇血症。在18 - 79岁的波兰人群中，LDL-C≥5 mmol/L的患病率为3.8%。在这些成年人中，有家族性高胆固醇血症（FH）患者。根据对6项波兰人群调查的荟萃分析，采用荷兰脂质诊所标准诊断的杂合子FH（HeFH）在20 - 74岁男女中的患病率为0.4%（95%CI 0.28 - 0.53%），即每250人中就有1人患病。由于HeFH是早发性冠心病的一个众所周知的病因，临床指南中已制定了严格的LDL-C治疗目标。即便使用高剂量的高效他汀类药物治疗，要实现这些目标也很困难甚至不可能。针对这一挑战，已开始使用新型强效降脂药物，即PCSK9抑制剂。依洛尤单抗和阿利西尤单抗这两种药物都在众多2期和3期试验中进行了广泛研究。到目前为止，关于博考izumab的研究较少。PCSK9抑制剂作为单一疗法以及与他汀类药物联合使用时，平均可使LDL-C降低约60%。这意味着，大多数患有严重高胆固醇血症（包括HeFH）且接受他汀类药物治疗的患者，在加用PCSK9抑制剂后能够使LDL-C水平降至<2.5 mmol/L（<100 mg/dL）或<1.8 mmol/L（<70 mg/dL）。另一组可能从PCSK9抑制剂中获益的患者包括那些需要降脂治疗但对他汀类药物不耐受的患者，尤其是因为他汀类药物相关肌肉症状（SAMS）而不耐受的患者。在我们的声明中，我们采用了欧洲动脉粥样硬化学会最近提出的SAMS诊断标准。目前，关于依洛尤单抗的最长临床试验（11个月）是开放标签的OSLER研究，关于阿利西尤单抗的是ODYSSEY LONG TERM研究（78周）。在第一项研究中，观察到心血管事件减少了53%（95%CI 22 - 72%），在第二项研究中减少了48%（10 - 69%）。与安慰剂相比，这两种药物报告的神经认知事件更为频繁。这种不良反应将是正在进行的研究的观察对象。我们仍在等待4项正在进行的大型安慰剂对照3期试验的结果，这些试验旨在研究在他汀类药物治疗基础上加用PCSK9抑制剂是否能减少心血管事件。与此同时，依洛尤单抗和阿利西尤单抗已被欧洲药品管理局批准用于临床实践。在这种情况下，波兰心脏病学会的专家们编写了一份关于使用PCSK9抑制剂的声明，首先适用于HeFH患者、他汀类药物不耐受者以及那些使用高效高剂量他汀类药物仍无法达到LDL-C目标水平的高危患者。
