Extracorporeal Therapeutic Techniques Unit, Department of Molecular Medicine, University of Rome 'Sapienza', 'Umberto I' Hospital, Rome, Italy.
Curr Med Chem. 2012;19(28):4861-8. doi: 10.2174/092986712803341485.
Patients with homozygous familial hypercholesterolemia (HoFH) represent the most severe patients within the spectrum of dyslipidemias. Untreated Low-Density Lipoprotein Cholesterol (LDL-C) levels in these patients are usually in the range 500 to 1200 mg/dL. Moreover, these patients exhibit a scarce responsiveness or even non responsiveness to oral lipid lowering agents. Patients with heterozygous familial hypercholesterolemia (HetFH) tend to have untreated LDL-C levels of 250-500 mg/dL. Many of these patients are responsive to 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA-reductase) inhibitors (statins) and/or other specific drugs. Unfortunately, a significant subset of these patients (5-10%) have a severe and/or refractory form of HetFH and after current maximal oral therapy, they remain significantly far from treatment goals (The National Cholesterol Education Program (NCEP) ATPIII guidelines). This would be defined as LDL-C levels of ≥ 190 mg/dL - prior Coronary Heart Disease (CHD) or CHD equivalent - or ≥ 250 mg/dL (no prior CHD or CHD risk-equivalent). The only current therapy option for these patients is Low Density Lipoprotein-apheresis (LDL_a). While LDL_a is very effective in reducing LDL-C, many patients do not receive this extracorporeal therapy because of costs and limited availability of LDL_a centers. Recently, new potent lipid-lowering drugs have been developed and are currently under investigation. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role controlling the levels of LDL-C. Studies have demonstrated that PCSK9 acts mainly by enhancing degradation of the Low-Density Lipoprotein receptor (LDLR) protein in the liver. Inactivation of PCSK9 in mice reduces plasma cholesterol levels. Since the loss of a functional PCSK9 in human is not associated with apparent deleterious effects, this protease is becoming an attractive target for lowering plasma LDL-C levels either alone or in combination with statins. Mipomersen, an apolipoprotein B (ApoB) synthesis inhibitor, for lowering of LDL-C showed to be an effective therapy to reduce LDL-C concentrations in patients with HoFH who are already receiving lipid-lowering drugs, including high-dose statins. Lomitapide is a potent inhibitor of microsomal triglyceride transfer protein and is highly efficacious in reducing LDL-C and triglycerides (TG). Lomitapide is currently being developed for patients with HoFH at doses up to 60 mg/d. These new powerful lipid-lowering drugs might be possibly superior than available hypolipidemic agents. Their mechanisms of action, effectiveness, safety, and indication in severe, genetically determined dyslipidemias, are reviewed.
患有纯合子家族性高胆固醇血症（HoFH）的患者是血脂异常谱中最严重的患者。这些患者未经治疗的低密度脂蛋白胆固醇（LDL-C）水平通常在 500 至 1200mg/dL 之间。此外，这些患者对口服降脂药物的反应较差甚至无反应。患有杂合子家族性高胆固醇血症（HetFH）的患者往往未经治疗的 LDL-C 水平为 250-500mg/dL。这些患者中的许多人对 3-羟基-3-甲基戊二酰基辅酶 A（HMGCoA-还原酶）抑制剂（他汀类药物）和/或其他特定药物有反应。不幸的是，这些患者中有相当一部分（5-10%）患有严重和/或难治性 HetFH，即使经过目前最大的口服治疗，他们仍远未达到治疗目标（国家胆固醇教育计划（NCEP）ATPIII 指南）。这将被定义为 LDL-C 水平≥190mg/dL-先前有冠心病（CHD）或 CHD 等效疾病-或≥250mg/dL（无先前 CHD 或 CHD 风险等效疾病）。这些患者唯一的当前治疗选择是低密度脂蛋白-吸附（LDL_a）。虽然 LDL_a 非常有效地降低 LDL-C，但由于成本和 LDL_a 中心的有限可用性，许多患者无法接受这种体外治疗。最近，已经开发出了新的强效降脂药物，目前正在进行研究。前蛋白转化酶枯草溶菌素/kexin 9 型（PCSK9）在控制 LDL-C 水平方面起着关键作用。研究表明，PCSK9 主要通过增强肝脏中 LDL 受体（LDLR）蛋白的降解来发挥作用。在小鼠中失活 PCSK9 可降低血浆胆固醇水平。由于人类中功能性 PCSK9 的丧失不与明显的有害影响相关，因此这种蛋白酶成为降低血浆 LDL-C 水平的有吸引力的靶标，无论是单独使用还是与他汀类药物联合使用。米泊美生，一种载脂蛋白 B（ApoB）合成抑制剂，用于降低 LDL-C，已被证明是一种有效的治疗方法，可降低已接受降脂药物治疗的 HoFH 患者的 LDL-C 浓度，包括高剂量他汀类药物。洛美他派是一种有效的微粒体甘油三酯转移蛋白抑制剂，可有效降低 LDL-C 和甘油三酯（TG）。洛美他派目前正在开发用于 HoFH 患者，剂量高达 60mg/d。这些新的强效降脂药物可能优于现有的降脂药物。对严重遗传性血脂异常的作用机制、有效性、安全性和适应证进行了综述。
