Metabolic and Atherosclerosis Research Center, 5355 Medpace Way, Cincinnati, OH 45227, USA.
Circulation. 2012 Nov 6;126(19):2283-92. doi: 10.1161/CIRCULATIONAHA.112.104125. Epub 2012 Oct 11.
Heterozygous familial hypercholesterolemia (HeFH) is a common genetic disorder leading to premature coronary artery disease. Despite statins and additional lipid-lowering therapies, many HeFH patients fail to achieve low-density lipoprotein cholesterol (LDL-C) goals. We evaluated mipomersen, an apolipoprotein B synthesis inhibitor, to further lower LDL-C in HeFH patients with coronary artery disease.
This double-blind, placebo-controlled, phase 3 trial randomized patients with HeFH and coronary artery disease on maximally tolerated statin and LDL-C ≥2.6 mmol/L (≥100 mg/dL) to weekly subcutaneous mipomersen 200 mg or placebo (2:1) for 26 weeks. The primary end point was percent change in LDL-C from baseline at week 28. Safety assessments included adverse events, laboratory tests, and magnetic resonance imaging assessment of hepatic fat. Of 124 randomized patients (41 placebo, 83 mipomersen), 114 (41 placebo, 73 mipomersen) completed treatment. Mean (95% confidence interval) LDL-C decreased significantly with mipomersen (-28.0% [-34.0% to -22.1%] compared with 5.2% [-0.5% to 10.9%] increase with placebo; P<0.001). Mipomersen significantly reduced apolipoprotein B (-26.3%), total cholesterol (-19.4%), and lipoprotein(a) (-21.1%) compared with placebo (all P<0.001). No significant change occurred in high-density lipoprotein cholesterol. Adverse events included injection site reactions and influenza-like symptoms. Five mipomersen patients (6%) had 2 consecutive alanine aminotransferase values ≥3 times the upper limit of normal at least 7 days apart; none were associated with significant bilirubin increases. Hepatic fat content increased a median of 4.9% with mipomersen versus 0.4% with placebo (P<0.001).
Mipomersen is an effective therapy to further reduce apolipoprotein B-containing lipoproteins, including LDL and lipoprotein(a), in HeFH patients with coronary artery disease on statins and other lipid-lowering therapy. The significance of hepatic fat and transaminase increases remains uncertain at this time.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00706849.
杂合子家族性高胆固醇血症（HeFH）是一种常见的遗传疾病，可导致早发冠状动脉疾病。尽管使用了他汀类药物和其他降脂疗法，许多 HeFH 患者仍未能达到低密度脂蛋白胆固醇（LDL-C）目标。我们评估了 mipomersen，一种载脂蛋白 B 合成抑制剂，以进一步降低患有冠状动脉疾病的 HeFH 患者的 LDL-C。
这是一项双盲、安慰剂对照、3 期试验，将接受最大耐受剂量他汀类药物治疗且 LDL-C≥2.6mmol/L（≥100mg/dL）的 HeFH 合并冠状动脉疾病患者随机分为每周皮下注射 mipomersen 200mg 或安慰剂（2:1），共 26 周。主要终点是第 28 周时 LDL-C 从基线的百分比变化。安全性评估包括不良事件、实验室检查和肝脏脂肪的磁共振成像评估。在 124 名随机患者中（41 名安慰剂，83 名 mipomersen），114 名（41 名安慰剂，73 名 mipomersen）完成了治疗。mipomersen 组 LDL-C 平均（95%置信区间）显著降低（-28.0%[-34.0%至-22.1%]与安慰剂组的 5.2%[-0.5%至 10.9%]升高；P<0.001）。与安慰剂相比，mipomersen 显著降低载脂蛋白 B（-26.3%）、总胆固醇（-19.4%）和脂蛋白（a）（-21.1%）（均 P<0.001）。高密度脂蛋白胆固醇无显著变化。不良事件包括注射部位反应和流感样症状。5 名 mipomersen 患者（6%）有 2 次连续丙氨酸氨基转移酶值至少间隔 7 天≥3 倍正常值上限；均与胆红素显著升高无关。mipomersen 组肝脏脂肪含量中位数增加 4.9%，安慰剂组增加 0.4%（P<0.001）。
在接受他汀类药物和其他降脂治疗的合并冠状动脉疾病的 HeFH 患者中，mipomersen 是一种有效的治疗方法，可进一步降低载脂蛋白 B 含量的脂蛋白，包括 LDL 和脂蛋白（a）。目前尚不确定肝脂肪和转氨酶升高的意义。
