Sarraju Ashish, Brennan Danielle, Hayden Kierstyn, Stronczek Amanda, Goldberg Anne C, Michos Erin D, McGuire Darren K, Mason Denise, Tercek Grace, Nicholls Stephen J, Kling Douglas, Neild Annie L, Kastelein John, Davidson Michael, Ditmarsch Marc, Nissen Steven E
Department of Cardiovascular Medicine and Cleveland Clinic Coordinating Center for Clinical Research, Cleveland Clinic, Cleveland, OH, USA.
NewAmsterdam Pharma, Naarden, Netherlands.
Lancet. 2025 May 17;405(10491):1757-1768. doi: 10.1016/S0140-6736(25)00721-4. Epub 2025 May 7.
Reducing LDL cholesterol prevents atherosclerotic cardiovascular disease (ASCVD) events. The aim of this study was to evaluate the LDL cholesterol-lowering efficacy of a fixed-dose combination (FDC) of obicetrapib, a CETP inhibitor, and ezetimibe.
This randomised, double-blind trial across 48 US sites including hospitals, private and group practices, and independent research centres included participants at least 18 years old with pre-existing or high risk for ASVCD or heterozygous familial hypercholesterolaemia with LDL cholesterol concentrations of 1·8 mmol/L (70 mg/dL) or greater despite maximally tolerated lipid-lowering therapy excluding ezetimibe, or having statin intolerance. Participants were randomly assigned (1:1:1:1) to obicetrapib 10 mg plus ezetimibe 10 mg FDC, obicetrapib 10 mg monotherapy, ezetimibe 10 mg monotherapy, or placebo administered daily for 84 days. The co-primary endpoints in the intention-to-treat population were the percent LDL cholesterol changes in the FDC group compared with placebo, ezetimibe monotherapy, and obicetrapib monotherapy, and the placebo-adjusted change in the obicetrapib monotherapy group. The trial was prospectively registered (NCT06005597) and is completed.
Between March 4 and July 3, 2024, 407 participants were randomly assigned. The median age was 68·0 years (IQR 62·0-73·0) and 177 (43%) were female. Mean baseline LDL cholesterol was 2·4 mmol/L, 2·5 mmol/L, 2·6 mmol/L, and 2·5 mmol/L in the placebo (n=102), ezetimibe monotherapy (n=101), obicetrapib monotherapy (n=102), and FDC groups (n=102), respectively. At day 84, percent differences in LDL cholesterol reduction with the FDC were -48·6% (95% CI -58·3 to -38·9) versus placebo, -27·9% (-37·5 to -18·4) versus ezetimibe, and -16·8% (-26·4 to -7·1) versus obicetrapib. Obicetrapib monotherapy decreased LDL cholesterol by 31·9% (22·1 to 41·6) versus placebo. Adverse event rates were similar in the FDC (52 [51%] of 102), obicetrapib (55 [54%] of 102), and ezetimibe (54 [53%] of 101) groups and lowest with placebo (38 [37%] of 102). Serious adverse event rates were generally similar across FDC (three [3%] of 102), obicetrapib (six [6%] of 102), ezetimibe (seven [7%] of 101), and placebo (four [4%] of 102) groups. Deaths occurred in one [1%] of 102 participants with FDC, one [1%] of 102 with obicetrapib, one [1%] of 101 with ezetimibe, and none with placebo.
Combination therapy of obicetrapib and ezetimibe significantly reduced LDL cholesterol. This oral, single-pill therapy could improve LDL cholesterol management in patients with pre-existing or high risk for ASCVD.
NewAmsterdam Pharma.
降低低密度脂蛋白胆固醇可预防动脉粥样硬化性心血管疾病（ASCVD）事件。本研究的目的是评估CETP抑制剂奥贝胆酸与依折麦布固定剂量复方制剂（FDC）降低低密度脂蛋白胆固醇的疗效。
这项在美国48个地点开展的随机、双盲试验，涵盖医院、私人诊所和团体诊所，以及独立研究中心，纳入了年龄至少18岁、患有ASCVD或杂合子家族性高胆固醇血症且存在既往病史或高危风险的参与者，尽管接受了最大耐受剂量的降脂治疗（不包括依折麦布），其低密度脂蛋白胆固醇浓度仍达到1.8 mmol/L（70 mg/dL）或更高，或者存在他汀类药物不耐受情况。参与者被随机分配（1:1:1:1）接受奥贝胆酸10 mg加依折麦布10 mg FDC、奥贝胆酸10 mg单药治疗、依折麦布10 mg单药治疗或安慰剂，每日给药，持续84天。在意向性治疗人群中的共同主要终点是FDC组与安慰剂、依折麦布单药治疗和奥贝胆酸单药治疗相比，低密度脂蛋白胆固醇的变化百分比，以及奥贝胆酸单药治疗组经安慰剂校正后的变化。该试验已进行前瞻性注册（NCT06005597）并已完成。
在2024年3月4日至7月3日期间，407名参与者被随机分配。中位年龄为68.0岁（四分位间距62.0 - 73.0），177名（43%）为女性。安慰剂组（n = 102）、依折麦布单药治疗组（n = 101）、奥贝胆酸单药治疗组（n = 102）和FDC组（n = 102）的平均基线低密度脂蛋白胆固醇分别为2.4 mmol/L、2.5 mmol/L、2.6 mmol/L和2.5 mmol/L。在第84天，FDC组低密度脂蛋白胆固醇降低的百分比差异与安慰剂相比为 -48.6%（95% CI -58.3至 -38.9），与依折麦布相比为 -27.9%（-37.5至 -18.4），与奥贝胆酸相比为 -16.8%（-26.4至 -7.1）。奥贝胆酸单药治疗与安慰剂相比，低密度脂蛋白胆固醇降低了31.9%（22.1至41.6）。FDC组（102例中的52例[51%]）、奥贝胆酸组（102例中的55例[54%]）和依折麦布组（101例中的54例[53%]）的不良事件发生率相似，安慰剂组最低（102例中的38例[37%]）。FDC组（102例中的3例[3%]）、奥贝胆酸组（102例中的6例[6%]）、依折麦布组（101例中的7例[7%]）和安慰剂组（102例中的4例[4%]）的严重不良事件发生率总体相似。FDC组102例参与者中有1例（1%）死亡，奥贝胆酸组102例中有1例（1%）死亡，依折麦布组101例中有1例（1%）死亡，安慰剂组无死亡病例。
奥贝胆酸与依折麦布联合治疗显著降低了低密度脂蛋白胆固醇。这种口服单丸疗法可改善ASCVD患者或有ASCVD高危风险患者的低密度脂蛋白胆固醇管理。
新阿姆斯特丹制药公司。
