近日，美国克利夫兰诊所Steven E Nissen团队研究了obicetrapib和依折麦布固定剂量组合降低LDL胆固醇的疗效。相关论文发表在2025年5月7日出版的《柳叶刀》杂志上。

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。该研究旨在评估obicetrapib（一种CETP抑制剂）和依折麦布的固定剂量组合（FDC）降低LDL胆固醇的疗效。

这项随机、双盲试验在美国48个地点进行，包括医院、私人和团体实践以及独立研究中心，参与者年龄至少18岁，存在ASVCD或杂合子家族性高胆固醇血症或高风险，LDL胆固醇浓度为1.8 mmol/L （70 mg/dL）或更高，尽管有最大耐受的降脂治疗（不包括依依折麦布），或有他汀类药物不耐受。参与者被随机分配（1:1:1:1），每天给予obicetrapib 10mg + 依折麦布10mg FDC， obicetrapib 10mg单药治疗，依折麦布10mg单药治疗，或安慰剂84天。意向治疗人群的共同主要终点是FDC组与安慰剂、依折麦布单药治疗和obicetrapib单药治疗相比LDL胆固醇变化的百分比，以及obicetrapib单药治疗组经安慰剂调整后的变化。该试验已前瞻性注册（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（IQR为62.0 ~ 73.0），女性为177例（43%）。安慰剂组（n=102）、依折麦布单药组（n=101）、obicetrapib单药组（n=102）和FDC组（n=102）的平均基线LDL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，与FDC相比，LDL胆固醇降低的百分比差异为- 48.6% (95% CI为- 58.3至- 38.9)，与依折麦布相比为- 27.9%(- 37.5至- 18.4)，与obicetrapib相比为- 16.8%（- 26.4至- 7.1）。与安慰剂相比，Obicetrapib单药治疗可降低低密度脂蛋白胆固醇31.9%（22.1 - 41.6）。

不良事件发生率在FDC组（102例中有52例[51%]）、obicetrapib组（102例中有55例[54%]）和依折麦布组（101例中有54例[53%]）相似，安慰剂组最低（102例中有38例[37%]）。FDC组（102例中有3例[3%]）、obicetrapib组（102例中有6例[6%]）、依折麦布组（101例中有7例[7%]）和安慰剂组（102例中有4例[4%]）的严重不良事件发生率大致相似。102例FDC患者中有1例（1%）死亡，102例obicetrapib患者中有1例（1%）死亡，101例依折麦布患者中有1例（1%）死亡，安慰剂组无死亡。

研究结果表明，obictrapib和依折麦布联合治疗可显著降低LDL胆固醇。这种口服单丸治疗可以改善已存在ASCVD或ASCVD高风险患者的LDL胆固醇管理。

附：英文原文

Title: Fixed-dose combination of obicetrapib and ezetimibe for LDL cholesterol reduction (TANDEM): a phase 3, randomised, double-blind, placebo-controlled trial

Author: Ashish Sarraju, Danielle Brennan, Kierstyn Hayden, Amanda Stronczek, Anne C Goldberg, Erin D Michos, Darren K McGuire, Denise Mason, Grace Tercek, Stephen J Nicholls, Douglas Kling, Annie L Neild, John Kastelein, Michael Davidson, Marc Ditmarsch, Steven E Nissen

Issue&Volume: 2025-05-07

Abstract:

Background

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.

Methods

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.

Findings

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.

Interpretation

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.

DOI: 10.1016/S0140-6736(25)00721-4

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)00721-4/abstract