ObicetrapibLandmark
TANDEM: obicetrapib plus ezetimibe fixed-dose combination cuts LDL-C by 48.6% versus placebo in 407 high-risk patients (Lancet 2025)
Original title: Fixed-dose combination of obicetrapib and ezetimibe for LDL cholesterol reduction (TANDEM): a phase 3, randomised, double-blind, placebo-controlled trial
The TANDEM trial randomised 407 participants with pre-existing or high risk for atherosclerotic cardiovascular disease, or heterozygous familial hypercholesterolaemia, with LDL-C of 70 mg/dL or above, 1:1:1:1 to an obicetrapib 10 mg plus ezetimibe 10 mg fixed-dose combination, obicetrapib monotherapy, ezetimibe monotherapy, or placebo daily for 84 days (median age 68, 43% female). At day 84 the fixed-dose combination reduced LDL-C by 48·6% versus placebo (95% CI 58·3 to 38·9), by 27·9 percentage points more than ezetimibe alone and 16·8 percentage points more than obicetrapib alone; obicetrapib monotherapy reduced LDL-C by 31·9% versus placebo. Adverse events were similar across active arms (51 to 54%) and lower with placebo (37%), with comparable serious adverse events. A single-pill combination positioned to simplify LDL-C management, funded by NewAmsterdam Pharma, registered as NCT06005597.
Original 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.
Funding: NewAmsterdam Pharma.
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Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.