Fixed-dose combination of obicetrapib and ezetimibe for LDL cholesterol reduction (TANDEM): a phase 3, randomised, double-blind, placebo-controlled trial
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Key result
Obicetrapib plus ezetimibe lowers LDL-C by an additional ~49% vs. placebo in high-risk ASCVD.
- MD -48.6%
- 95% CI -58.3 to -38.9
- P<0.0001
- n=407
Why the study?
Reducing LDL cholesterol prevents ASCVD events, but the LDL cholesterol-lowering efficacy of a fixed-dose combination of obicetrapib and ezetimibe had not been evaluated.
Does a fixed-dose combination of obicetrapib and ezetimibe reduce LDL cholesterol in patients with pre-existing or high risk for ASCVD on maximally tolerated lipid-lowering therapy?
Key Points
- To evaluate the LDL cholesterol-lowering efficacy and safety of a fixed-dose combination of the CETP inhibitor obicetrapib and ezetimibe in patients with pre-existing or high risk for atherosclerotic cardiovascular disease or heterozygous familial hypercholesterolaemia.
- Phase 3, randomized, double-blind, placebo-controlled trial across 48 US sites enrolling 407 participants aged ≥18 years with LDL cholesterol ≥1.8 mmol/L despite maximally tolerated lipid-lowering therapy or statin intolerance (NCT06005597).
- Participants were randomly assigned (1:1:1:1) to receive daily obicetrapib 10 mg plus ezetimibe 10 mg fixed-dose combination, obicetrapib 10 mg monotherapy, ezetimibe 10 mg monotherapy, or placebo for 84 days.
- At day 84, percent differences in LDL cholesterol reduction with the fixed-dose combination were -48·6% (95% CI -58·3 to -38·9) versus placebo, -27·9% (-37·5 to -18·4) versus ezetimibe monotherapy, and -16·8% (-26·4 to -7·1) versus obicetrapib monotherapy.
- Obicetrapib monotherapy decreased LDL cholesterol by 31·9% (95% CI 22·1 to 41·6) compared with placebo.
- Adverse events occurred in 51% (52 of 102) with combination therapy, 54% (55 of 102) with obicetrapib, 53% (54 of 101) with ezetimibe, and 37% (38 of 102) with placebo; serious adverse events occurred in 3% (three of 102), 6% (six of 102), 7% (seven of 101), and 4% (four of 102), respectively.
Study Design
Type
RCT (n=407)
Blinding
Double-blind
Randomization
1:1:1:1
Multicenter
Yes
Structured PICO
Does a fixed-dose combination of obicetrapib and ezetimibe reduce LDL cholesterol in patients with pre-existing or high risk for ASCVD on maximally tolerated lipid-lowering therapy?
P
Population
407 adults with pre-existing or high risk for ASCVD or heterozygous familial hypercholesterolemia with elevated LDL cholesterol on maximally tolerated lipid-lowering therapy, followed for 84 days.
I
Intervention
Obicetrapib 10 mg plus ezetimibe 10 mg fixed-dose combination (FDC) administered orally once daily for 84 days, added to maximally tolerated background lipid-lowering therapy.
C
Comparator
Obicetrapib 10 mg monotherapy, ezetimibe 10 mg monotherapy, or placebo administered orally once daily for 84 days, added to maximally tolerated background lipid-lowering therapy.
O
Outcome
Percent change in LDL cholesterol concentrations (measured by preparative ultracentrifugation) from baseline to day 84. Co-primary endpoints evaluated the FDC compared with placebo, ezetimibe monotherapy, and obicetrapib monotherapy, as well as obicetrapib monotherapy compared with placebo.surrogate
Main Result
Mean Difference: -48.6 (95% CI -58.3–-38.9)
Absolute Event Rate: -45.6% vs 3%
p-value: p=<0.0001
A fixed-dose combination of obicetrapib and ezetimibe significantly and substantially reduced LDL cholesterol levels by 48.6% compared to placebo, offering an effective oral non-statin option for high-risk patients.
Limitations
- Short follow-up duration of 84 days
- Lack of long-term cardiovascular morbidity and mortality outcome data
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Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“The TANDEM data presented today are highly encouraging, demonstrating obicetrapib in combination with ezetimibe delivering a roughly 50% LDL-C reduction and improvements across other lipid parameters. Simple and effective oral therapies like this are needed alongside maximally tolerated statins in the current CVD treatment paradigm.”
“We need to give patients and their doctors all the options we can to try to get LDL under control if they are at risk for—or already have— cardiovascular disease. In higher-risk patients, you want to get LDL down as quickly as possible and keep it there as long as possible.”
“Our aim should be to provide patients and doctors with as many different options in terms of route of administration, efficacy, safety, and tolerability as possible [so they can] play with the permutations of medications. That's where studying new therapies like this makes sense.”
Implication
Offers an oral fixed-dose option for additional LDL-C lowering in high-risk patients; extends prior CETP inhibitor evidence pending outcomes data.
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.
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Cite This Study
Sarraju et al. (2025) conducted an RCT in Pre-existing or high risk for ASCVD or heterozygous familial hypercholesterolemia with elevated LDL cholesterol (n=407). Fixed-dose combination of obicetrapib and ezetimibe vs. Placebo was evaluated on Percent change in LDL cholesterol from baseline to day 84 (MD -48.6%, 95% CI -58.3 to -38.9, p=<0.0001). The once-daily fixed-dose combination of obicetrapib and ezetimibe reduced LDL cholesterol by an additional 48.6% compared to placebo over 84 days in patients with or at high risk for ASCVD.
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