medwireNews: A fixed-dose combination (FDC) of obicetrapib plus ezetimibe for 12 weeks reduced low-density lipoprotein (LDL) cholesterol by almost 50% in people with or at high risk for atherosclerotic cardiovascular disease (ASCVD)in the phase 3 TANDEM trial.
“This oral, single-pill therapy could improve LDL cholesterol management in patients with pre-existing or high risk for ASCVD,” a group “who can be challenging to treat,” report the researchers in The Lancet.
Steven Nissen, from the Cleveland Clinic in Ohio, USA, and colleagues led the double-blind trial across 48 treatment centers. The study included 407 adults (median age 68 years; 57% men; 83% White, 14% Black or African American) with pre-existing ASCVD, heterozygous familial hypercholesterolemia, or multiple ASCVD risk factors – defined as either type 2 diabetes plus one additional risk factor, or three non-diabetes risk factors.
All the patients had fasting LDL cholesterol levels of 1.8 mmol/L (70 mg/dL) or above and were either receiving maximally tolerated lipid-lowering therapies (excluding ezetimibe) or had documented statin intolerance.
The participants were randomly assigned to receive once-daily therapy for 84 days with either the FDC of obicetrapib 10 mg plus ezetimibe 10 mg, the same dose of obicetrapib or ezetimibe as monotherapy, or placebo.
At baseline, LDL cholesterol levels were similar across all groups (mean 2.5 mmol/L; 96.4 mg/dL), with 71% of participants receiving high-intensity statin therapy.
Treatment with the FDC led to a 48.6% greater least squares mean reduction in LDL cholesterol levels than was achieved with placebo, with a mean decrease from baseline of 45.6% versus an increase of 3.0%.
The FDC also outperformed treatment with either obicetrapib or ezetimibe monotherapy, with respective least squares mean decreases in LDL cholesterol levels that were a significant 16.8% and 27.9% greater with the FDC. The respective mean reductions from baseline were 28.8% with obicetrapib alone and 17.6% with ezetimibe. Obicetrapib monotherapy also reduced LDL cholesterol to a greater extent than placebo, at a significant 31.9%.
The authors highlight that “the effects of the obicetrapib–ezetimibe FDC were rapid, reaching a maximal effect within 28 days which was maintained to 84 days.”
Absolute LDL cholesterol reductions over the 84-day treatment period were a mean of 1.2 mmol/L (46.4 mg/dL) with the FDC, compared with 0.9 mmol/L (34.8 mg/dL) with obicetrapib and 0.5 mmol/L (19.3 mg/dL) with ezetimibe. Levels remained largely unchanged in the placebo group (0.05 mmol/L; 1.9 mg/dL).
The investigators highlight that 71% of patients treated with the FDC achieved LDL cholesterol levels below the recommended threshold of 1.4 mmol/L (54.1 mg/dL), a level of reduction that they note “might allow this medication to contribute to cardiovascular prevention.” By comparison, this threshold was achieved by 41% of those on obicetrapib, 25% on ezetimibe, and 7% on placebo.
Secondary endpoints also favored the FDC therapy. Compared with placebo, non-high-density lipoprotein (HDL) cholesterol and apolipoprotein B levels were reduced by a significant 45.1% and 29.2%, respectively. Both reductions were also significantly more pronounced than with either monotherapy, at a corresponding 15.2% and 9.4% compared with obicetrapib and 25.4% and 14.2% compared with ezetimibe.
The researchers note that the FDC was well tolerated. Adverse events occurred in 51% of patients in the FDC group versus 37% in the placebo group. The rate of adverse events for the FDC group was comparable to that seen with obicetrapib (54%) and ezetimibe (53%) monotherapy. Serious adverse events, discontinuations, and laboratory findings “were not meaningfully different between the FDC, obicetrapib monotherapy, and ezetimibe monotherapy treatment groups,” the authors say. There was one death in each of the treatment groups and none in the placebo group.
In an accompanying commentary, Seung-Jun Lee and Byeong-Keuk Kim, both from Yonsei University College of Medicine, Seoul, South Korea, write that while, “[t]he nearly 50% reduction of LDL cholesterol compared with placebo […], is slightly lower than that observed with injectable PCSK9 inhibitors,” the cost and adherence issues associated with injectables make this oral FDC “a compelling therapeutic option for ASCVD management.”
While Lee and Kim praise the study’s robust methodology and “comprehensive blinding,” they highlight “the need for longer-term follow-up data,” particularly to assess sustained efficacy and delayed adverse effects.
They conclude that the “demonstrated efficacy of the obicetrapib-ezetimibe FDC in the TANDEM trial holds promise for broadening the therapeutic landscape for patients with pre-existing or high risk for ASCVD.”
medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2025 Springer Healthcare Ltd, part of Springer Nature.
Lancet 2025: doi:10.1016/S0140-6736(25)00721-4
Lancet 2025: doi:10.1016/S0140-6736(25)00827-X
