Article Impact Level: HIGH Data Quality: STRONG Summary of The Lancet, 405(10491), 1757–1768. https://doi.org/10.1016/S0140-6736(25)00721-4 Dr. Ashish Sarraju et al.
Points
- This Phase 3 trial tested a fixed-dose combination of obicetrapib and ezetimibe in 407 patients with resistant hypertension and elevated LDL cholesterol despite statin use.
- The fixed-dose combination reduced LDL cholesterol by 48.6 percent compared to placebo and showed significantly greater reductions than either monotherapy.
- Obicetrapib monotherapy reduced LDL cholesterol by 31.9 percent, while the combination showed additive efficacy over both individual treatments.
- Adverse event rates were similar across active treatment groups, with no significant differences in serious events or mortality compared to placebo.
- These findings support the fixed-dose combination as a practical option for patients with persistently high LDL cholesterol despite statin therapy, warranting further outcome studies.
Summary
This Phase 3 clinical trial evaluated the LDL cholesterol-lowering efficacy of a fixed-dose combination (FDC) of obicetrapib, a CETP inhibitor, and ezetimibe in patients with resistant hypertension. The study included 407 participants with an average age of 68 years, all of whom had LDL cholesterol levels above 70 mg/dL despite receiving statin therapy. Participants were randomized to receive the FDC, obicetrapib monotherapy, ezetimibe monotherapy, or placebo for 84 days. The primary outcome was the home-measured systolic blood pressure (SBP) change between the FDC and other treatment groups.
Results indicated that the FDC significantly reduced LDL cholesterol by 48.6% (95% CI, −58.3 to −38.9) compared to placebo, 27.9% (95% CI, −37.5 to −18.4) compared to ezetimibe, and 16.8% (95% CI, −26.4 to −7.1) compared to obicetrapib. Obicetrapib monotherapy reduced LDL cholesterol by 31.9% (95% CI, 22.1–41.6) compared to placebo. The adverse event rates were similar across the FDC (51%), obicetrapib (54%), and ezetimibe (53%) groups, with the placebo group reporting the lowest rate (37%). Serious adverse events were similar across all groups, and no significant differences in mortality were observed.
These findings suggest that combining obicetrapib and ezetimibe offers a potent LDL cholesterol-lowering effect, with the FDC demonstrating a substantial advantage over individual therapies. The results support the use of this combination as a potential treatment for patients with high cardiovascular risk, particularly those whose LDL levels remain inadequately controlled despite statin therapy. Further studies are required to confirm the long-term cardiovascular outcomes of this combination therapy.
Link to the article: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)00721-4/abstract
References Sarraju, A., Brennan, D., Hayden, K., Stronczek, A., Goldberg, A. C., Michos, E. D., McGuire, D. K., Mason, D., Tercek, G., Nicholls, S. J., Kling, D., Neild, A. L., Kastelein, J., Davidson, M., Ditmarsch, M., & Nissen, S. E. (2025). Fixed-dose combination of obicetrapib and ezetimibe for LDL cholesterol reduction (Tandem): A phase 3, randomised, double-blind, placebo-controlled trial. The Lancet, 405(10491), 1757–1768. https://doi.org/10.1016/S0140-6736(25)00721-4
