Comparative Effectiveness of Cholesteryl Ester Transfer Protein (CETP) Inhibitors on Lipid Profiles in Adults With Hyperlipidemia: A Comprehensive Systematic Review and Frequentist Network Meta-Analysis of Randomized Controlled Trials

Abstract

Background

Hyperlipidemia, a key risk factor for cardiovascular disease, is characterized by elevated low-density lipoprotein cholesterol (LDL-C), triglycerides, and reduced high-density lipoprotein cholesterol (HDL-C). Cholesteryl ester transfer protein (CETP) inhibitors, such as anacetrapib, obicetrapib, evacetrapib, dalcetrapib, and torcetrapib, aim to improve lipid profiles by increasing HDL-C and reducing LDL-C, but their comparative efficacy remains unclear.

Methods

This systematic review and frequentist network meta-analysis, conducted per PRISMA-NMA guidelines, included 33 randomized controlled trials (RCTs) involving 120,292 adults with hyperlipidemia. We compared CETP inhibitors, alone or with statins, against placebo or other lipid-lowering therapies. Primary outcome was LDL-C reduction; secondary outcomes included HDL-C, triglycerides, and total cholesterol changes. Random-effects models calculated mean differences (MD) with 95% confidence intervals (CI), and P-scores ranked interventions.

Results

Atorvastatin + obicetrapib showed the largest reduction in LDL-C levels (MD: −69.00, 95% CI: −95.96 to −42.04, p < 0.0001), followed by rosuvastatin + obicetrapib (MD: −60.70, 95% CI: −99.28 to −22.12, p = 0.0020). Atorvastatin + obicetrapib yielded highly significant increase in HDL-C levels (MD: 149.90, 95% CI: 121.70 to 178.10, p < 0.0001), but rosuvastatin + obicetrapib showed the greatest increase (MD: 158.90, 95% CI: 118.59 to 199.21, p < 0.0001) and obicetrapib monotherapy (MD: 139.00, 95% CI: 129.05 to 148.96, p < 0.0001), while rosuvastatin + evacetrapib led triglyceride reductions (MD: −31.70 mg/dL). Rosuvastatin was most effective for total cholesterol (MD: −31.60 mg/dL).

Conclusion

CETP inhibitors, particularly anacetrapib and obicetrapib combined with statins, significantly improve lipid profiles, offering potential therapeutic benefits for hyperlipidemia management and cardiovascular risk reduction.

Trial Registration: The study was registered with PROSPERO to ensure transparency and adherence to methodological rigor (Registration ID: CRD420250652666).