Heterogeneous biomarker responses to CETP inhibitors: a phase 3 trials systematic review and network meta-analysis

Background Cholesteryl ester transfer protein (CETP) inhibitors have produced some of the most discrepant findings in lipid therapy to date: large biomarker effects but variable clinical efficacy across compounds. As residual ASCVD risk persists from apoB-containing lipoproteins, Lp(a), triglycerides, inflammation, and metabolic factors, the relative biological activities of individual CETP inhibitors remain incompletely defined. Purpose To evaluate the effects of individual CETP inhibitors on lipid, inflammatory, and metabolic biomarkers using data from randomized phase 3 clinical trials. Methods We performed a systematic review and network meta-analysis of randomized controlled trials comparing CETP inhibitors with placebo or active comparators. Databases were searched from inception through February 2026. Trials reporting changes in lipid, metabolic, or inflammatory biomarkers were included. Two reviewers independently screened studies, extracted data, and assessed risk of bias. A frequentist random-effects network meta-analysis estimated mean differences (MDs) in percentage change from baseline with 95% confidence intervals (CIs). Heterogeneity was quantified with I² and treatments were ranked using P-scores. Results Twenty-six RCTs including 60,489 patients were analyzed. CETP inhibition was associated with favorable lipid changes versus placebo. For LDL-C, anacetrapib (MD −37.14 mg/dL; 95% CI −39.01 to −35.26) and evacetrapib (MD −37.10 mg/dL; 95% CI −38.22 to −35.98) produced the largest reductions; obicetrapib also significantly reduced LDL-C (MD −24.00 mg/dL; 95% CI −28.64 to −19.36) (Fig. 1). HDL-C increased substantially with anacetrapib (MD 125.13 mg/dL; 95% CI 106.31 to 143.95), evacetrapib (MD 129.14 mg/dL; 95% CI 87.99 to 170.29), and obicetrapib (MD 122.00 mg/dL; 95% CI 80.53 to 163.47) (Fig 1). Triglycerides were modestly reduced with evacetrapib (MD −6.13 mg/dL; 95% CI −7.20 to −5.06), obicetrapib (MD −5.70 mg/dL; 95% CI −11.17 to −0.23), and anacetrapib (MD −4.60 mg/dL; 95% CI −7.43 to −1.77) (Fig 1). For lipoprotein(a), anacetrapib reduced Lp(a) (MD −39.05 nmol/L; 95% CI −52.49 to −25.60) and evacetrapib showed a smaller reduction (MD −22.30 nmol/L; 95% CI −44.43 to −0.17) (Fig 1). CRP increased versus placebo with anacetrapib (MD 16.85%; 95% CI 9.79 to 23.92) and evacetrapib (MD 8.60%; 95% CI 6.29 to 10.91) (Fig 2). Conclusion CETP inhibitors produce substantial and consistent improvements in lipid biomarkers, but inflammatory responses differ across agents (CRP elevation with anacetrapib and evacetrapib), indicating class heterogeneity. Ongoing cardiovascular outcome trials are needed to determine whether these biomarker changes translate into reductions in residual ASCVD risk.Figure 1Figure 2