Abstract Body (Do not enter title and authors here): Background:
Low-density lipoprotein (LDL) particle number is an important predictor of cardiovascular risk compared to LDL cholesterol concentration alone, reflecting actual atherogenic burden. Cholesteryl ester transfer protein (CETP) inhibition represents a unique mechanism for lipid modification, reducing the synthesis of small LDL particles. Unlike statins, ezetimibe, PCSK9 inhibitors or other lipid-lowering therapies primarily affecting LDL particle removal, CETP inhibitors uniquely target exchange of cholesteryl esters for triglycerides between lipoproteins, leading to lower total and small LDL particle concentrations. We evaluated the effects of obicetrapib, an oral selective CETP inhibitor, on LDL particle number in high-risk patients.

Methods:
We conducted a pooled analysis of nuclear magnetic resonance (NMR) spectroscopy data from two phase 3 trials (BROOKLYN, NCT05425745; BROADWAY, NCT05142722) evaluating obicetrapib 10 mg daily versus placebo in patients with (ASCVD) and/or familial hypercholesterolemia receiving maximally tolerated lipid-lowering therapy. 2,024 patients received obicetrapib and1,064, received placebo. Primary endpoints were baseline percent changes in total and small LDL particle numbers, measured by NMR spectroscopy.

Results:
At post-baseline assessment, obicetrapib produced a least-squares mean total LDL particle number reduction of 32.62% (95% CI: -34.49 to -30.75) compared to a 7.51% increase with placebo (95% CI: 4.92 to 10.11%), representing a between-group difference of -40.13% (95% CI: -43.33 to -36.93, P<0.0001). Obicetrapib’s effect on small LDL particles was more pronounced, reducing small LDL particle number by 68.02% (95% CI: -73.90 to -62.14) versus a 32.58% increase with placebo (95% CI: 24.44 to 40.72), yielding a between-group difference of -100.61% (95% CI: -110.65 to -90.57, P<0.0001).
Conclusions:
Obicetrapib significantly reduces both total and small LDL particle numbers, particularly small LDL particles. These LDL particle number reductions exceeded the magnitude observed with conventional lipid-lowering therapies. The reductions in small LDL particles, known to be per particle more atherogenic, may translate into greater cardiovascular benefits than predicted from conventional LDL-C differences alone. These findings support the therapeutic potential of obicetrapib in addressing residual cardiovascular risk through mechanisms that are favorably differentiated from currently available lipid-lowering approaches.