Abstract Body (Do not enter title and authors here): Background and aims
Regression of pre-existing atherosclerotic vascular disease has only been observed with aggressive lipid lowering therapy. Therefore, the aim of the present study is to evaluate the effect of the novel cholesterol ester transfer protein (CETP) inhibitor obicetrapib in combination with the intestinal cholesterol absorption inhibitor ezetimibe on top of high dose atorvastatin as a potent combination for regression of established atherosclerosis in APOE*3Leiden.CETP mice, a translational mouse model for hyperlipidemia and atherosclerosis.

Methods
Female APOE*3-Leiden.CETP transgenic mice were fed a Western-type diet (WTD) with 0.3% w/w cholesterol for 12 weeks to induce atherosclerosis. Hereafter, an initial/baseline control group was sacrificed and the remaining mice were divided into 4 groups and treated with WTD with 0.05% w/w cholesterol (equivalent to daily human intake) or this diet containing atorvastatin (5 mg/kg bw/d), obicetrapib (2 mg/kg/day) + ezetimibe (0.6 mg/kg/day) or the combination of atorvastatin, obicetrapib and ezetimibe for 24 weeks. Effects on plasma lipids and atherosclerotic lesion size were assessed.

Results
After 24 weeks of treatment atorvastatin alone, the combo treatment of obicetrapib + ezetimibe and the triple combo treatment of obicetrapib + ezetimibe + atorvastatin reduced total plasma cholesterol levels (-40%, -58% and -76%, all p<0.001; respectively), mainly attributed to a decrease in non-HDL-C levels (-41%, -73% and -88%, all p<0.001; respectively). Triple combo treatment decreased non-HDL-C to 50 mg/dL. Obicetrapib + ezetimibe combo and the triple combo treatment nearly completely blocked CETP activity resulting in increased HDL-C levels (+161% and +95%, all p <0.001; respectively). Mono-treatment with atorvastatin reduced progression of atherosclerosis (-28%, p=0.001, versus control) and the obicetrapib + ezetimibe combo treatment completely blocked progression. Obicetrapib + ezetimibe + atorvastatin triple combo treatment regressed lesion size as compared to baseline (-44%, p=0.032), thereby diminishing lesion severity and increasing the lesion-free area. Compared to atorvastatin monotreatment, triple combo treatment further reduced lesion size (-60%, p<0.001).

Conclusions
High-intensive cholesterol-lowering triple combo treatment with obicetrapib + ezetimibe on top of atorvastatin robustly decreases non-HDL-C and regresses atherosclerotic lesion area in APOE*3Leiden.CETP mice.