Unlike torcetrapib, dalcetrapib shifts cholesterol homeostasis toward absorption markers rather than synthesis markers (Atherosclerosis 2011)

Original title: Effect of dalcetrapib, a CETP modulator, on non-cholesterol sterol markers of cholesterol homeostasis in healthy subjects

Atherosclerosis · 16 September 2011 · 6

Niesor EJ, Chaput E, Staempfli A, Blum D, Derks M, Kallend D

In a randomized, open-label, crossover study of 22 healthy subjects given dalcetrapib 900 mg, ezetimibe 10 mg, or both over three 7-day periods, dalcetrapib alone increased the cholesterol-absorption markers campesterol, beta-sitosterol, and cholestanol by 27%, 32%, and 12% respectively, while leaving the synthesis markers lathosterol and desmosterol unchanged. Combining dalcetrapib with ezetimibe reduced campesterol by 11%. In hamsters, dalcetrapib and torcetrapib increased HDL cholesterol by 49% and 72% respectively, but only dalcetrapib shifted cholesterol homeostasis toward absorption markers, with synthesis markers unaffected by either drug. Dalcetrapib also increased the fraction of labeled cholesterol appearing in plasma HDL versus non-HDL after oral dosing, suggesting the absorption-marker rise reflects nascent HDL lipidation by intestinal ABCA1.

Original abstract

Objective: Subjects with high HDL-C show elevated plasma markers of cholesterol absorption and reduced markers of cholesterol synthesis. We evaluated the effect of dalcetrapib, a cholesteryl ester transfer protein modulator, on markers of cholesterol homeostasis in healthy subjects.

Methods: Dalcetrapib was administered daily with or without ezetimibe in a randomized, open-label, crossover study in 22 healthy subjects over three 7-day periods: dalcetrapib 900 mg, ezetimibe 10mg, dalcetrapib 900 mg plus ezetimibe 10mg. Plasma non-cholesterol sterols lathosterol and desmosterol (cholesterol synthesis markers) and campesterol, β-sitosterol and cholestanol (intestinal cholesterol absorption markers) were measured. A hamster model was used to compare the effect of dalcetrapib and torcetrapib with or without ezetimibe on these markers and determine the effect of dalcetrapib on cholesterol absorption.

Results: Dalcetrapib increased campesterol, β-sitosterol, and cholestanol by 27% (p = 0.001), 32% (p < 0.001), and 12% (p = 0.03), respectively, in man (non-cholesterol sterol/cholesterol ratio). Dalcetrapib+ezetimibe reduced campesterol by 11% (p = 0.02); β-sitosterol and cholestanol were unaffected. Lathosterol and desmosterol were unchanged with dalcetrapib, but both increased with ezetimibe alone (56-148%, p < 0.001) and with dalcetrapib + ezetimibe (32-38%, p < 0.001). In hamsters, dalcetrapib and torcetrapib increased HDL-C by 49% (p = 0.04) and 72% (p = 0.003), respectively. Unlike torcetrapib, dalcetrapib altered cholesterol homeostasis towards increased markers of cholesterol absorption; cholesterol synthesis markers were unaffected by either treatment. Dalcetrapib did not change plasma (3)H-cholesterol level but increased (3)H-cholesterol in plasma HDL vs non-HDL, after oral dosing of labeled cholesterol.

Conclusion: Dalcetrapib specifically increased markers of cholesterol absorption, most likely reflecting nascent HDL lipidation by intestinal ABCA1, without affecting markers of synthesis.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.