CETP inhibition with dalcetrapib differentially affects cholesterol absorption when ABCA1 or ApoA1 is mutated

Treatment of Low HDL-C Subjects with the CETP Modulator Dalcetrapib Increases Plasma Campesterol Only in Those Without ABCA1 and/or ApoA1 Mutations.

Literature - Niesor EJ et al., Lipds Oct 2014

Niesor EJ, Kallend D, Bentley D et al.
Lipids. 2014 Oct 4. [Epub ahead of print]


Cholesterol absorption is thought to partly occur through the intestinal ATP-binding cassette transporter A1 (ABCA1) expressed on enterocytes, although its precise role in HDL homeostasis is unclear [1,2]. Experimental evidence suggests that uptake of cholesterol into HDL via ABCA1 may facilitate efficient absorption of cholesterol into HDL and its delivery to the liver. 
Dalcetrapib is a cholesteryl ester transfer protein (CETP) modulator increases CETP activity involved in HDL remodelling and generation of pre-β-HDL, the selective acceptor of lipids effluxed by the ABCA1 transporter [3,4]. Both in normolipidaemic hamsters and healthy human volunteers it was observed that dalcetrapib not only raised HDL-c, but also simultaneously increased phytosterol markers of intestinal cholesterol absorption [5]. It was hypothesised that HDL particles may be partly lapidated with phytosterol of intestinal origin. High phytosterol levels were indeed found in patients with high HDL-c levels [6].
This study therefore investigated whether apoliprotein (Apo) A1 and ABCA1 are determinants of plasma phytosterol levels. Campesterol (sterol marker of intestinal origin) was measured, as well as lathosterol (marker from endogenous cholesterol synthesis). Patients treated with dalcetrapib with low HDL-c due to familial hypoalphalipoproteinemia (FHA), with mutations in ABCA1 or APOA1 were compared with patients with familial combined hyperlipidemia (FCH), in which there is no genetic cause and low HDL-c is secondary to dyslipidaemia.

Main results

  • Patients with FHA (+19.3%, n=19) and with FCH (+18.2%, n=21) showed a similar increase in HDL-c levels with dalcetrapib (both P<0.001 vs. placebo).
  • HDL-free cholesterol and HDL phospholipids were significantly increased in patients with FHA, but not in FCH.
  • ApoA1 was similarly increased in patients with FHA (+13.9%, P<0.0013) and FCH (+12.1%, P<0.005). CETP activity and CETP mass were also similarly affected in FHA (Activity: -31.5, mass: +120.9%) and FCH (activity: -26.6%, mass: +111.9%).
  • Plasma lathosterol did not change significantly with dalcetrapib treatment in either patient group (+3.0 in FHA and +9.4% in FCH).
  • Plasma campesterol did not change in patients with FHA (+3.8%), but in patients with FCH a striking increase was seen (+25.0%, P<0.0001 vs placebo).


Lowering CETP activity with dalcetrapib in patients with low levels of HDL-c yielded similar increases in HDL-c and ApoA1 levels, irrespective of the presence of identified mutations in ABCA1 or ApoA1.
The observed changes in phytosterols in this study tend to support the hypothesis that the ABCA1-ApoA1 axis is central to the lipidation of nascent HDL by ABCA1 and that it contributes to the intestinal absorption of cholesterol and phytosterols, since patients with FHA did not show an increase of campesterol. It appears that FCH patients have normal cholesterol balance, despite low HDL-c, while gene mutations that affect HDL generation and/or remodelling (in ApoA1, ABCA1, lecithin-cholesterol acyltransferase) are more important determinants of sterol balance than plasma HDL-c.

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1. Brunham LR, Kruit JK, Iqbal J, et al. (2006) Intestinal ABCA1 directly contributes to HDL biogenesis in vivo. J Clin Investig116:1052–1062
2. Brunham LR, Kruit JK, Pape TD, et al.(2006) Tissue-specific induction of intestinal ABCA1 expression with a liver X receptor agonist raises plasma HDL cholesterol levels. Circ Res 99:672–674
3. Niesor EJ, Magg C, Ogawa N, et al (2010) Modulating cholesteryl ester transfer protein activity maintains efficient pre-beta-HDL formation and increases reverse cholesterol transport. J Lipid Res 51:3443–3454
4. Maugeais C, Perez A, von der Mark E, et al. (2013) Evidence for a role of CETP in HDL remodelling and cholesterol efflux: role of cysteine 13 of CETP. Biochim Biophys Acta 1831:1644–1650
5. Niesor EJ, Chaput E, Staempfli A, et al.(2011) Effect of dalcetrapib, a CETP modulator, on non-cholesterol
sterol markers of cholesterol homeostasis in healthy subjects. Atherosclerosis 219:761–767
6. Nunes VS, Leanca CC, Panzoldo NB, et al. (2011) HDL-C concentration is related to markers of absorption and of cholesterol synthesis: study in subjects with low vs. high HDL-C. Clin Chim Acta 412:176–180

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