Anacetrapib as lipid-modifying therapy in patients with heterozygous familial hypercholesterolaemia (REALIZE): a randomised, double-blind, placebo-controlled, phase 3 study

Kastelein, John J.P.; Besseling, Joost; Shah, Sukrut; Bergeron, Jean; Langslet, Gisle; Hovingh, G. Kees; Al-Saady, N.; Koeijvoets, Michiel; Hunter, John; Johnson‐Levonas, Amy O.; Fable, Jennifer; Sapre, Aditi; Mitchel, Yale

doi:10.1016/s0140-6736(14)62115-2

Cited by 91 publications

(54 citation statements)

References 28 publications

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“…115 The REALIZE study (Randomized Evaluation of Anacetrapib Lipid-Modifying Therapy in Patients with Heterozygous Familial Hypercholesterolemia) enrolled 306 subjects with FH and randomized them to treatment with anacetrapib 100 mg daily on top of background statin therapy. 116 Lipid and lipoprotein changes were consistent with other trials of anacetrapib, but a nonsignificant increase in CVD events was noted. Another CETPi in development, TA-8895, has been tested in a phase IIb trial with 364 dyslipidemia patients and demonstrate LDL-C lowering of ≤68% in combination with a statin, whereas raising HDL-C ≤179% and decreasing Lp(a) ≤37%.…”

Section: Cetpisupporting

confidence: 83%

From Lipids to Inflammation

Shapiro

Fazio

2016

Circulation Research

177

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Abstract:The introduction of statins ≈30 years ago ushered in the era of lipid lowering as the most effective way to reduce risk of atherosclerotic cardiovascular disease. Nonetheless, residual risk remains high, and statin intolerance is frequently encountered in clinical practice. After a long dry period, the field of therapeutics targeted to lipids and atherosclerosis has entered a renaissance. Moreover, the demonstration of clinical benefits from the addition of ezetimibe to statin therapy in subjects with acute coronary syndromes has renewed the enthusiasm for the cholesterol hypothesis and the hope that additional agents that lower low-density lipoprotein will decrease risk of atherosclerotic cardiovascular disease. Drugs in the orphan disease category are now available for patients with the most extreme hypercholesterolemia. Furthermore, discovery and rapid translation of a novel biological pathway has given rise to a new class of cholesterol-lowering drugs, the proprotein convertase subtilisin kexin-9 inhibitors. Trials of niacin added to statin have failed to demonstrate cardiac benefits, and 3 cholesterol ester transfer protein inhibitors have also failed to reduce atherosclerotic cardiovascular disease risk, despite producing substantial increases in HDL levels.

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Section: Cetpisupporting

confidence: 83%

From Lipids to Inflammation

Shapiro

Fazio

2016

Circulation Research

177

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“…Human genetic studies positively correlated CETP and LDL-C levels (20). In fact, CETP inhibition is now recognized as an LDL-C lowering therapy, although its clinical impact on cardiovascular outcomes needs to be clarified (23). The new CETP inhibitor K-312 decreased LDL-C in animal models.…”

Section: Discussionmentioning

confidence: 99%

New CETP inhibitor K-312 reduces PCSK9 expression: a potential effect on LDL cholesterol metabolism

Miyosawa

Watanabe

Murakami

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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Despite significant reduction of cardiovascular events by statin treatment, substantial residual risk persists, driving emerging needs for the development of new therapies. We identified a novel cholesteryl ester transfer protein (CETP) inhibitor, K-312, that raises HDL and lowers LDL cholesterol levels in animals. K-312 also suppresses hepatocyte expression of proprotein convertase subtilisin/kexin 9 (PCSK9), a molecule that increases LDL cholesterol. We explored the underlying mechanism for the reduction of PCSK9 expression by K-312. K-312 inhibited in vitro human plasma CETP activity (IC50; 0.06 M). Administration of K-312 to cholesterol-fed New Zealand White rabbits for 18 wk raised HDL cholesterol, decreased LDL cholesterol, and attenuated aortic atherosclerosis. Our search for additional beneficial characteristics of this compound revealed that K-312 decreases PCSK9 expression in human primary hepatocytes and in the human hepatoma cell line HepG2. siRNA silencing of CETP in HepG2 did not compromise the suppression of PCSK9 by K-312, suggesting a mechanism independent of CETP. In HepG2 cells, K-312 treatment decreased the active forms of sterol regulatory element-binding proteins (SREBP-1 and -2) that regulate promoter activity of PCSK9. Chromatin immunoprecipitation assays demonstrated that K-312 decreased the occupancy of SREBP-1 and SREBP-2 on the sterol regulatory element of the PCSK9 promoter. PCSK9 protein levels decreased by K-312 treatment in the circulating blood of cholesterol-fed rabbits, as determined by two independent mass spectrometry approaches, including the recently developed, highly sensitive parallel reaction monitoring method. New CETP inhibitor K-312 decreases LDL cholesterol and PCSK9 levels, serving as a new therapy for dyslipidemia and cardiovascular disease. cholesteryl ester transfer protein; proprotein convertase subtilisin/ kexin 9; atherosclerosis; sterol regulatory element-binding protein; lipoproteins; mass spectrometry; parallel reaction monitoring

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“…33 Treatment with CETP inhibitor (100 mg of anacetrapib/day) for 52 weeks has been shown to reduce LDL-cholesterol by 30% and elevate HDL-cholesterol levels 2-fold. 34 Treatment with 150 mg of anacetrapib for 8 weeks was shown to have the same beneficial effect in the form of 1.4-fold higher apoA-I level and 30% lower apo-B level. 35 In the same context, the current results show that PCO-rHDL possesses much higher CETP inhibitory activity than rHDL 20 alone, which showed 10% inhibition at 1.7 M apoA-I.…”

Section: Page 18 Of 40mentioning

confidence: 92%

Enhancement of High-Density Lipoprotein Cholesterol Functions by Encapsulation of Policosanol Exerts Anti-Senescence and Tissue Regeneration Effects Via Improvement of Anti-Glycation, Anti-Apoptosis, and Cholesteryl Ester Transfer Inhibition

Lim

Yoo

Lee

et al. 2016

Rejuvenation Research

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Consumption of policosanol (PCO), a refined mixture of sugar cane wax alcohols, can elevate serum levels of high-density lipoprotein cholesterol (HDL-C), although the molecular mechanism is still unknown. To investigate the mechanism of action responsible for the anti-senescence effects of PCO on lipoprotein metabolism and HDL functionality, we synthesized reconstituted HDL (rHDL) containing PCO. Encapsulation of PCO by rHDL (PCO-rHDL) enhanced anti-oxidant activity against cupric ion-mediated low-density lipoprotein (LDL) oxidation. PCO-rHDL (final concentration, 9 μM PCO) showed more potent anti-oxidant activity than vitamin C treatment (final concentration, 100 μM). PCO-rHDL inhibited fructose-mediated glycation, which is a major pathological mechanism of diabetic complications, in a dose-dependent manner. PCO also showed cytoprotective effects in monocytes and macrophages with less triggering of apoptotic processes and reactive oxygen species (ROS) production in the presence of hydrogen peroxide (H2O2). PCO-rHDL strongly inhibited uptake of acetylated LDL into macrophages, which is an initial atherosclerotic process. Surprisingly, PCO-rHDL inhibited human serum cholesteryl ester transfer protein (CETP) activity by up to 47% (final concentration, 10 μM PCO). Subcutaneous injection of PCO-rHDL dose-dependently enhanced tissue regeneration activity by 2.4-fold and 3.6-fold compared to that of the phosphate-buffered saline (PBS) control. In conclusion, PCO in HDL showed potent anti-oxidant, anti-glycation, and CETP inhibitory activities along with tissue regenerative activity, especially upon incorporation into HDL. These results suggest that PCO can enhance functionality of HDL in serum to exert anti-senescence and longevity effects.

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Anacetrapib as lipid-modifying therapy in patients with heterozygous familial hypercholesterolaemia (REALIZE): a randomised, double-blind, placebo-controlled, phase 3 study

Cited by 91 publications

References 28 publications

From Lipids to Inflammation

From Lipids to Inflammation

New CETP inhibitor K-312 reduces PCSK9 expression: a potential effect on LDL cholesterol metabolism

Enhancement of High-Density Lipoprotein Cholesterol Functions by Encapsulation of Policosanol Exerts Anti-Senescence and Tissue Regeneration Effects Via Improvement of Anti-Glycation, Anti-Apoptosis, and Cholesteryl Ester Transfer Inhibition

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