Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome

Schwartz, Gregory G.; Olsson, Anders; Abt, Markus; Ballantyne, Christie M.; Barter, Philip J.; Brumm, Jochen; Chaitman, Bernard R.; Holme, Ingar; Kallend, David; Leiter, Lawrence A.; Leitersdorf, Eran; McMurray, John J.V.; Mundl, Hardi; Nicholls, Stephen J.; Shah, Prediman K.; Tardif, Jean‐Claude; Wright, R. Scott

doi:10.1056/nejmoa1206797

Cited by 1,763 publications

(1,101 citation statements)

References 34 publications

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“…As reported in our previous report [5], the luciferase activity was detected in HepG2 cells when used pGL3-Basic vector inserted with 5'-flanking region of Y2R gene containing rs6857530GG plus rs6857715TT but not rs6857530AA plus rs6857715CC. We therefore directly sequenced the 5'-flanking region of Y2R gene in HepG2 cells.…”

Section: Discussionsupporting

confidence: 74%

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Blockade of the neuropeptide Y Y2 receptor with the potent antagonist BIIE0246 regulates gene expression levels in the lipid metabolic pathways in human hepatoma cell line HepG2

Kaji¹,

Okada²,

Hamaue³

et al. 2016

Integr Mol Med

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Neuropeptide Y (NPY) and NPY Y2 receptor (Y2R) is involved in the stress-induced visceral obesity in mice. We have previously reported the association between 5'-flanking region of Y2R gene SNPs and plasma HDL-cholesterol levels in healthy subjects. Plasma HDL-cholesterol levels were significantly different in subjects with each SNPs (rs6857530; GG1.5-fold) 743 entities, and down-regulated (<0.67-fold) 492 entities of 54,675 probe sets. BIIE0246-upregulated genes significantly (P-value<0.001) related to gene ontology (GO) categories of 3 biological processes, 7 cellular components and 1 molecular function. Three biological processes were chylomicron remodeling, negative regulation of cholesterol and sterol transport. BIIE0246-downregulated genes significantly related to GO categories of 44 biological processes, 11 cellular components and 1 molecular function. Furthermore, BIIE0246-downregulated genes were significantly involved in 44 pathways (P<0.01), in which sterol responsive element binding protein signaling were included. BIIE0246-upregulated genes were significantly involved in 22 pathways including vitamin B12/ lipoprotein metabolism (P=0.0048). These results suggest that Y2R blockade might inhibit cholesterol synthesis and raise plasma HDL-cholesterol levels, suggesting a new therapeutic drug for dyslipidemia in subjects with specific Y2R SNPs.

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Section: Discussionsupporting

confidence: 74%

“…Recently, the clinical trial of cholesterol ester transfer protein (CETP) inhibitor could raise plasma HDL-cholesterol levels but not improve cardiovascular events [5]. HDL has a variety of functions such as reverse transport of cholesterol to the liver, anti-oxidation, antiinflammation and immune functions [6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Blockade of the neuropeptide Y Y2 receptor with the potent antagonist BIIE0246 regulates gene expression levels in the lipid metabolic pathways in human hepatoma cell line HepG2

Kaji¹,

Okada²,

Hamaue³

et al. 2016

Integr Mol Med

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show abstract

“…The validity of HDL as a surrogate for cardiovascular risk has recently been questioned (Tuteja and Rader, 2014), and initial efforts to develop CETP inhibitors for increasing HDL levels clinically have been hampered either by unwanted side effects, such as blood pressure increases caused by Pfizer's torcetrapib (Barter et al, 2007), or by lack of efficacy, as was the case for Roche's dalcetrapib (Schwartz et al, 2012) and Lilly's evacetrapib (Nicholls et al, 2015). Nonetheless, pharmaceutical companies continue to invest significant resources into the development of safe and effective CETP inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Disposition into Adipose Tissue Determines Accumulation and Elimination Kinetics of the Cholesteryl Ester Transfer Protein Inhibitor Anacetrapib in Mice

Hartmann

Kumar

Johns

et al. 2015

Drug Metabolism and Disposition

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The cholesteryl ester transfer protein (CETP) inhibitor anacetrapib exhibits a long terminal half-life (t ½ ) in humans; however, the dispositional mechanisms that lead to this long t ½ are still being elucidated. As it is hypothesized that disposition into adipose tissue and binding to CETP might play a role, we sought to delineate the relative importance of these factors using a preclinical animal model. A multiple-dose pharmacokinetic study was conducted in C57BL6 wild-type (WT) lean, WT diet-induced obese (DIO), natural flanking region (NFR) CETP-transgenic lean, and NFR-DIO mice. Mice were dosed orally with 10 mg/kg anacetrapib daily for 42 days. Drug concentrations in blood, brown and white adipose tissue, liver, and brain were measured up to 35 weeks postdose. During dosing, a 3-to 9-fold accumulation in 72-hour postdose blood concentrations of anacetrapib was observed. Drug concentrations in white adipose tissue accumulated ∼20-to 40-fold, whereas 10-to 17-fold accumulation occurred in brown adipose and approximately 4-fold in liver. Brain levels were very low (<0.1 mM), and a trend of accumulation was not seen. The presence of CETP as well as adiposity seems to play a role in determining the blood concentrations of anacetrapib. The highest blood concentrations were observed in NFR DIO mice, whereas the lowest concentrations were seen in WT lean mice. In adipose and liver tissue, higher concentrations were seen in DIO mice, irrespective of the presence of CETP. This finding suggests that white adipose tissue serves as a potential depot and that disposition into adipose tissue governs the long-term kinetics of anacetrapib in vivo.

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“…Aldosterone can cause cardiovascular injury independently of blood pressure-elevating effects. Data from dalcetrapib trials demonstrated a modest blood pressure-elevating effect (Schwartz et al, 2012), whereas anacetrapib does not seem to influence blood pressure, although clinical trials are still ongoing (Robinson and Frishman, 2014). Variable effects on plasma aldosterone have been demonstrated for these CETP inhibitors (Kontush et al, 2008;Johns et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Cholesteryl Ester-Transfer Protein Inhibitors Stimulate Aldosterone Biosynthesis in Adipocytes through Nox-Dependent Processes

Neves

Cat

Even

et al. 2015

J Pharmacol Exp Ther

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Hyperaldosteronism and hypertension were unexpected side effects observed in trials of torcetrapib, a cholesteryl ester-transfer protein (CETP) inhibitor that increases high-density lipoprotein. Given that CETP inhibitors are lipid soluble, accumulate in adipose tissue, and have binding sites for proteins involved in adipogenesis, and that adipocytes are a source of aldosterone, we questioned whether CETP inhibitors (torcetrapib, dalcetrapib, and anacetrapib) influence aldosterone production by adipocytes. Studies were performed using human adipocytes (SW872), which express CETP, and mouse adipocytes (3T3-L1), which lack the CETP gene. Torcetrapib, dalcetrapib, and anacetrapib increased expression of CYP11B2, CYP11B1, and steroidogenic acute regulatory protein, enzymes involved in mineralocorticoid and glucocorticoid generation. These effects were associated with increased reactive oxygen species formation. Torcetrapib, dalcetrapib, and anacetrapib upregulated signal transducer and activator of transcription 3 (STAT3) and peroxisome proliferation-activated receptor-g, important in adipogenesis, but only torcetrapib stimulated production of chemerin, a proinflammatory adipokine. To determine mechanisms whereby CETP inhibitors mediate effects, cells were pretreated with inhibitors of Nox1/Nox4 [GKT137831; 2-(2-chlorophenyl)-4-[3- sulfonyloxy)acetyl)amino)-benzoic acid]). In torcetrapib-stimulated cells, Nox inhibitors, rotenone, and S3I-201 downregulated CYP11B2 and steroidogenic acute regulatory protein and reduced aldosterone. Dalcetrapib and anacetrapib effects on aldosterone were variably blocked by GKT137831, ML171, rotenone, and S3I-201. In adipocytes, torcetrapib, dalcetrapib, and anacetrapib inhibit enzymatic pathways responsible for aldosterone production through Nox1/Nox4-and mitochondrial-generated reactive oxygen species and STAT3. CETP inhibitors also influence adipokine production. These processes may be CETP independent. Our findings identify novel adipocyte-related mechanisms whereby CETP inhibitors increase aldosterone production. Such phenomena may contribute to hyperaldosteronism observed in CETP inhibitor clinical trials.

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Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome

Cited by 1,763 publications

References 34 publications

Blockade of the neuropeptide Y Y2 receptor with the potent antagonist BIIE0246 regulates gene expression levels in the lipid metabolic pathways in human hepatoma cell line HepG2

Blockade of the neuropeptide Y Y2 receptor with the potent antagonist BIIE0246 regulates gene expression levels in the lipid metabolic pathways in human hepatoma cell line HepG2

Disposition into Adipose Tissue Determines Accumulation and Elimination Kinetics of the Cholesteryl Ester Transfer Protein Inhibitor Anacetrapib in Mice

Cholesteryl Ester-Transfer Protein Inhibitors Stimulate Aldosterone Biosynthesis in Adipocytes through Nox-Dependent Processes

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