Evaluation of Lipids, Drug Concentration, and Safety Parameters Following Cessation of Treatment With the Cholesteryl Ester Transfer Protein Inhibitor Anacetrapib in Patients With or at High Risk for Coronary Heart Disease

Gotto, Antonio M.; Cannon, Christopher P.; Li, Xiujiang Susie; Vaidya, Sanskruti; Kher, Uma; Brinton, Eliot A.; Davidson, Michael; Moon, Jennifer; Shah, Sukrut; Dansky, Hayes M.; Mitchel, Yale; Barter, Philip J.

doi:10.1016/j.amjcard.2013.08.041

Cited by 80 publications

(69 citation statements)

References 10 publications

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“…First, we previously demonstrated that adipocytes have a functional renin angiotensin aldosterone system and produce aldosterone in a highly regulated manner (Briones et al, 2011(Briones et al, , 2012. Second, CETP inhibitors are lipid soluble and accumulate, to variable degrees, in adipocytes (Dalvie et al, 2008;Gotto et al, 2014). Third, by computational analysis, these drugs were found to bind to several endogenous proteins related to adipogenesis, such as PPARa, PPARb, PPARg, and LXR (Xie et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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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Section: Discussionmentioning

confidence: 99%

“…Considering the fact that CETP inhibitors are lipophilic and may accumulate in adipose tissue (Dalvie et al, 2008;Gotto et al, 2014), we hypothesized that adipocytes may be an extra-adrenal source of CETP inhibitor-induced aldosterone production.…”

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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“…It has been suggested that dalcetrapib-induced increase in HDL-C levels might not have been sufficient or it was not accompanied by an enhancement of the protective properties of HDL (Rader and deGoma, 2014; Toth et al, 2013). Two new CETP inhibitors, anacetrapib and evacetrapib, are much more potent than dalcetrapib and do not have the off-target adverse effects of torcetrapib (Gotto et al, 2014; Nicholls et al, 2011). Outcomes from ongoing large clinical trials with anacetrapib (ClinicalTrials.gov number NCT01252953) and evacetrapib (ClinicalTrials.gov number NCT01687998) are eagerly awaited with high expectations.…”

Section: Hdl-enhancing Pharmacotherapies To Improve Cognitive Functionmentioning

confidence: 99%

HDL and cognition in neurodegenerative disorders

Hottman

Chernick

Cheng

et al. 2014

Neurobiology of Disease

139

129

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High-density lipoproteins (HDL) are a heterogeneous group of lipoproteins composed of various lipids and proteins. HDL is formed both in the systemic circulation and in the brain. In addition to being a crucial player in the reverse cholesterol transport pathway, HDL possesses a wide range of other functions including anti-oxidation, anti-inflammation, pro-endothelial function, anti-thrombosis, and modulation of immune function. It has been firmly established that high plasma levels of HDL protect against cardiovascular disease. Accumulating evidence indicates that the beneficial role of HDL extends to many other systems including the central nervous system. Cognition is a complex brain function that includes all aspects of perception, thought, and memory. Cognitive function often declines during aging and this decline manifests as cognitive impairment/dementia in age-related and progressive neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. A growing concern is that no effective therapy is currently available to prevent or treat these devastating diseases. Emerging evidence suggests that HDL may play a pivotal role in preserving cognitive function under normal and pathological conditions. This review attempts to summarize recent genetic, clinical and experimental evidence for the impact of HDL on cognition in aging and in neurodegenerative disorders as well as the potential of HDL-enhancing approaches to improve cognitive function.

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“…On the other hand, there is also evidence that CETP mutations are associated with an increased incidence of coronary heart diseases4. Despite these inconsistencies and because of the urgent public desire to expand treatment options beyond statins, the most financially successful drug to reduce LDL-C levels to date, CETP has been used as a promising drug target for designing inhibitors in order to treat heart disease5678910. Four large clinical trials of CETP inhibitors58910 have been undertaken to date.…”

mentioning

confidence: 99%

HDL surface lipids mediate CETP binding as revealed by electron microscopy and molecular dynamics simulation

Zhang

Charles

Tong

et al. 2015

Sci Rep

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Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesterol esters (CE) from atheroprotective high-density lipoproteins (HDL) to atherogenic low-density lipoproteins (LDL). CETP inhibition has been regarded as a promising strategy for increasing HDL levels and subsequently reducing the risk of cardiovascular diseases (CVD). Although the crystal structure of CETP is known, little is known regarding how CETP binds to HDL. Here, we investigated how various HDL-like particles interact with CETP by electron microscopy and molecular dynamics simulations. Results showed that CETP binds to HDL via hydrophobic interactions rather than protein-protein interactions. The HDL surface lipid curvature generates a hydrophobic environment, leading to CETP hydrophobic distal end interaction. This interaction is independent of other HDL components, such as apolipoproteins, cholesteryl esters and triglycerides. Thus, disrupting these hydrophobic interactions could be a new therapeutic strategy for attenuating the interaction of CETP with HDL.

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Evaluation of Lipids, Drug Concentration, and Safety Parameters Following Cessation of Treatment With the Cholesteryl Ester Transfer Protein Inhibitor Anacetrapib in Patients With or at High Risk for Coronary Heart Disease

Cited by 80 publications

References 10 publications

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

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

HDL and cognition in neurodegenerative disorders

HDL surface lipids mediate CETP binding as revealed by electron microscopy and molecular dynamics simulation

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