Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: two double-blind, randomised placebo-controlled phase I studies

Krishna, Rajesh; Anderson, Matt S.; Bergman, Arthur; Jin, Bo; Fallon, Marissa S.; Côté, Josée; Rosko, Kim; Chavez‐Eng, Cynthia; Lutz, Ryan; Bloomfield, Daniel M.; Gutiérrez, María J.; Doherty, James; Bieberdorf, Fredrick; Chodakewitz, Jeffrey A.; Gottesdiener, Keith; Wagner, John A.

doi:10.1016/s0140-6736(07)61813-3

Cited by 264 publications

(207 citation statements)

References 28 publications

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“…More potent and highly selective CETP inhibitors are being developed. For instance, anacetrapib increases levels of HDL-C and decreases levels of both LDL-C and apoB-100 (89,90), and, when added to statin treatment, results in further reductions in LDL-C (91,92). Anacetrapib treatment also increases the LDL TG/cholesterol ratio and LDL size and increases LDL-apoB-100 clearance (93).…”

Section: Cholesteryl Ester Transfer Protein Inhibitorsmentioning

confidence: 99%

Pharmacological Targeting of the Atherogenic Dyslipidemia Complex: The Next Frontier in CVD Prevention Beyond Lowering LDL Cholesterol

et al. 2016

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Notwithstanding the effectiveness of lowering LDL cholesterol, residual CVD risk remains in high-risk populations, including patients with diabetes, likely contributed to by non-LDL lipid abnormalities. In this Perspectives in Diabetes article, we emphasize that changing demographics and lifestyles over the past few decades have resulted in an epidemic of the "atherogenic dyslipidemia complex," the main features of which include hypertriglyceridemia, low HDL cholesterol levels, qualitative changes in LDL particles, accumulation of remnant lipoproteins, and postprandial hyperlipidemia. We briefly review the underlying pathophysiology of this form of dyslipidemia, in particular its association with insulin resistance, obesity, and type 2 diabetes, and the marked atherogenicity of this condition. We explain the failure of existing classes of therapeutic agents such as fibrates, niacin, and cholesteryl ester transfer protein inhibitors that are known to modify components of the atherogenic dyslipidemia complex. Finally, we discuss targeted repurposing of existing therapies and review promising new therapeutic strategies to modify the atherogenic dyslipidemia complex. We postulate that targeting the central abnormality of the atherogenic dyslipidemia complex, the elevation of triglyceriderich lipoprotein particles, represents a new frontier in CVD prevention and is likely to prove the most effective strategy in correcting most aspects of the atherogenic dyslipidemia complex, thereby preventing CVD events.

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Section: Cholesteryl Ester Transfer Protein Inhibitorsmentioning

confidence: 99%

Pharmacological Targeting of the Atherogenic Dyslipidemia Complex: The Next Frontier in CVD Prevention Beyond Lowering LDL Cholesterol

et al. 2016

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“…108 The reason for this is not completely known but may relate to a change in the delivery of cholesterol to the liver on plasma lipoproteins. Cholesterol delivered to the liver on HDL is thought to be targeted for biliary excretion whereas delivery on LDL is thought to enter the cholesterol regulatory pool where it can be re-secreted on VLDL.…”

Section: Cetp Inhibitorsmentioning

confidence: 99%

Overview of the LDL receptor: relevance to cholesterol metabolism and future approaches for the treatment of coronary heart disease

Lagor¹,

Millar²

2009

JRLCR

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“…Furthermore, a manufacturer-sponsored phase 1 randomized controlled trial of a different CETP inhibitor, ancetrapib, found no effect on blood pressure despite a large reduction in CETP levels. 12 In that double-blind, placebo-controlled crossover study of healthy normotensive adults, effects on 24-hour average ambulatory systolic and diastolic blood pressures were tested on the last day of a 10-day course of treatment. The study was adequately powered to detect a 6-mm Hg difference in systolic or diastolic blood pressure.…”

Section: Discussionmentioning

confidence: 99%

Cholesteryl Ester Transfer Protein (CETP) Genotype and Reduced CETP Levels Associated With Decreased Prevalence of Hypertension

Schechter

Barzilai

Crandall

et al. 2010

Mayo Clinic Proceedings

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A decrease in cholesteryl ester transfer protein (CETP) leads to increased high-density lipoprotein (HDL) cholesterol levels and lipoprotein particle size, which may provide significant cardiovascular protection. 1 Earlier work by our group has shown that homozygosity for a single nucleotide polymorphism (SNP), resulting in substitution of valine (V) for isoleucine (I) at codon 405 in the CETP gene, is overrepresented in centenarians. 2 Therefore, this finding, validated in an independent study, 3 suggests that this mutation may contribute to healthy aging by protection from several age-related diseases. 4 Individuals homozygous for this SNP have decreased CETP levels, increased HDL cholesterol levels, and increased lipoprotein particle sizes. Homozygosity for this SNP is seen significantly more often in the offspring of parents with exceptional longevity than in the offspring of parents with shorter life spans. 2 CONCluSION: Reduced levels of CETP are associated with lower, not higher, blood pressure. The adverse results with torcetrapib, if mediated through blood pressure, are likely to represent effects of this specific drug, rather than a result of lower CETP levels.Mayo Clin Proc. 2010;85(6):522-526 CETP = cholesteryl ester transfer protein; CI = confidence interval; HDL = high-density lipoprotein; LDL = low-density lipoprotein; SNP = single nucleo tide polymorphism different genotypes, and decreased risk of coronary artery disease. 5 These observations suggest that interventions that reduce CETP levels might promote cardiovascular health and contribute to longevity. Despite the potential cardiovascular benefits of lower CETP levels, a phase 3 trial of torcetrapib, a CETP inhibitor, was terminated early because of increased risk of death due to cardiovascular disease in the active treatment group. 6 Torcetrapib has been associated with increased blood pressure, 7 which is suspected of contributing to the observed increase in mortality. Other investigators have called for investigation of the connection between low CETP levels and blood pressure. 8 To examine whether naturally occurring CETP polymorphism, decreased CETP levels, increased HDL cholesterol levels, and increased lipoprotein particle sizes are associated with increased blood pressure, we analyzed data from our cohorts of older adults. We reasoned that if blood pressure is independent of spontaneous CETP levels, the problems found in the torcetrapib trial may be specific collateral effects of that drug and not generalizable to its pharmacological class. However, if reduction in CETP levels, due to genetic or other causes, is associated with increased blood pressure, beneficial effects of low CETP levels may apply only to those who have lived to old age or it may be that resulting higher blood pressure levels are tolerated because of other beneficial effects. PaTIENTS aND METHoDSRecruitment for the Searching for Longevity Genes in the Historically Unique Ashkenazi Jewish Population study has been described in detail. 2 Briefly, Ashkenazi Jews l...

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Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: two double-blind, randomised placebo-controlled phase I studies

Cited by 264 publications

References 28 publications

Pharmacological Targeting of the Atherogenic Dyslipidemia Complex: The Next Frontier in CVD Prevention Beyond Lowering LDL Cholesterol

Pharmacological Targeting of the Atherogenic Dyslipidemia Complex: The Next Frontier in CVD Prevention Beyond Lowering LDL Cholesterol

Overview of the LDL receptor: relevance to cholesterol metabolism and future approaches for the treatment of coronary heart disease

Cholesteryl Ester Transfer Protein (CETP) Genotype and Reduced CETP Levels Associated With Decreased Prevalence of Hypertension

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