Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients

Bloomfield, Daniel M.; Carlson, Gary; Sapre, Aditi; Tribble, Diane L.; McKenney, James M.; Littlejohn, Thomas; Sisk, Christine McCrary; Mitchel, Yale; Pasternak, Richard C.

doi:10.1016/j.ahj.2008.09.022

Cited by 233 publications

(181 citation statements)

References 25 publications

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“…However, other CETP inhibitors, such as dalcetrapib ( 33 ) and anacetrapib ( 34 ), have now progressed into phase III clinical trials without showing any off-target toxicity. Additionally, niacin effectively increases HDL by 25-30% ( 35 ) and improves carotid intima-media thickness ( 36 ).…”

Section: E3lmentioning

confidence: 99%

CETP expression reverses the reconstituted HDL-induced increase in VLDL

Wang

Berbée

Stroes

et al. 2011

Journal of Lipid Research

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Section: E3lmentioning

confidence: 99%

CETP expression reverses the reconstituted HDL-induced increase in VLDL

Wang

Berbée

Stroes

et al. 2011

Journal of Lipid Research

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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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“…In addition to lowering LDL and raising HDL, the phase 3 Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib trial demonstrated that CETP inhibition by anacetrapib was well tolerated and that anacetrapib was devoid of torcetrapib-like liabilities such as blood pressure increases (Krishna et al, 2008;Bloomfield et al, 2009;Gotto et al, 2014 a,b); however, anacetrapib exhibits complex accumulation and washout kinetics in circulation in humans. As the clinical development of anacetrapib progressed and patients were treated for longer duration, the t ½ appeared to be longer than had been predicted from initial studies with shorter treatment duration.…”

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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Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients

Cited by 233 publications

References 25 publications

CETP expression reverses the reconstituted HDL-induced increase in VLDL

CETP expression reverses the reconstituted HDL-induced increase in VLDL

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

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

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