Cholesterol ester transfer protein inhibition by TA-8995 in patients with mild dyslipidaemia (TULIP): a randomised, double-blind, placebo-controlled phase 2 trial

Hovingh, G. Kees; Kastelein, John J.P.; Deventer, S. J. H. Van; Round, Patrick; Ford, John M.; Saleheen, Danish; Rader, Daniel J.; Brewer, H. Bryan; Barter, Philip J.

doi:10.1016/s0140-6736(15)60158-1

Cited by 181 publications

(118 citation statements)

References 18 publications

Supporting

Mentioning

117

Contrasting

Order By: Relevance

“…ISIS -APO(a) Rx also has the potential to bind to 11 alternative sites within the transcript containing one to four mismatched nucleotides, relative to the active site. The concentration of ISIS -APO(a) Rx that produced an IC 50 of the apo(a) mRNA in LPA transgenic mouse primary hepatocytes was 0.12 M. In cynomolgus monkey primary hepatocytes, the observed IC 50 was 0.49 M. In contrast, the IC 50 values for control ASOs not targeted to the apo(a) mRNA were >10 M in both primary cell isolates (data not shown). Table 2 ).…”

Section: Identification Of a Second Generation Antisense Drug To Humamentioning

confidence: 91%

“…Recent data has demonstrated that Lp(a) can be signifi cantly lowered by 20-40% with ASOs to apoB ( 35 ), monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (46)(47)(48), and cholesterol ester transfer protein inhibitors ( 49,50 ). However, in patients at or above the 80th percentile, corresponding to ‫ف‬ 50 mg/dl plasma Lp(a) concentrations, much greater reduction than is currently achieved with these indirect therapeutic agents would be required to signifi cantly reduce CVD risk, which is thought to occur at levels which exceed [25][26][27][28][29][30] or OxPL-apoB concentrations, consistent with the independence of lowering of Lp(a) and OxPL-apoB on isoform size ( Fig.…”

Section: Alternative Therapies To Lower Lp(a)mentioning

confidence: 99%

See 1 more Smart Citation

Antisense inhibition of apolipoprotein (a) to lower plasma lipoprotein (a) levels in humans

Graham

Viney

Crooke

et al. 2016

Journal of Lipid Research

118

View full text Add to dashboard Cite

Section: Identification Of a Second Generation Antisense Drug To Humamentioning

confidence: 91%

Section: Alternative Therapies To Lower Lp(a)mentioning

confidence: 99%

Antisense inhibition of apolipoprotein (a) to lower plasma lipoprotein (a) levels in humans

Graham

Viney

Crooke

et al. 2016

Journal of Lipid Research

118

View full text Add to dashboard Cite

“…HDLs isolated from people treated with torcetrapib (Yvan-Charvet et al, 2007), anacetrapib (Yvan-Charvet et al, 2010), and TA-8995 (Hovingh et al, 2015) have been shown in ex vivo studies to have a normal or enhanced ability to promote the efflux of cholesterol from macrophages. In a post hoc analysis of the Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events trial, the level of HDL-C achieved in the torcetrapib-treated patients was an inverse predictor of events (Barter, 2009), suggesting that the HDLs were functional.…”

Section: B Therapies That Target High-density Lipoproteinmentioning

confidence: 99%

New Era of Lipid-Lowering Drugs

Barter

Rye

2016

Pharmacol Rev

View full text Add to dashboard Cite

“…The effects of CETP inhibition in humans treated with torcetrapib, 8 dalcetrapib, 9 evacetrapib, 10 anacetrapib, 11 and TA-8995 12 on plasma lipids are summarized in the Table. All of these inhibitors increase the concentration of HDL cholesterol and apolipoprotein A-I. With the exception of dalcetrapib, they also reduce LDL cholesterol and apolipoprotein B levels.…”

Section: What Are the Effects Of Inhibiting Cetp On Plasma Lipids Andmentioning

confidence: 99%

Cholesteryl Ester Transfer Protein Inhibition Is Not Yet Dead—Pro

Barter

Rye

2016

ATVB

View full text Add to dashboard Cite

Abstract-Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from nonatherogenic high-density lipoproteins to potentially proatherogenic non-high-density lipoprotein fractions. Human genetic studies and human cohort studies have concluded that CETP gene polymorphisms associated with decreased CETP activity are accompanied by a significantly lower risk of atherosclerotic cardiovascular disease. Inhibition of CETP in rabbits reduces development of diet-induced atherosclerosis. Inhibition of CETP in humans reduces non-high-density lipoprotein cholesterol while increasing high-density lipoproteins cholesterol, consistent with a reduced risk of having an atherosclerotic cardiovascular disease event. What Are the Effects of Inhibiting CETP on Plasma Lipids and HDL Function in Humans?The effects of CETP inhibition in humans treated with torcetrapib, 8 dalcetrapib, 9 evacetrapib, 10 anacetrapib, 11 and TA-8995 12 on plasma lipids are summarized in the Table. All of these inhibitors increase the concentration of HDL cholesterol and apolipoprotein A-I. With the exception of dalcetrapib, they also reduce LDL cholesterol and apolipoprotein B levels. CETP inhibitors also reduce levels of the proatherogenic lipoprotein (a).Effects of CETP inhibition on HDL function have also been investigated. HDLs isolated from people treated with torcetrapib, 13 anacetrapib, 14 and TA-8995 12 have a normal or enhanced ability to efflux cholesterol from macrophages. TorcetrapibThe effect of torcetrapib on clinical cardiovascular events was investigated in the ILLUMINATE trial that included 15 067 high-risk statin-treated people. 8 Torcetrapib increased HDL cholesterol levels by 72% and decreased LDL cholesterol levels by 25%. This trial was terminated after 18 months because of a statistically significant excess of deaths (93 versus 59) in those treated with torcetrapib. No single cause of death explained the harm caused by torcetrapib. There was also a significant 25% increase in ASCVD events in those taking torcetrapib.The explanation for the harm caused by torcetrapib is not known but may have been the consequence of off-target adverse effects of the drug, including increased blood pressure, 8 increased synthesis, secretion of aldosterone, 1 and increased endothelin-1 levels in the artery wall. 17 DalcetrapibThe effect of dalcetrapib on clinical ASCVD events was investigated in the dal-OUTCOMES study that included 15 871 participants recruited soon after an acute coronary syndrome event.9 Treatment with dalcetrapib increased the concentration of HDL cholesterol by ≈30% but minimally affected LDL cholesterol and apoB levels. Treatment with dalcetrapib did not reduce ASCVD events. 9The failure of the dal-OUTCOMES trial may have been because this agent did not reduce the level of LDL cholesterol. However, it may also have been because this trial was conducted in patients soon after an acute coronary syndrome event at a time when HDL function is compromised.18 This explanation was supported by the observation in the place...

show abstract

Cholesterol ester transfer protein inhibition by TA-8995 in patients with mild dyslipidaemia (TULIP): a randomised, double-blind, placebo-controlled phase 2 trial

Abstract: Dezima.

Cited by 181 publications

References 18 publications

Antisense inhibition of apolipoprotein (a) to lower plasma lipoprotein (a) levels in humans

Antisense inhibition of apolipoprotein (a) to lower plasma lipoprotein (a) levels in humans

New Era of Lipid-Lowering Drugs

Cholesteryl Ester Transfer Protein Inhibition Is Not Yet Dead—Pro

Contact Info

Product

Resources

About