Present therapeutic role of cholesteryl ester transfer protein inhibitors

Ferri, Nicola; Corsini, Alberto; Sirtori, Cesare R.; Ruscica, Massimiliano

doi:10.1016/j.phrs.2017.12.028

Cited by 46 publications

(38 citation statements)

References 138 publications

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“…HDL) to relatively cholesterol-depleted particles (e.g. A second drug, dalcetrapib, increased HDLcholesterol by 30% but had no effect on LDL-cholesterol or CVD event rates in people with ACS [37]. In exchange, it transfers triglycerides to triglyceride-depleted particles, i.e.…”

Section: Cholesterol Ester Transfer Protein Inhibitorsmentioning

confidence: 99%

“…very low-density lipoprotein or LDL) [37]. The Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High-Risk for Vascular Outcomes (ACCELERATE) study was abandoned for futility after 1.7 years [37]. LDL.…”

Section: Cholesterol Ester Transfer Protein Inhibitorsmentioning

confidence: 99%

“…HDL) to relatively cholesterol-depleted particles (e.g. very low-density lipoprotein or LDL) [37]. In exchange, it transfers triglycerides to triglyceride-depleted particles, i.e.…”

Section: Cholesterol Ester Transfer Protein Inhibitorsmentioning

confidence: 99%

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Further options for treating lipids in people with diabetes: targeting LDL‐cholesterol and beyond

Wierzbicki

2018

Diabet. Med.

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Diabetes is associated with increased cardiovascular disease (CVD) risk. Previous studies with statins have established that a 1 mmol/l reduction in LDL-cholesterol reduces CVD events by 21% over 5 years in people with diabetes. More recently, trials in people with acute coronary syndromes showed that ezetimibe reduced CVD events by 6% at 5 years and achieved a LDL-cholesterol of 1.6 mmol/l with better results in people with Type 2 diabetes. Several novel lipid-lowering therapies have recently been developed. Most data have been accumulated with proprotein convertase subtilisin kexin-9 (PCSK-9) inhibitors, which reduce LDL-cholesterol by 50-55%. A large CVD outcome trial with evolocumab, in which 40% of participants had diabetes, achieved a LDL-cholesterol of 0.8 mmol/l and showed a consistent 20% relative risk reduction within 2 years, including in people with diabetes. Trials to increase HDL-cholesterol using cholesterol ester transfer protein (CETP) inhibitors have generally underwhelmed. Although anacetrapib reduced coronary ischaemic events by 7% in a population with chronic CVD, more expansive CVD endpoints were not improved. The complex nature of CETP inhibitor trial outcomes means that these compounds are not being developed further. Trials targeting inflammation-associated lipids have been generally unsuccessful but recent data on the interleukin-1B receptor antagonist canakinumab have shown a reduction in acute coronary intervention, validating this target although at the cost of increased infections. The ability to achieve low LDL-cholesterol with off-patent medications and the costs of novel therapies will confine the use of novel agents to subgroups of people at highest risk of CVD.

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Section: Cholesterol Ester Transfer Protein Inhibitorsmentioning

confidence: 99%

Section: Cholesterol Ester Transfer Protein Inhibitorsmentioning

confidence: 99%

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Further options for treating lipids in people with diabetes: targeting LDL‐cholesterol and beyond

Wierzbicki

2018

Diabet. Med.

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“…Inhibiting the cholesteryl ester transfer protein (CETP), a protein that facilitates the transfer of cholesteryl esters from HDL to LDL, seems to be effective in increasing plasma HDL cholesterol levels . However, the exact value of inhibiting CETP and its effect on lipoproteins as a therapeutic tool for reducing cardiovascular risk remains unclear due to lack of efficacy and unwanted effects in phase 3 clinical trials . One of the first large clinical outcome trials with a CETP inhibitor was prematurely ended due to increased mortality and cardiac events in patients receiving the CETP inhibitor torcetrapib.…”

mentioning

confidence: 99%

“…Chemical structure of DRL-17822. lack of efficacy and unwanted effects in phase 3 clinical trials. [7][8][9][10][11] One of the first large clinical outcome trials with a CETP inhibitor was prematurely ended due to increased mortality and cardiac events in patients receiving the CETP inhibitor torcetrapib. Torcetrapib substantially increased HDL and decreased LDL compared to baseline, but also increased blood pressure, serum sodium, bicarbonate, and aldosterone and decreased serum potassium.…”

mentioning

confidence: 99%

Effect of Food on the Pharmacokinetics of 2 Formulations of DRL‐17822, a Novel Selective Cholesteryl Ester Transfer Protein (CETP) Inhibitor, in Healthy Males

Kruithof

Kumar

Stevens

et al. 2019

Clinical Pharm in Drug Dev

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DRL‐17822 is a novel selective cholesteryl ester transfer protein inhibitor that showed an increased exposure, including an increase of >20‐fold of maximum concentration and area under the plasma concentration–time curve from time zero to the time of the last quantifiable concentration, following a high‐fat breakfast using a nanocrystal formulation. To reduce this effect of food, we generated an amorphous solid dispersion formulation. In this study, we compared the food effect of both formulations of DRL‐17822 in a 2‐part randomized, open‐label, 4‐way crossover study involving healthy adult males 18‐45 years of age. In both parts of the study, 12 subjects received both formulations of DRL‐17822 in both the fasted and fed states; a low‐fat breakfast was provided in the first part and a high‐fat breakfast in the second part. Compared to the nanocrystal formulation, the amorphous solid dispersion formulation substantially increased DRL‐17822 exposure in the fasted state, including increased maximum concentration, area under the plasma concentration–time curve from time zero to the time of the last quantifiable concentration, and area under plasma concentration–time curve from time zero to infinity. Following a high‐fat breakfast, DRL‐17822 exposure was increased to a lesser extent in the amorphous solid dispersion formulation compared to the nanocrystal formulation (P < .001). Moreover, compared to the nanocrystal formulation the amorphous solid dispersion formulation caused a more pronounced increase in high‐density lipoprotein in the fasted state. Consuming breakfast increased the effect of DRL‐17822 on high‐density lipoprotein. Taken together, our results indicate that by improving its formulation, DRL‐17822 has a favorable exposure profile and therefore a more predictable food effect profile.

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Atherosclerosis: Cholesterol Management

Edmondson

Burnett²,

Davis

2021

Burger's Medicinal Chemistry and Drug Discovery

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Cardiovascular disease (CVD) is the most common cause of death in the United States and the industrialized world. The principal components of CVD are coronary heart disease (CHD), stroke, heart failure, and congenital heart disorders. Atherosclerosis, the chronic inflammatory arterial wall disease associated with the deposition of cholesterol into arterial plaques and hardening of the arteries, is a major contributor to CHD and is the principal cause of heart attacks and stroke. The risk factor most closely associated with a higher incidence of CHD is serum cholesterol levels. This report summarizes efforts in the pharmaceutical industry to manage cholesterol levels to reduce risk for CHD due to atherosclerosis.

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Present therapeutic role of cholesteryl ester transfer protein inhibitors

Cited by 46 publications

References 138 publications

Further options for treating lipids in people with diabetes: targeting LDL‐cholesterol and beyond

Further options for treating lipids in people with diabetes: targeting LDL‐cholesterol and beyond

Effect of Food on the Pharmacokinetics of 2 Formulations of DRL‐17822, a Novel Selective Cholesteryl Ester Transfer Protein (CETP) Inhibitor, in Healthy Males

Atherosclerosis: Cholesterol Management

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