Cholesteryl ester transfer protein inhibition: a pathway to reducing risk of morbidity and promoting longevity DOI Creative Commons
Michael H. Davidson, Andrew Hsieh, John J.P. Kastelein

и другие.

Current Opinion in Lipidology, Год журнала: 2024, Номер 35(6), С. 303 - 309

Опубликована: Окт. 17, 2024

Purpose of review To the evidence and describe biological plausibility for benefits inhibiting cholesteryl ester transfer protein (CETP) on multiple organ systems through modification lipoprotein metabolism. Recent findings Results from observational studies, Mendelian randomization analyses, randomized clinical trials support potential CETP inhibition to reduce atherosclerotic cardiovascular disease (ASCVD) risk a reduction apolipoprotein B-containing lipoproteins. In contrast, raising high-density (HDL) particles, as previously hypothesized, did not contribute ASCVD reduction. There is also an expanding body supporting safeguarding against other conditions associated with aging, particularly new-onset type 2 diabetes mellitus dementia, well age-related macular degeneration, septicemia, possibly chronic kidney disease. The latter are likely mediated improved functionality HDL particle, including its role cholesterol efflux antioxidative, anti-inflammatory, antimicrobial activities. Summary At present, there robust reducing activity reduction, exists promotion longevity by risks several conditions. An ongoing large trial program latest potent inhibitor, obicetrapib, expected provide further insight into therapeutic target these various

Язык: Английский

Obicetrapib on top of maximally tolerated lipid‐modifying therapies in participants with or at high risk for atherosclerotic cardiovascular disease: rationale and designs of BROADWAY and BROOKLYN DOI Creative Commons
Stephen J. Nicholls, Adam J. Nelson, Marc Ditmarsch

и другие.

American Heart Journal, Год журнала: 2024, Номер 274, С. 32 - 45

Опубликована: Май 4, 2024

Obicetrapib, a novel, selective cholesteryl ester transfer protein (CETP) inhibitor, reduces low-density lipoprotein cholesterol (LDL-C), LDL particles, apolipoprotein (Apo) B, and lipoprotein(a) [Lp(a)] increases high-density (HDL-C) when added to statins with or without ezetimibe. By substantially reducing LDL-C, obicetrapib has the potential lower atherogenic lipoproteins in patients atherosclerotic cardiovascular disease (ASCVD) heterozygous familial hypercholesterolemia (HeFH) whose LDL-C levels remain high despite treatment available maximally tolerated lipid-modifying therapies, addressing an unmet medical need patient population at risk for events. BROADWAY (NCT05142722) BROOKLYN (NCT05425745) are ongoing placebo-controlled, double-blind, randomized Phase III trials designed examine efficacy, safety, tolerability of as adjunct dietary intervention therapies participants history ASCVD and/or underlying HeFH is not adequately controlled. The primary efficacy endpoint was percent change from baseline day 84. Other endpoints included changes Apo non-HDL-C, HDL-C, A1, Lp(a) triglycerides addition parameters evaluating tolerability, pharmacokinetics. also adjudicated assessment major adverse events, measurements glucose homeostasis, ambulatory blood pressure monitoring substudy. A total 2532 were 354 receive 10 mg placebo (2:1) 365 days follow-up through 35 after last dose. Results both anticipated 2024. These will provide safety data support use among elevated whom existing sufficiently effective well-tolerated.

Язык: Английский

Процитировано

17
Safety and Efficacy of Obicetrapib in Patients at High Cardiovascular Risk DOI
Stephen J. Nicholls, Adam J. Nelson, Marc Ditmarsch

и другие.

New England Journal of Medicine, Год журнала: 2025, Номер unknown

Опубликована: Май 7, 2025

Obicetrapib is a highly selective cholesteryl ester transfer protein inhibitor that reduces low-density lipoprotein (LDL) cholesterol levels. The efficacy and safety of obicetrapib have not been fully characterized among patients at high risk for cardiovascular events. We conducted multinational, randomized, placebo-controlled trial involving with heterozygous familial hypercholesterolemia or history atherosclerotic disease who were receiving maximum tolerated doses lipid-lowering therapy. Patients an LDL level 100 mg per deciliter higher non-high-density (HDL) 130 higher, as well those 55 to non-HDL 85 least one additional factor, eligible inclusion. randomly assigned in 2:1 ratio receive either 10 once daily matching placebo 365 days. primary end point was the percent change from baseline day 84. A total 2530 underwent randomization; 1686 844 placebo. mean age 65 years, 34% women, 98 deciliter. least-squares 84 -29.9% (95% confidence interval [CI], -32.1 -27.8) group, compared 2.7% CI, -0.4 5.8) between-group difference -32.6 percentage points -35.8 -29.5; P<0.001). incidence adverse events appeared be similar two groups. Among therapy events, reduced levels by 29.9%. (Funded NewAmsterdam Pharma; BROADWAY ClinicalTrials.gov number, NCT05142722.).

Язык: Английский

Процитировано

2
Quo Vadis after AEGIS: New Opportunities for Therapies Targeted at Reverse Cholesterol Transport? DOI Creative Commons
Nick S. R. Lan,

Gerald F. Watts

Current Atherosclerosis Reports, Год журнала: 2025, Номер 27(1)

Опубликована: Фев. 26, 2025

Abstract Purpose of Review High-density lipoprotein (HDL) is integral to reverse cholesterol transport (RCT), a process considered protect against atherosclerotic cardiovascular disease (ASCVD). We summarise findings from the recent AEGIS-II trial and discuss new opportunities for HDL therapeutics targeted at RCT. Recent Findings Mendelian randomisation studies have suggested causal association between functional properties ASCVD. However, CSL112, an apolipoprotein A-I therapy that enhances efflux, did not meet its primary endpoint. Exploratory analyses demonstrated CSL112 significantly reduced ASCVD events among participants with baseline low-density (LDL)-cholesterol ≥ 100 mg/dL, suggesting RCT may depend on LDL-cholesterol levels. Summary The role in patients familial hypercholesterolaemia, inherited low HDL-cholesterol impaired function, especially inadequately controlled LDL-cholesterol, merits further investigation. treatment monogenic defects metabolism remains significant gap care needs research.

Язык: Английский

Процитировано

1
Lipid-lowering effect of combined therapy with high-intensity statins and CETP inhibitors: a Systematic Review and meta-analysis DOI Creative Commons

Liang Xiang,

Huan Wu, Zhihao Zhao

и другие.

Frontiers in Endocrinology, Год журнала: 2025, Номер 16

Опубликована: Май 1, 2025

This study aimed to evaluate the impact of combining high-intensity statins with CETP inhibitors on lipid levels, as well explore their potential clinical significance. We conducted a comprehensive search relevant studies in PubMed, Embase, Cochrane Library, and Web Science databases. The Risk Bias Tool RoB 2.0 was employed quality included studies. Statistical analyses were carried out using STATA 15 software, primary outcomes being high-density lipoprotein cholesterol (HDL-C) low-density (LDL-C). Out 2,552 records, 7 final analysis. findings revealed that combination significantly raised HDL-C levels (SMD 2.47 [1.77, 3.18], p < 0.001) lowered LDL-C -1.75 [-2.19, -1.31], 0.001). Compared statin monotherapy, resulted more pronounced increase ApoAI, while reducing LDL-C, triglycerides (TG), ApoB without increasing incidence adverse events.

Язык: Английский

Процитировано

0
A Randomized, Parallel, Open‐Label, Single‐Dose and Multiple‐Dose Clinical Trial to Investigate the Pharmacokinetic, Pharmacodynamic, and Safety Profiles of Obicetrapib in Healthy Participants in China DOI Creative Commons
Jing Zhang, Guoying Cao, Yong Huo

и другие.

The Journal of Clinical Pharmacology, Год журнала: 2024, Номер unknown

Опубликована: Авг. 19, 2024

Obicetrapib is a selective cholesteryl ester transfer protein (CETP) inhibitor. Previous research has demonstrated similar pharmacokinetic (PK) responses to single doses of obicetrapib between Japanese and White males, but the PK have not been established in Chinese individuals. The purpose this randomized, parallel, open-label trial was characterize pharmacodynamic (PD; CETP activity plasma lipids) safety (5, 10, or 25 mg; N = 36) multiple (10 mg for 14 days; 12) healthy maximum concentration area under drug concentration-time curve from 0 h infinity increased with dose after all obicetrapib. After 7 consecutive days dosing, low-density lipoprotein cholesterol high-density reached their minimum changes 42% reduction 108% increase, respectively. Primary PD parameters single- multiple-dose administration were those white participants previous studies. One participant 5 group experienced treatment-emergent adverse event decreased blood cell neutrophil counts, which resolved without intervention. In conclusion, these findings support inclusion individuals ongoing phase 3 clinical development program

Язык: Английский

Процитировано

2
Obicetrapib: There is still Life in the CETP Inhibitor! DOI Open Access
Masatsune Ogura

Journal of Atherosclerosis and Thrombosis, Год журнала: 2024, Номер unknown

Опубликована: Янв. 1, 2024

Язык: Английский

Процитировано

1
Obicetrapib exhibits favorable physiochemical and pharmacokinetic properties compared to previous cholesteryl ester transfer protein inhibitors: An integrated summary of results from non‐human primate studies and clinical trials DOI Creative Commons
Stephen J. Nicholls, Adam J. Nelson, John J.P. Kastelein

и другие.

Pharmacology Research & Perspectives, Год журнала: 2024, Номер 12(6)

Опубликована: Окт. 18, 2024

Abstract Anacetrapib, a cholesteryl ester transfer protein (CETP) inhibitor previously under development, exhibited an usually extended terminal half‐life and large food effect accumulated in adipose tissue. Other CETP inhibitors have not shown such effects. Obicetrapib, potent selective inhibitor, is undergoing Phase III clinical development. Dedicated assessments were conducted pre‐clinical I II studies of obicetrapib to examine the pharmacokinetic issues observed with anacetrapib. After 9 months dosing up 50 mg/kg/day cynomolgus monkeys, was completely eliminated from systemic circulation detected tissue after 13‐week recovery period. In healthy humans receiving 1–25 mg obicetrapib, mean 148, 131, 121 h at 5, 10, 25 mg, respectively, increased plasma levels by ~1.6‐fold 10 dose. At end treatment trials, ranged 194.5 ng/mL 2.5 506.3 mg. Plasma decreased 92.2% 98.5% four 15 weeks post‐treatment, respectively. Obicetrapib shows no clinically relevant accumulation, minimally affected food, has 131 for These data support once daily, chronic trials dyslipidemia management.

Язык: Английский

Процитировано

1
Lipid-lowering efficacy of obicetrapib: A comprehensive systematic review and meta-analysis. DOI
Walter Massón,

Leandro Barbagelata,

Martín Lobo

и другие.

Journal of clinical lipidology, Год журнала: 2024, Номер unknown

Опубликована: Дек. 1, 2024

Язык: Английский

Процитировано

1
New perspectives on the high-density lipoprotein system and its role in the prevention and treatment of atherosclerotic cardiovascular disease DOI
Nick S. R. Lan, Gerald F. Watts

Current Opinion in Endocrinology Diabetes and Obesity, Год журнала: 2024, Номер unknown

Опубликована: Авг. 2, 2024

The causal role of high-density lipoprotein (HDL) in atherosclerotic cardiovascular disease (CVD) remains debated. Considering recent evidence, the purpose this review is to a provide focused update and new perspectives on HDL CVD.

Язык: Английский

Процитировано

0
Evaluating obicetrapib as an emerging treatment for patients with dyslipidemia: a game changer? DOI
Stephen J. Nicholls, Sean Tan,

Julie Butters

и другие.

Expert Opinion on Pharmacotherapy, Год журнала: 2024, Номер unknown

Опубликована: Сен. 26, 2024

Cholesteryl ester transfer protein (CETP) plays an important role in lipid metabolism. Early interest the development of CETP inhibitors proved to be disappointing. Recent has focused on potential for inhibition reduce cardiovascular risk by lowering levels low-density lipoprotein cholesterol (LDL-C).

Язык: Английский

Процитировано

0