Obicetrapib: Reversing the Tide of CETP Inhibitor Disappointments

Kastelein, John J. P.; Hsieh, Andrew; Dicklin, Mary R.; Ditmarsch, Marc; Davidson, Michael H.

doi:10.1007/s11883-023-01184-1

Cited by 10 publications

(3 citation statements)

References 63 publications

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“… 50 Analyses of lipoprotein particle subpopulations by nuclear magnetic resonance indicated that higher CETP concentrations are associated with lower levels of L-HDL, consistent with our study, and with more small VLDL particles. 51 It is possible that highly specific next-generation CETP inhibitors, such as obicetrapib 52 will be more effective. In addition, CETP inhibitors appear to reduce incident type 2 diabetes through an unclear mechanism.…”

Section: Discussionmentioning

confidence: 99%

Imbalance of APOB Lipoproteins and Large HDL in Type 1 Diabetes Drives Atherosclerosis

Kothari,

Ho,

Cabodevilla

et al. 2024

Circulation Research

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BACKGROUND: Individuals with type 1 diabetes (T1D) generally have normal or even higher HDL (high-density lipoprotein)-cholesterol levels than people without diabetes yet are at increased risk for atherosclerotic cardiovascular disease (CVD). Human HDL is a complex mixture of particles that can vary in cholesterol content by >2-fold. To investigate if specific HDL subspecies contribute to the increased atherosclerosis associated with T1D, we created mouse models of T1D that exhibit human-like HDL subspecies. We also measured HDL subspecies and their association with incident CVD in a cohort of people with T1D. METHODS: We generated LDL receptor–deficient ( Ldlr −/− ) mouse models of T1D expressing human APOA1 (apolipoprotein A1). Ldlr −/− APOA1 Tg mice exhibited the main human HDL subspecies. We also generated Ldlr −/− APOA1 Tg T1D mice expressing CETP (cholesteryl ester transfer protein), which had lower concentrations of large HDL subspecies versus mice not expressing CETP. HDL particle concentrations and sizes and proteins involved in lipoprotein metabolism were measured by calibrated differential ion mobility analysis and targeted mass spectrometry in the mouse models of T1D and in a cohort of individuals with T1D. Endothelial transcytosis was analyzed by total internal reflection fluorescence microscopy. RESULTS: Diabetic Ldlr −/− APOA1 Tg mice were severely hyperglycemic and hyperlipidemic and had markedly elevated plasma APOB levels versus nondiabetic littermates but were protected from the proatherogenic effects of diabetes. Diabetic Ldlr −/− APOA1 Tg mice expressing CETP lost the atheroprotective effect and had increased lesion necrotic core areas and APOB accumulation, despite having lower plasma APOB levels. The detrimental effects of low concentrations of larger HDL particles in diabetic mice expressing CETP were not explained by reduced cholesterol efflux. Instead, large HDL was more effective than small HDL in preventing endothelial transcytosis of LDL mediated by scavenger receptor class B type 1. Finally, in humans with T1D, increased concentrations of larger HDLs relative to APOB100 negatively predicted incident CVD independently of HDL-cholesterol levels. CONCLUSIONS: Our results suggest that the balance between APOB lipoproteins and the larger HDL subspecies contributes to atherosclerosis progression and incident CVD in the setting of T1D and that larger HDLs exert atheroprotective effects on endothelial cells rather than by promoting macrophage cholesterol efflux.

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Section: Discussionmentioning

confidence: 99%

Imbalance of APOB Lipoproteins and Large HDL in Type 1 Diabetes Drives Atherosclerosis

Kothari,

Ho,

Cabodevilla

et al. 2024

Circulation Research

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“…Similar results have been shown in ACCELERATE and REVEAL trials [ 119 ]. A new CETP inhibitor, obicetrapib, which has demonstrated excellent safety and tolerability in phase 1 and 2 trials (ROSE2 or Systematic Coronary Risk Evaluation ROSE2 study) [ 120 ], is being studied in a phase 3 trial and is anticipated to be a promising agent in the prevention of CVDs.…”

Section: Hdl Interaction With Major Proteins and Receptors Involved I...mentioning

confidence: 99%

High-Density Lipoprotein Metabolism and Function in Cardiovascular Diseases: What about Aging and Diet Effects?

Morvaridzadeh,

Zoubdane,

Heshmati

et al. 2024

Nutrients

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Cardiovascular diseases (CVDs) have become the leading global cause of mortality, prompting a heightened focus on identifying precise indicators for their assessment and treatment. In this perspective, the plasma levels of HDL have emerged as a pivotal focus, given the demonstrable correlation between plasma levels and cardiovascular events, rendering them a noteworthy biomarker. However, it is crucial to acknowledge that HDLs, while intricate, are not presently a direct therapeutic target, necessitating a more nuanced understanding of their dynamic remodeling throughout their life cycle. HDLs exhibit several anti-atherosclerotic properties that define their functionality. This functionality of HDLs, which is independent of their concentration, may be impaired in certain risk factors for CVD. Moreover, because HDLs are dynamic parameters, in which HDL particles present different atheroprotective properties, it remains difficult to interpret the association between HDL level and CVD risk. Besides the antioxidant and anti-inflammatory activities of HDLs, their capacity to mediate cholesterol efflux, a key metric of HDL functionality, represents the main anti-atherosclerotic property of HDL. In this review, we will discuss the HDL components and HDL structure that may affect their functionality and we will review the mechanism by which HDL mediates cholesterol efflux. We will give a brief examination of the effects of aging and diet on HDL structure and function.

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“…To date, five CETP inhibitors including torcetrapib, dalcetrapib, evacetrapib, anacetrapib, and, most recently, obicetrapib have reached late-stage clinical development for ASCVD risk reduction (reviewed in [24]). It has been observed that all CETP inhibitors have a significantly positive effect on apolipoprotein A-I and HDL-C concentrations.…”

Section: Introductionmentioning

confidence: 99%

Cholesteryl Ester Transfer Protein Inhibitors and Cardiovascular Outcomes: A Systematic Review and Meta-Analysis

Rehman,

Yarkoni,

Ilyas

et al. 2024

JCDD

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Background: Atherosclerosis is a multi-factorial disease, and low-density lipoprotein cholesterol (LDL-C) is a critical risk factor in developing atherosclerotic cardiovascular disease (ASCVD). Cholesteryl-ester transfer-protein (CETP), synthesized by the liver, regulates LDL-C and high-density lipoprotein cholesterol (HDL-C) through the bidirectional transfer of lipids. The novelty of CETP inhibitors (CETPis) has granted new focus towards increasing HDL-C, besides lowering LDL-C strategies. To date, five CETPis that are projected to improve lipid profiles, torcetrapib, dalcetrapib, evacetrapib, anacetrapib, and obicetrapib, have reached late-stage clinical development for ASCVD risk reduction. Early trials failed to reduce atherosclerotic cardiovascular occurrences. Given the advent of some recent large-scale clinical trials (ACCELERATE, HPS3/TIMI55-REVEAL Collaborative Group), conducting a meta-analysis is essential to investigate CETPis’ efficacy. Methods: We conducted a thorough search of randomized controlled trials (RCTs) that commenced between 2003 and 2023; CETPi versus placebo studies with a ≥6-month follow-up and defined outcomes were eligible. Primary outcomes: major adverse cardiovascular events (MACEs), cardiovascular disease (CVD)-related mortality, all-cause mortality. Secondary outcomes: stroke, revascularization, hospitalization due to acute coronary syndrome, myocardial infarction (MI). Results: Nine RCTs revealed that the use of a CETPi significantly reduced CVD-related mortality (RR = 0.89; 95% CI: 0.81–0.98; p = 0.02; I2 = 0%); the same studies also reduced the risk of MI (RR = 0.92; 95% CI: 0.86–0.98; p = 0.01; I2 = 0%), which was primarily attributed to anacetrapib. The use of a CETPi did not reduce the likelihood any other outcomes. Conclusions: Our meta-analysis shows, for the first time, that CETPis are associated with reduced CVD-related mortality and MI.

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Obicetrapib: Reversing the Tide of CETP Inhibitor Disappointments

Cited by 10 publications

References 63 publications

Imbalance of APOB Lipoproteins and Large HDL in Type 1 Diabetes Drives Atherosclerosis

Imbalance of APOB Lipoproteins and Large HDL in Type 1 Diabetes Drives Atherosclerosis

High-Density Lipoprotein Metabolism and Function in Cardiovascular Diseases: What about Aging and Diet Effects?

Cholesteryl Ester Transfer Protein Inhibitors and Cardiovascular Outcomes: A Systematic Review and Meta-Analysis

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