Cholesteryl ester transfer protein inhibition: a pathway to reducing risk of morbidity and promoting longevity.

Purpose Of Review: To review the evidence and describe the biological plausibility for the benefits of inhibiting cholesteryl ester transfer protein (CETP) on multiple organ systems through modification of lipoprotein metabolism.

Recent Findings: Results from observational studies, Mendelian randomization analyses, and randomized clinical trials support the potential of CETP inhibition to reduce atherosclerotic cardiovascular disease (ASCVD) risk through a reduction of apolipoprotein B-containing lipoproteins. In contrast, raising high-density lipoprotein (HDL) particles, as previously hypothesized, did not contribute to ASCVD risk reduction.

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.

Anacetrapib, a cholesteryl ester transfer protein (CETP) inhibitor previously under development, exhibited an usually extended terminal half-life and large food effect and accumulated in adipose tissue. Other CETP inhibitors have not shown such effects. Obicetrapib, a potent selective CETP inhibitor, is undergoing Phase III clinical development.

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.

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 responses have not been established in Chinese individuals. The purpose of this randomized, parallel, open-label trial was to characterize the PK and pharmacodynamic (PD; CETP activity and plasma lipids) responses and safety of single doses (5, 10, or 25 mg; N = 36) and multiple doses (10 mg for 14 days; N = 12) of obicetrapib in healthy Chinese individuals.

CETP and SGLT2 inhibitor combination therapy increases glycemic control: a 2x2 factorial Mendelian randomization analysis.

Introduction: Cholesteryl ester transfer protein (CETP) inhibitors, initially developed for treating hyperlipidemia, have shown promise in reducing the risk of new-onset diabetes during clinical trials. This positions CETP inhibitors as potential candidates for repurposing in metabolic disease treatment. Given their oral administration, they could complement existing oral medications like sodium-glucose cotransporter 2 (SGLT2) inhibitors, potentially delaying the need for injectable therapies such as insulin.

Guiding Dyslipidemia Treatment: A Population Pharmacokinetic-Pharmacodynamic Framework for Obicetrapib.

Obicetrapib is a selective inhibitor of cholesteryl ester transfer protein that is currently in phase 3 of development for the treatment of dyslipidemia as adjunct therapy. The purpose of this study was to comprehensively characterize the pharmacokinetic (PK) and pharmacodynamic (PD) disposition of obicetrapib. Data from 7 clinical trials conducted in healthy adults and those with varying degrees of dyslipidemia were included for model development.

Obicetrapib: Reversing the Tide of CETP Inhibitor Disappointments.

Purpose Of Review: To discuss the history of cardiovascular outcomes trials of cholesteryl ester transfer protein (CETP) inhibitors and to describe obicetrapib, a next-generation, oral, once-daily, low-dose CETP inhibitor in late-stage development for dyslipidemia and atherosclerotic cardiovascular disease (ASCVD).

Recent Findings: Phase 1 and 2 trials have evaluated the safety and lipid/lipoprotein effects of obicetrapib as monotherapy, in conjunction with statins, on top of high-intensity statins (HIS), and with ezetimibe on top of HIS. In ROSE2, 10 mg obicetrapib monotherapy and combined with 10 mg ezetimibe, each on top of HIS, significantly reduced low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B, total LDL particles, small LDL particles, small, dense LDL-C, and lipoprotein (a), and increased HDL-C.

CETP and SGLT2 inhibitor combination therapy improves glycemic control.

Importance: Cholesteryl ester transfer protein (CETP) inhibition has been associated with decreased risk of new-onset diabetes in past clinical trials exploring their efficacy in cardiovascular disease and can potentially be repurposed to treat metabolic disease. Notably, as an oral drug it can potentially be used to supplement existing oral drugs such as sodium-glucose cotransporter 2 (SGLT2) inhibitors before patients are required to take injectable drugs such as insulin.

Objective: To identify whether CETP inhibitors could be used as an oral add-on to SGLT2 inhibition to improve glycemic control.

Obicetrapib plus ezetimibe as an adjunct to high-intensity statin therapy: A randomized phase 2 trial.

Background: Obicetrapib, a selective cholesteryl ester transfer protein (CETP) inhibitor, reduces low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein particles, and apolipoproteins, when added to high-intensity statin in patients with dyslipidemia.

Objective: To evaluate the safety and lipid-altering efficacy of obicetrapib plus ezetimibe combination therapy as an adjunct to high-intensity statin therapy.

Methods: This double-blind, randomized, phase 2 trial administered 10 mg obicetrapib plus 10 mg ezetimibe (n = 40), 10 mg obicetrapib (n = 39), or placebo (n = 40) for 12 weeks to patients with LDL-C >70 mg/dL and triglycerides (TG) <400 mg/dL, on stable high-intensity statin.

Comparison of low-density lipoprotein cholesterol equations in patients with dyslipidaemia receiving cholesterol ester transfer protein inhibition.

Aims: Low-density lipoprotein (LDL-C) lowering is imperative in cardiovascular disease prevention. We aimed to compare accuracy of three clinically-implemented LDL-C equations in a clinical trial of cholesterol ester transfer protein (CETP) inhibition.

Methods And Results: Men and women aged 18-75 years with dyslipidaemia were recruited from 17 sites in the Netherlands and Denmark.

Cholesteryl Ester Transfer Protein Inhibition Reduces Major Adverse Cardiovascular Events by Lowering Apolipoprotein B Levels.

Cholesteryl ester transfer protein (CETP) facilitates the exchange of cholesteryl esters and triglycerides (TG) between high-density lipoprotein (HDL) particles and TG-rich, apolipoprotein (apo) B-containing particles. Initially, these compounds were developed to raise plasma HDL cholesterol (HDL-C) levels, a mechanism that was previously thought to lower the risk of atherosclerotic cardiovascular disease (ASCVD). More recently, the focus changed and the use of pharmacologic CETP inhibitors to reduce low-density lipoprotein cholesterol (LDL-C), non-HDL-C and apoB concentrations became supported by several lines of evidence from animal models, observational investigations, randomized controlled trials and Mendelian randomization studies.

Lipid lowering effects of the CETP inhibitor obicetrapib in combination with high-intensity statins: a randomized phase 2 trial.

Global guidelines for the management of high-cardiovascular-risk patients include aggressive goals for low-density lipoprotein cholesterol (LDL-C). Statin therapy alone is often insufficient to reach goals and nonstatin options have limitations. Here, we tested the lipid-lowering effects of the cholesteryl ester transfer protein (CETP) inhibitor drug obicetrapib in a randomized, double-blind, placebo-controlled trial in dyslipidaemic patients (n = 120, median LDL-C 88 mg dl) with background high-intensity statin treatment (NCT04753606).

Targeting the cytoskeleton and extracellular matrix in cardiovascular disease drug discovery.

Introduction: Currently, cardiovascular disease (CVD) drug discovery has focused primarily on addressing the inflammation and immunopathology aspects inherent to various CVD phenotypes such as cardiac fibrosis and coronary artery disease. However, recent findings suggest new biological pathways for cytoskeletal and extracellular matrix (ECM) regulation across diverse CVDs, such as the roles of matricellular proteins (e.g.

Left ventricular mass regression, all-cause and cardiovascular mortality in chronic kidney disease: a meta-analysis.

Background: Cardiovascular disease is an important driver of the increased mortality associated with chronic kidney disease (CKD). Higher left ventricular mass (LVM) predicts increased risk of adverse cardiovascular outcomes and total mortality, but previous reviews have shown no clear association between intervention-induced LVM change and all-cause or cardiovascular mortality in CKD.

Methods: The primary objective of this meta-analysis was to investigate whether treatment-induced reductions in LVM over periods ≥12 months were associated with all-cause mortality in patients with CKD.

Lipid measurements in the management of cardiovascular diseases: Practical recommendations a scientific statement from the national lipid association writing group.

Lipoprotein measurements are pivotal in the management of patients at risk for atherosclerotic coronary heart disease (CHD) with myocardial infarction and coronary death as the main outcomes, and for atherosclerotic cardiovascular disease (ASCVD), which includes CHD and stroke. Recent developments and changes in guidelines affect optimization of using lipid measures as cardiovascular biomarkers. This scientific statement reviews the pre-analytical, analytical, post-analytical, and clinical aspects of lipoprotein measurements.

Association Between Achieved ω-3 Fatty Acid Levels and Major Adverse Cardiovascular Outcomes in Patients With High Cardiovascular Risk: A Secondary Analysis of the STRENGTH Trial.

Importance: In patients treated with ω-3 fatty acids, it remains uncertain whether achieved levels of eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) are associated with cardiovascular outcomes.

Objective: To determine the association between plasma levels of EPA and DHA and cardiovascular outcomes in a trial of ω-3 fatty acids compared with corn oil placebo.

Design, Setting, And Participants: A double-blind, multicenter trial enrolled patients at high cardiovascular risk with elevated triglyceride levels and low levels of high-density lipoprotein cholesterol at 675 centers (enrollment from October 30, 2014, to June 14, 2017; study termination January 8, 2020; last visit May 14, 2020).

The clinical black, white, and gray lessons.

Purpose Of Review: This review examines recent contradictory large, well-controlled randomized control trials assessing the effects of omega-3 fatty acids and colchicine on cardiovascular (CV) outcomes.

Recent Findings: The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) and Statin Residual Risk Reduction with Epanova in high Cardiovascular Risk patients with Hypertriglyceridemia (STRENGTH) trial assessed the CV outcomes using high-dose omega-3 fatty acids in statin-treated patients with moderate hypertriglyceridemia and high-risk for CV disease with differing results. Similarly, Colchicine Cardiovascular Outcomes trial, (COLCOT) second Low Dose Colchicine (LoDoCo2), and Colchicine in patients with Acute Coronary Syndrome (COPS) assessed the CV outcomes using low-dose colchicine in patients with coronary artery disease with inconsistent results.

Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Management of Dyslipidemia and Prevention of Cardiovascular Disease Algorithm - 2020 Executive Summary.

The treatment of lipid disorders begins with lifestyle therapy to improve nutrition, physical activity, weight, and other factors that affect lipids. Secondary causes of lipid disorders should be addressed, and pharmacologic therapy initiated based on a patient's risk for atherosclerotic cardiovascular disease (ASCVD). Patients at extreme ASCVD risk should be treated with high-intensity statin therapy to achieve a goal low-density lipoprotein cholesterol (LDL-C) of <55 mg/dL, and those at very high ASCVD risk should be treated to achieve LDL-C <70 mg/dL.

How I treat statin-associated side effects in an outpatient setting.

Dyslipidemia promotes atherosclerosis and causes cardiovascular diseases. Statins are potent lipid-lowering medications with a cardiovascular mortality benefit. They are generally safe and well tolerated but sometimes can be associated with side effects of variable severity.