Impact of the COVID-19 Pandemic on Conduct and Results of CLEAR Outcomes Trial.

Introduction: The COVID-19 pandemic disrupted clinical research. CLEAR Outcomes investigated the effect of bempedoic acid (BA) versus placebo in 13 970 patients with statin intolerance and high cardiovascular (CV) risk. BA reduced the risk of the primary endpoint (composite of CV death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization) by 13%.

Comparative Cardiovascular Benefits of Bempedoic Acid and Statin Drugs.

Background: In the CLEAR (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen) Outcomes trial, treatment of statin-intolerant patients with bempedoic acid produced a 21% decrease in low-density lipoprotein cholesterol (LDL-C) relative to placebo and a 13% relative reduction in the risk of major adverse cardiovascular events.

Objectives: This study sought to determine whether the relationship between LDL-C lowering and cardiovascular benefit achieved with bempedoic acid resembles that observed with statins when standardized per unit change in LDL-C.

Methods: To compare the treatment effect of bempedoic acid with statins, the methodology of the Cholesterol Treatment Trialists' Collaboration (CTTC) was applied to outcomes among the 13,970 patients enrolled in the CLEAR Outcomes trial.

Population pharmacokinetic and pharmacokinetic-pharmacodynamic modeling of bempedoic acid and low-density lipoprotein cholesterol in healthy subjects and patients with dyslipidemia.

Population pharmacokinetics (popPK) of bempedoic acid and the popPK/pharmacodynamic (popPK/PD) relationship between bempedoic acid concentrations and serum low-density lipoprotein cholesterol (LDL-C) from baseline were characterized. A two-compartment disposition model with a transit absorption compartment and linear elimination best described bempedoic acid oral pharmacokinetics (PK). Multiple covariates, including renal function, sex, and weight, had statistically significant effects on the predicted steady-state area under the curve.

Bempedoic acid lowers high-sensitivity C-reactive protein and low-density lipoprotein cholesterol: Analysis of pooled data from four phase 3 clinical trials.

Background And Aims: High-sensitivity C-reactive protein (hsCRP), a marker for atherosclerotic cardiovascular disease risk, is reduced by bempedoic acid. We assessed the relationship between changes in low-density lipoprotein cholesterol (LDL-C) and hsCRP in relation to baseline statin use.

Methods: Pooled data from four phase 3 trials (patients on maximally tolerated statins [Pool 1] and patients receiving no or low-dose statins [Pool 2]) were used to determine the proportion of patients with baseline hsCRP ≥2 mg/L who achieved hsCRP <2 mg/L at week 12.

Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients.

Background: Bempedoic acid, an ATP citrate lyase inhibitor, reduces low-density lipoprotein (LDL) cholesterol levels and is associated with a low incidence of muscle-related adverse events; its effects on cardiovascular outcomes remain uncertain.

Methods: We conducted a double-blind, randomized, placebo-controlled trial involving patients who were unable or unwilling to take statins owing to unacceptable adverse effects ("statin-intolerant" patients) and had, or were at high risk for, cardiovascular disease. The patients were assigned to receive oral bempedoic acid, 180 mg daily, or placebo.

Potential Cardiovascular Events Avoided with Bempedoic Acid Plus Ezetimibe Fixed-Dose Combination Compared with Ezetimibe Alone in Patients with Atherosclerotic Cardiovascular Disease Taking Maximally Tolerated Statins.

Background: Patients with atherosclerotic cardiovascular disease who require additional low-density lipoprotein cholesterol (LDL-C) lowering despite maximally tolerated statins have a significant unmet medical need and are at increased risk of future cardiovascular events and a reduced quality of life.

Objective: We aimed to estimate the percentage of cardiovascular events avoided following treatment with a fixed-dose combination of bempedoic acid plus ezetimibe (BA+EZE FDC) versus ezetimibe (EZE) in patients with atherosclerotic cardiovascular disease receiving maximally tolerated statins across a range of baseline LDL-C levels.

Methods: A Markov cohort simulation model estimated major adverse cardiovascular events avoided over a lifetime horizon among patients with atherosclerotic cardiovascular disease and baseline LDL-C levels from 80 to >200 mg/dL.

Pharmacokinetics of bempedoic acid in patients with renal impairment.

Bempedoic acid is an ATP citrate lyase inhibitor approved for the treatment of hypercholesterolemia. The objective of this phase I study was to assess the pharmacokinetics (PKs) and safety of bempedoic acid in 24 subjects with normal renal function or mild, moderate, or severe renal impairment. All subjects received a single oral bempedoic acid 180-mg dose and PK parameters were monitored for up to 23 days.

Absence of effect of steady state bempedoic acid on cardiac repolarization: Results of a thorough QT/QTc study in healthy volunteers.

Bempedoic acid is an inhibitor of adenosine triphosphate-citrate lyase approved for use in adults with hypercholesterolemia. Nonclinical studies assessed binding to the human ether-a-go-go-related gene (hERG) potassium channel in vitro and the effect of bempedoic acid on QT/QTc in cynomolgus monkeys. A randomized, double-blind, parallel-design clinical study assessed the effects of steady-state bempedoic acid at a supratherapeutic dose (240 mg/day, 33.

Pharmacodynamic effect of bempedoic acid and statin combinations: predictions from a dose-response model.

Aims: Many patients are unable to achieve guideline-recommended LDL cholesterol (LDL-C) targets, despite taking maximally tolerated lipid-lowering therapy. Bempedoic acid, a competitive inhibitor of ATP citrate lyase, significantly lowers LDL-C with or without background statin therapy in diverse populations. Because pharmacodynamic interaction between statins and bempedoic acid is complex, a dose-response model was developed to predict LDL-C pharmacodynamics following administration of statins combined with bempedoic acid.

Rationale and design of the CLEAR-outcomes trial: Evaluating the effect of bempedoic acid on cardiovascular events in patients with statin intolerance.

Although statins play a pivotal role in the prevention of atherosclerotic cardiovascular disease, many patients fail to achieve recommended lipid levels due to statin-associated muscle symptoms. Bempedoic acid is an oral pro-drug that is activated in the liver and inhibits cholesterol synthesis in hepatocytes, but is not activated in skeletal muscle which has the potential to avoid muscle-related adverse events. Accordingly, this agent effectively lowers atherogenic lipoproteins in patients who experience statin-associated muscle symptoms.

Pharmacodynamic relationship between PCSK9, alirocumab, and LDL-C lowering in the ODYSSEY CHOICE I trial.

Background: The ODYSSEY CHOICE I study (NCT01926782) evaluated alirocumab 300 mg every 4 weeks (Q4W) in patients with hypercholesterolemia receiving maximally tolerated statin or no statin.

Objective: The objective of the study was to assess the relationship between alirocumab, proprotein convertase subtilisin/kexin type 9 (PCSK9), and low-density lipoprotein cholesterol (LDL-C) concentrations with the CHOICE I alirocumab dosing regimen.

Methods: This analysis included 803 patients (547 statin-treated, 256 without statin) who were randomized to alirocumab 300 mg Q4W, alirocumab 75 mg every 2 weeks (Q2W), or placebo.

Simulation of impact on cardiovascular events due to lipid-lowering therapy intensification in a population with atherosclerotic cardiovascular disease.

Unlabelled: In patients with atherosclerotic cardiovascular disease (ASCVD), guidelines recommend statins as first-line lipid-lowering therapy (LLT) with addition of nonstatin agents in those with persistently elevated low-density lipoprotein cholesterol levels.

Methods: To estimate the cardiovascular (CV) risk reduction implications of treatment intensification, we used a previously reported simulation model with enhancements. An ASCVD cohort was developed from a US claims database.

Inhibition of Angiopoietin-Like Protein 3 With a Monoclonal Antibody Reduces Triglycerides in Hypertriglyceridemia.

Background: Hypertriglyceridemia is associated with increased cardiovascular risk and may be caused by impaired lipoprotein clearance. Angiopoietin-like protein 3 (ANGPTL3) inhibits lipoprotein lipase activity, increasing triglycerides and other lipids. Evinacumab, an ANGPTL3 inhibitor, reduced triglycerides in healthy human volunteers and in homozygous familial hypercholesterolemic individuals.

Simulation of the Impact of Statin Intolerance on the Need for Ezetimibe and/or Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor for Meeting Low-Density Lipoprotein Cholesterol Goals in a Population With Atherosclerotic Cardiovascular Disease.

In a population with atherosclerotic cardiovascular disease, previous research indicated that approximately 86% can achieve low-density lipoprotein cholesterol (LDL-C) of <70 mg/dL with oral lipid-lowering therapies (LLT) only, whereas 14% would require a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. We aim to estimate these values accounting for varying levels of statin intolerance. A simulation model described previously was used to estimate the utilization of LLT needed to achieve LDL-C <70 mg/dL via an intensification algorithm which maximized statins before adding ezetimibe or a PCSK9 inhibitor.

Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome.

Background: Patients who have had an acute coronary syndrome are at high risk for recurrent ischemic cardiovascular events. We sought to determine whether alirocumab, a human monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9), would improve cardiovascular outcomes after an acute coronary syndrome in patients receiving high-intensity statin therapy.

Methods: We conducted a multicenter, randomized, double-blind, placebo-controlled trial involving 18,924 patients who had an acute coronary syndrome 1 to 12 months earlier, had a low-density lipoprotein (LDL) cholesterol level of at least 70 mg per deciliter (1.

New strategies for the development of lipid-lowering therapies to reduce cardiovascular risk.

The very high occurrence of cardiovascular events presents a major public health issue, because treatment remains suboptimal. Lowering LDL cholesterol (LDL-C) with statins or ezetimibe in combination with a statin reduces major adverse cardiovascular events. The cardiovascular risk reduction in relation to the absolute LDL-C reduction is linear for most interventions without evidence of attenuation or increase in risk at low LDL-C levels.

Assessing the Equivalence of Paper, Mobile Phone, and Tablet Survey Responses at a Community Mental Health Center Using Equivalent Halves of a 'Gold-Standard' Depression Item Bank.

Background: The computerized administration of self-report psychiatric diagnostic and outcomes assessments has risen in popularity. If results are similar enough across different administration modalities, then new administration technologies can be used interchangeably and the choice of technology can be based on other factors, such as convenience in the study design. An assessment based on item response theory (IRT), such as the Patient-Reported Outcomes Measurement Information System (PROMIS) depression item bank, offers new possibilities for assessing the effect of technology choice upon results.

A Quantitative Systems Pharmacology Platform to Investigate the Impact of Alirocumab and Cholesterol-Lowering Therapies on Lipid Profiles and Plaque Characteristics.

Reduction in low-density lipoprotein cholesterol (LDL-C) is associated with decreased risk for cardiovascular disease. Alirocumab, an antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduces LDL-C. Here, we report development of a quantitative systems pharmacology (QSP) model integrating peripheral and liver cholesterol metabolism, as well as PCSK9 function, to examine the mechanisms of action of alirocumab and other lipid-lowering therapies, including statins.

Simulation of Lipid-Lowering Therapy Intensification in a Population With Atherosclerotic Cardiovascular Disease.

Importance: In patients with atherosclerotic cardiovascular disease (ASCVD), guidelines recommend optimizing statin treatment, and consensus pathways suggest use of ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in patients with persistently elevated low-density lipoprotein cholesterol (LDL-C) levels despite use of statins. Recent trials have provided evidence of benefit in reduction of cardiovascular events with these agents.

Objective: To estimate the percentage of patients with ASCVD who would require a PCSK9 inhibitor when oral lipid-lowering therapy (LLT) is intensified first.

Long-term treatment adherence to the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab in 6 ODYSSEY Phase III clinical studies with treatment duration of 1 to 2 years.

Background: Nonadherence to cardiovascular medications, including daily, oral statin therapy, negatively impacts outcomes in patients requiring low-density lipoprotein cholesterol (LDL-C)-lowering therapy. The proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab also reduces LDL-C, but has a different mode of administration (subcutaneous injection).

Objective: The objective of the study was to assess long-term adherence to alirocumab 75 or 150 mg, given every 2 weeks, in phase III trials of patients with sub-optimally controlled hypercholesterolemia.

Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease.

Background: Loss-of-function variants in the angiopoietin-like 3 gene (ANGPTL3) have been associated with decreased plasma levels of triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. It is not known whether such variants or therapeutic antagonism of ANGPTL3 are associated with a reduced risk of atherosclerotic cardiovascular disease.

Methods: We sequenced the exons of ANGPTL3 in 58,335 participants in the DiscovEHR human genetics study.

Safety of Very Low Low-Density Lipoprotein Cholesterol Levels With Alirocumab: Pooled Data From Randomized Trials.

Background: Proprotein convertase subtilisin/kexin type 9 monoclonal antibodies can reduce low-density lipoprotein cholesterol (LDL-C) to very low levels when added to background lipid-lowering therapy.

Objectives: The safety of alirocumab was evaluated in patients with at least 2 consecutive LDL-C values <25 or <15 mg/dl in the ODYSSEY program, with follow-up as long as 104 weeks.

Methods: Pooled data from 14 trials were analyzed (double-blind treatment 8 to 104 weeks; n = 3,340 alirocumab, n = 1,894 control [placebo or ezetimibe]; representing 4,029 [alirocumab] and 2,114 [control] double-blind patient-years' exposure).