Lipid lowering with bempedoic acid added to a proprotein convertase subtilisin/kexin type 9 inhibitor therapy: A randomized, controlled trial.

Background: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9is) lower low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia. However, some patients receiving PCSK9i therapy might require additional lipid-lowering therapy (LLT) to reach LDL-C goals. Bempedoic acid is an oral, once-daily, ATP-citrate lyase inhibitor that significantly lowers LDL-C in patients with hypercholesterolemia when given alone or as add-on therapy to statins and/or ezetimibe.

Effect of Bempedoic Acid vs Placebo Added to Maximally Tolerated Statins on Low-Density Lipoprotein Cholesterol in Patients at High Risk for Cardiovascular Disease: The CLEAR Wisdom Randomized Clinical Trial.

Importance: Additional treatment options are needed for patients who do not achieve sufficient reduction in low-density lipoprotein cholesterol (LDL-C) level with available lipid-lowering therapies.

Objective: To assess the efficacy of bempedoic acid vs placebo in patients at high cardiovascular risk receiving maximally tolerated lipid-lowering therapy.

Design, Setting, And Participants: Phase 3, randomized, double-blind, placebo-controlled clinical trial conducted at 91 clinical sites in North America and Europe from November 2016 to September 2018, with a final date of follow-up of September 22, 2018.

Complementary low-density lipoprotein-cholesterol lowering and pharmacokinetics of adding bempedoic acid (ETC-1002) to high-dose atorvastatin background therapy in hypercholesterolemic patients: A randomized placebo-controlled trial.

Background: Bempedoic acid is an oral, once-daily, first-in-class medication being developed to treat hypercholesterolemia.

Objective: The aim of the study was to assess the low-density lipoprotein cholesterol (LDL-C)-lowering efficacy of bempedoic acid added to stable high-intensity atorvastatin background therapy and multiple-dose plasma pharmacokinetics of atorvastatin alone and combined with steady-state bempedoic acid.

Methods: This was a phase 2 study in patients with hypercholesterolemia (NCT02659397).

Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol.

Background: Short-term studies have shown that bempedoic acid, an inhibitor of ATP citrate lyase, reduces levels of low-density lipoprotein (LDL) cholesterol. Data are limited regarding the safety and efficacy of bempedoic acid treatment in long-term studies involving patients with hypercholesterolemia who are receiving guideline-recommended statin therapy.

Methods: We conducted a randomized, controlled trial involving patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both.

Targeting ATP-Citrate Lyase in Hyperlipidemia and Metabolic Disorders.

Chronic overnutrition and a sedentary lifestyle promote imbalances in metabolism, often manifesting as risk factors for life-threating diseases such as atherosclerotic cardiovascular disease (ASCVD) and nonalcoholic fatty liver disease (NAFLD). Nucleocytosolic acetyl-coenzyme A (CoA) has emerged as a central signaling node used to coordinate metabolic adaptations in response to a changing nutritional status. ATP-citrate lyase (ACL) is the enzyme primarily responsible for the production of extramitochondrial acetyl-CoA and is thus strategically positioned at the intersection of nutrient catabolism and lipid biosynthesis.

Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis.

Despite widespread use of statins to reduce low-density lipoprotein cholesterol (LDL-C) and associated atherosclerotic cardiovascular risk, many patients do not achieve sufficient LDL-C lowering due to muscle-related side effects, indicating novel treatment strategies are required. Bempedoic acid (ETC-1002) is a small molecule intended to lower LDL-C in hypercholesterolemic patients, and has been previously shown to modulate both ATP-citrate lyase (ACL) and AMP-activated protein kinase (AMPK) activity in rodents. However, its mechanism for LDL-C lowering, efficacy in models of atherosclerosis and relevance in humans are unknown.

Effect of ETC-1002 on Serum Low-Density Lipoprotein Cholesterol in Hypercholesterolemic Patients Receiving Statin Therapy.

ETC-1002 is an oral, once-daily medication that inhibits adenosine triphosphate citrate lyase, an enzyme upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, to reduce cholesterol biosynthesis. ETC-1002 monotherapy has demonstrated significant reduction in low-density lipoprotein cholesterol (LDL-C) compared with placebo in phase 2 studies. The objective of this study was to compare the lipid-lowering efficacy of ETC-1002 versus placebo when added to ongoing statin therapy in patients with hypercholesterolemia.

HDL mimetic peptide CER-522 treatment regresses left ventricular diastolic dysfunction in cholesterol-fed rabbits.

Objectives: High-density lipoprotein (HDL) infusions induce rapid improvement of experimental atherosclerosis in rabbits but their effect on ventricular function remains unknown. We aimed to evaluate the effects of the HDL mimetic peptide CER-522 on left ventricular diastolic dysfunction (LVDD).

Methods: Rabbits were fed with a cholesterol- and vitamin D2-enriched diet until mild aortic valve stenosis and hypercholesterolemia-induced LV hypertrophy and LVDD developed.

HDL and CER-001 Inverse-Dose Dependent Inhibition of Atherosclerotic Plaque Formation in apoE-/- Mice: Evidence of ABCA1 Down-Regulation.

Objective: CER-001 is a novel engineered HDL-mimetic comprised of recombinant human apoA-I and charged phospholipids that was designed to mimic the beneficial properties of nascent pre-ß HDL. In this study, we have evaluated the dose-dependent regulation of ABCA1 expression in vitro and in vivo in the presence of CER-001 and native HDL (HDL3).

Methods And Results: CER-001 induced cholesterol efflux from J774 macrophages in a dose-dependent manner similar to natural HDL.

P2Y13 receptor regulates HDL metabolism and atherosclerosis in vivo.

High-density lipoprotein (HDL) is known to protect against atherosclerosis by promoting the reverse cholesterol transport. A new pathway for the regulation of HDL-cholesterol (HDL-c) removal involving F1-ATPase and P2Y13 receptor (P2Y13R) was described in vitro, and recently in mice. However, the physiological role of F1-ATPase/P2Y13R pathway in the modulation of vascular pathology i.

CER-001, a HDL-mimetic, stimulates the reverse lipid transport and atherosclerosis regression in high cholesterol diet-fed LDL-receptor deficient mice.

Objective: CER-001 is a novel engineered HDL-mimetic comprised of recombinant human apoA-I and phospholipids that was designed to mimic the beneficial properties of nascent pre-β HDL. In this study, we have evaluated the capacity of CER-001 to perform reverse lipid transport in single dose studies as well as to regress atherosclerosis in LDLr(-/-) mice after short-term multiple-dose infusions.

Approach And Results: CER-001 induced cholesterol efflux from macrophages and exhibited anti-inflammatory response similar to natural HDL.

Influence of various central moieties on the hypolipidemic properties of long hydrocarbon chain diols and diacids.

A series of long (11-15) hydrocarbon chain diols and diacids with various central functional groups and terminal gem-dimethyl or -methyl/aryl substituents was synthesized and evaluated in both in vivo and in vitro assays for its potential to favorably alter lipid disorders including metabolic syndrome. Compounds were assessed for their effects on the de novo incorporation of radiolabeled acetate into lipids in primary cultures of rat hepatocytes, as well as for their effects on lipid and glycemic variables in obese female Zucker fatty rats, Crl:(ZUC)-faBR. The most active compounds were hydroxyl-substituted symmetrical diacids and diols with a 13-atom chain and terminal gem-dimethyl substituents.