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. A total of 779 patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both met randomization criteria, which included LDL-C level 70 mg/dL (1.8 mmol/L) or greater while receiving maximally tolerated lipid-lowering therapy. INTERVENTIONS Patients were randomized 2:1 to treatment with bempedoic acid (180 mg) (n = 522) or placebo (n = 257) once daily for 52 weeks. MAIN OUTCOMES AND MEASURES The primary end point was percent change from baseline in LDL-C level at week 12. Secondary measures included changes in levels of lipids, lipoproteins, and biomarkers. RESULTS Among 779 randomized patients (mean age, 64.3 years; 283 women [36.3%]), 740 (95.0%) completed the trial. At baseline, mean LDL-C level was 120.4 (SD, 37.9) mg/dL. Bempedoic acid lowered LDL-C levels significantly more than placebo at week 12 (-15.1% vs 2.4%, respectively; difference,-17.4% [95% CI,-21.0% to-13.9%]; P < .001). Significant reductions with bempedoic acid vs placebo were observed at week 12 for non-high-density lipoprotein cholesterol (-10.8% vs 2.

Bempedoic acid may provide an oral therapeutic option complementary to ezetimibe in statin intolerant patients who require additional LDL-C lowering.

This article is available online at http://www.jlr.org termed as metabolic syndrome (MetS) ( 1 ), characterized by a clustering of major risk factors for developing cardiovascular disease. Obesity, representing derangement in energy balances, is tightly linked with the development of type-2 diabetes through its ability to engender insulin resistance, leading to glucose intolerance and development of type-2 diabetes and dyslipidemia. Thus, insulin resistance The pathophysiology of diabetes and obesity is a very complex process involving many pathways. Deregulation of these pathways gives rise to metabolic abnormalities

Background-In clinical studies, sphingomyelin (SM) plasma levels correlated with the occurrence of coronary heart disease independently of plasma cholesterol levels. We hypothesized that inhibition of SM synthesis would have antiatherogenic effects. To test this hypothesis, apolipoprotein E (apoE)-knockout (KO) mice were treated with myriocin, a potent inhibitor of serine palmitoyltransferase, the rate-limiting enzyme in SM biosynthesis. Methods and Results-Diet-admix treatment of apoE-KO mice with myriocin in Western diet for 12 weeks lowered SM and sphinganine plasma levels. Decreases in sphinganine and SM concentrations were also observed in the liver and aorta of myriocin-treated animals compared with controls. Inhibition of de novo sphingolipid biosynthesis reduced total cholesterol and triglyceride plasma levels. Cholesterol distribution in lipoproteins demonstrated a decrease in ␤-VLDL and LDL cholesterol and an increase in HDL cholesterol. Oil red O staining of total aortas demonstrated reduction of atherosclerotic lesion coverage in the myriocin-treated group. Atherosclerotic plaque area was also reduced in the aortic root and brachiocephalic artery. Conclusions-Inhibition of de novo SM biosynthesis in apoE-KO mice lowers plasma cholesterol and triglyceride levels, raises HDL cholesterol, and prevents development of atherosclerotic lesions.

This article is available online at http://www.jlr.org Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality in the Western world ( 1 ). Elevated levels of LDL-cholesterol (LDL-C) have consistently shown a positive association with the development of CVD, justifying the current therapeutic strategies to prevent CVD primarily by the use of statins. Members of this drug class inhibit HMG-CoA reductase (HMGR), the rate-limiting enzyme for de novo cholesterol synthesis, thereby leading to decreased LDL-C ( 2-4 ). While the benefi ts of statins have been documented ( 2 ), many individuals on statin therapy still remain at a higher risk of developing CVD. It is possible this residual risk is a result of other metabolic syndrome (MetS) risk factors characterized by dyslipidemia and insulin resistance and is also in part due to statin intolerance ( 5-7 ) and noncompliance often related to statininduced myalgia ( 8, 9 ). Statins are effective at decreasing LDL-C and CVD; however, frequent muscle-related side effects limit dosage and impede maximal risk reduction in dyslipidemic patients ( 10 ). Furthermore, recent evidence suggests that high-dose statins may increase the risk of developing type 2 diabetes (T2D) ( 11 ), further justifying the need for alternative therapeutic interventions that have statin-like effects for lowering LDL-C and are designed to Abstract ETC-1002 (8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid) is a novel investigational drug being developed for the treatment of dyslipidemia and other cardio-metabolic risk factors. The hypolipidemic, anti-atherosclerotic, anti-obesity, and glucose-lowering properties of ETC-1002, characterized in preclinical disease models, are believed to be due to dual inhibition of sterol and fatty acid synthesis and enhanced mitochondrial long-chain fatty acid ␤ -oxidation. However, the molecular mechanism(s) mediating these activities remained undefi ned.