Safety of bempedoic acid in patients at high cardiovascular risk and with statin intolerance.

Background: Bempedoic acid is an oral adenosine triphosphate citrate lyase (ACL) inhibitor that lowers low-density lipoprotein cholesterol (LDL-C) blood levels. The Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen (CLEAR) Outcomes study demonstrated that bempedoic acid reduced cardiovascular (CV) risk in patients at high risk for CV events who were unwilling or unable to take guideline-recommended doses of statins.

Objective: To describe detailed safety information from CLEAR Outcomes, including events in the United States (US) prescribing information based on previous phase 3 hyperlipidemia studies.

Efficacy and safety of bempedoic acid in patients not receiving statins in phase 3 clinical trials.

Background: Despite the high incidence of patients with statin tolerance problems, randomized evaluations of nonstatin oral treatment options for lowering of low-density lipoprotein cholesterol (LDL-C) in this population are sparse.

Objective: To assess the LDL-C lowering effect of bempedoic acid in patients not taking statins.

Methods: This was a pooled analysis of data from patients enrolled in four phase 3 bempedoic acid studies (12 to 52 weeks in duration) who were not taking concomitant statins (Phase 3 No Statin Cohort) and a phase 3 bempedoic acid plus ezetimibe fixed-dose combination study (BA+EZE FDC No Statin Cohort).

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.

Efficacy and Safety of Bempedoic Acid in Patients With Hypercholesterolemia and Statin Intolerance.

Background Inability to tolerate statins because of muscle symptoms contributes to uncontrolled cholesterol levels and insufficient cardiovascular risk reduction. Bempedoic acid, a prodrug that is activated by a hepatic enzyme not present in skeletal muscle, inhibits ATP -citrate lyase, an enzyme upstream of β-hydroxy β-methylglutaryl-coenzyme A reductase in the cholesterol biosynthesis pathway. Methods and Results The phase 3, double-blind, placebo-controlled CLEAR (Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen) Serenity study randomized 345 patients with hypercholesterolemia and a history of intolerance to at least 2 statins (1 at the lowest available dose) 2:1 to bempedoic acid 180 mg or placebo once daily for 24 weeks.

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.

Oral Apolipoprotein A-I Mimetic D-4F Lowers HDL-Inflammatory Index in High-Risk Patients: A First-in-Human Multiple-Dose, Randomized Controlled Trial.

A single dose of the apolipoprotein (apo)A-I mimetic peptide D-4F rendered high-density lipoprotein (HDL) less inflammatory, motivating the first multiple-dose study. We aimed to assess safety/tolerability, pharmacokinetics, and pharmacodynamics of daily, orally administered D-4F. High-risk coronary heart disease (CHD) subjects added double-blinded placebo or D-4F to statin for 13 days, randomly assigned 1:3 to ascending cohorts of 100, 300, then 500 mg (n = 62; 46 men/16 women).

Pharmacokinetic interactions of the microsomal triglyceride transfer protein inhibitor, lomitapide, with drugs commonly used in the management of hypercholesterolemia.

Study Objective: To characterize the effects of two doses (10 and 60 mg) of lomitapide—a microsomal triglyceride transfer protein inhibitor approved as adjunct treatment to lower low-density lipoprotein cholesterol levels in patients with homozygous familial hypercholesterolemia—on the pharmacokinetics of several lipid-lowering therapies: atorvastatin, simvastatin, rosuvastatin, fenofibrate, ezetimibe, and niacin.

Design: Two prospective open-label studies (study 1 and study 2).

Setting: Two clinical research units.

Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study.

Background: Patients with homozygous familial hypercholesterolaemia respond inadequately to existing drugs. We aimed to assess the efficacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in adults with this disease.

Methods: We did a single-arm, open-label, phase 3 study of lomitapide for treatment of patients with homozygous familial hypercholesterolemia.

Effect of rosiglitazone on HDL metabolism in subjects with metabolic syndrome and low HDL.

Treatment with the peroxisome proliferator-activated receptor γ agonist rosiglitazone has been reported to increase HDL-cholesterol (HDL-C) levels, although the mechanism responsible for this is unknown. We sought to determine the effect of rosiglitazone on HDL apolipoprotein A-I (apoA-I) and apoA-II metabolism in subjects with metabolic syndrome and low HDL-C. Subjects were treated with placebo followed by rosiglitazone (8 mg) once daily.

Iyengar Yoga versus Enhanced Usual Care on Blood Pressure in Patients with Prehypertension to Stage I Hypertension: a Randomized Controlled Trial.

The prevalence of prehypertension and Stage 1 hypertension continues to increase despite being amenable to non-pharmacologic interventions. Iyengar yoga (IY) has been purported to reduce blood pressure (BP) though evidence from randomized trials is lacking. We conducted a randomized controlled trial to assess the effects of 12 weeks of IY versus enhanced usual care (EUC) (based on individual dietary adjustment) on 24-h ambulatory BP in yoga-naïve adults with untreated prehypertension or Stage 1 hypertension.

Chromium picolinate does not improve key features of metabolic syndrome in obese nondiabetic adults.

Background: The use of chromium-containing dietary supplements is widespread among patients with type 2 diabetes. Chromium's effects in patients at high risk for developing diabetes, especially those with metabolic syndrome, is unknown. The objective of this study was to determine the effects of chromium picolinate (CrPic) on glucose metabolism in patients with metabolic syndrome.

Potent and selective PPAR-alpha agonist LY518674 upregulates both ApoA-I production and catabolism in human subjects with the metabolic syndrome.

Objective: The study of PPAR-alpha activation on apoA-I production in humans has been limited to fibrates, relatively weak PPAR-alpha agonists that may have other molecular effects. We sought to determine the effect of a potent and highly specific PPAR-alpha agonist, LY518674, on apoA-I, apoA-II, and apoB-100 kinetics in humans with metabolic syndrome and low levels of HDL cholesterol (C).

Methods And Results: Subjects were randomized to receive LY518674 (100 microg) once daily (n=13) or placebo (n=15) for 8 weeks.

Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia.

Background: Many patients with coronary heart disease do not achieve recommended LDL-cholesterol levels, due to either intolerance or inadequate response to available lipid-lowering therapy. Microsomal triglyceride transfer protein (MTP) inhibitors might provide an alternative way to lower LDL-cholesterol levels. We tested the safety and LDL-cholesterol-lowering efficacy of an MTP inhibitor, AEGR-733 (Aegerion Pharmaceuticals Inc.

Flaxseed and cardiovascular risk factors: results from a double blind, randomized, controlled clinical trial.

Objective: Flaxseed is a rich source of alpha linolenic acid (ALA), fiber and lignans, making it a potentially attractive functional food for modulating cardiovascular risk. We studied the effects of flaxseed on markers of cardiovascular risk in hypercholesterolemic adults.

Methods: Sixty-two men and post-menopausal women with pre-study low density lipoprotein cholesterol (LDL-C) between 130 and 200 mg/dl were randomized to 40g/day of ground flaxseed-containing baked products or matching wheat bran products for 10 weeks while following a low fat, low cholesterol diet.

Safety, pharmacokinetics, and pharmacodynamics of oral apoA-I mimetic peptide D-4F in high-risk cardiovascular patients.

Patients with coronary heart disease or equivalent risk received a single dose of 30, 100, 300, or 500 mg of unformulated D-4F (n = 8, each dose) or placebo (n = 8) under fasting conditions. An additional 10 patients received 500 mg (n = 8) or placebo (n = 2) with a low-fat meal. There were no significant trends in any safety parameter.

Flaxseed reduces plasma cholesterol levels in hypercholesterolemic mouse models.

Objective: We examined the effects of whole ground flaxseed added to a Western diet on plasma and hepatic lipids and hepatic gene expression in male and female human apolipoprotein B-100 transgenic (hApoBtg) mice which have a plasma lipid profile more closely resembling man than wild type mice and in mice lacking the low density lipoprotein receptor (LDLr) and apolipoprotein B mRNA editing enzyme complex 1 (LDLr(-/-)/apobec(-/-)).

Methods: The Westernized control diet containing 0.1% cholesterol and 30% kcal as fat was fed for 10 days to hApoBtg mice and for 14 days to LDLr(-/-)/apobec(-/-) mice.

Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia.

Background: Patients with homozygous familial hypercholesterolemia have markedly elevated cholesterol levels, which respond poorly to drug therapy, and a very high risk of premature cardiovascular disease. Inhibition of the microsomal triglyceride transfer protein may be effective in reducing cholesterol levels in these patients.

Methods: We conducted a dose-escalation study to examine the safety, tolerability, and effects on lipid levels of BMS-201038, an inhibitor of the microsomal triglyceride transfer protein, in six patients with homozygous familial hypercholesterolemia.

Effects of rosiglitazone on lipids, adipokines, and inflammatory markers in nondiabetic patients with low high-density lipoprotein cholesterol and metabolic syndrome.

Background: PPAR-gamma agonists improve insulin sensitivity and glycemic control in type 2 diabetes and may reduce atherosclerosis progression. Thus, PPAR-gamma agonists may be an effective therapy for metabolic syndrome. However, the full spectrum of potentially antiatherogenic mechanisms of PPAR-gamma agonists have not been fully tested in nondiabetic patients with metabolic syndrome.

Effects of pioglitazone on lipoproteins, inflammatory markers, and adipokines in nondiabetic patients with metabolic syndrome.

Objective: The purpose of this research was to evaluate the short-term effects of pioglitazone (PIO) on high-density lipoprotein cholesterol (HDL-C) and other metabolic parameters in nondiabetic patients with metabolic syndrome (MetSyn).

Methods And Results: Sixty nondiabetic adults with low HDL-C and MetSyn were randomized to PIO or matching placebo for 12 weeks. PIO increased HDL-C by 15% and 14% at 6 and 12 weeks, respectively, compared with placebo (P<0.

Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol.

Background: Decreased high-density lipoprotein (HDL) cholesterol levels constitute a major risk factor for coronary heart disease; however, there are no therapies that substantially raise HDL cholesterol levels. Inhibition of cholesteryl ester transfer protein (CETP) has been proposed as a strategy to raise HDL cholesterol levels.

Methods: We conducted a single-blind, placebo-controlled study to examine the effects of torcetrapib, a potent inhibitor of CETP, on plasma lipoprotein levels in 19 subjects with low levels of HDL cholesterol (<40 mg per deciliter [1.

Flaxseed and cardiovascular risk.

Flaxseed has recently gained attention in the area of cardiovascular disease primarily because it is the richest known source of both alpha-linolenic acid (ALA) and the phytoestrogen, lignans, as well as being a good source of soluble fiber. Human studies have shown that flaxseed can modestly reduce serum total and low-density lipoprotein cholesterol concentrations, reduce postprandial glucose absorption, decrease some markers of inflammation, and raise serum levels of the omega-3 fatty acids, ALA and eicosapentaenoic acid. Data on the antiplatelet, antioxidant, and hypotensive effects of flaxseed, however, are inconclusive.

Physical activity and its effects on lipids.

Physical activity is an important component of weight control, and is widely recommended to prevent and treat obesity-related complications such as diabetes and coronary heart disease (CHD). Although the cardiovascular benefits of increased physical activity are likely multifactorial, much of the attention has been focused on the known high-density lipoprotein (HDL) cholesterol-raising properties of regular physical activity. Physical activity, however, can also reliably lower triglycerides and favorably affect both low-density lipoprotein (LDL) and HDL particle sizes.

Guggulipid for the treatment of hypercholesterolemia: a randomized controlled trial.

Context: Herbal extracts from Commiphora mukul (guggul) have been widely used in Asia as cholesterol-lowering agents, and their popularity is increasing in the United States. Recently, guggulsterones, the purported bioactive compounds of guggul, have been shown to be potent antagonists of 2 nuclear hormone receptors involved in cholesterol metabolism, establishing a plausible mechanism of action for the hypolipidemic effects of these extracts. However, there are currently no published safety or efficacy data on the use of guggul extracts in Western populations.