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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.To assess the LDL-C lowering effect of bempedoic acid in patients not taking statins.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). The primary endpoint for all studies was the percent change from baseline to week 12 in LDL-C levels. Safety and tolerability were assessed by laboratory values and adverse events.In the Phase 3 No Statin Cohort, bempedoic acid (n = 394) lowered LDL-C levels at week 12 significantly more than placebo (n = 192; -26.5% [95% CI, -29.7%, -23.2%]; P0.001). The fixed-dose combination of bempedoic acid with ezetimibe lowered LDL-C by 39.2% (95% CI, -51.7% to -26.7%; P0.001). Muscle-related disorders occurred at a rate of 26.4 and 28.6 per 100 person-years with bempedoic acid and placebo, respectively.In patients with hypercholesterolemia unable to take statins, bempedoic acid lowered LDL-C levels by a mean of 26.5% vs placebo and bempedoic acid + ezetimibe fixed-dose combination lowered LDL-C by 39.2%. The treatments were generally well tolerated, suggesting that bempedoic acid may be efficacious and well tolerated in this challenging-to-treat patient population.

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. Patients had to have an LDL cholesterol level of at least 70 mg per deciliter while they were receiving maximally tolerated statin therapy with or without additional lipid-lowering therapy. (Maximally tolerated statin therapy was defined as the highest intensity statin regimen that a patient was able to maintain, as determined by the investigator.) Patients were randomly assigned in a 2:1 ratio to receive bempedoic acid or placebo. The primary end point was safety, and the principal secondary end point (principal efficacy end point) was the percentage change in the LDL cholesterol level at week 12 of 52 weeks. RESULTS The trial involved 2230 patients, of whom 1488 were assigned to receive bempedoic acid and 742 to receive placebo. The mean (±SD) LDL cholesterol level at baseline was 103.2±29.4 mg per deciliter. The incidence of adverse events (1167 of 1487 patients [78.5%] in the bempedoic acid group and 584 of 742 [78.7%] in the placebo group) and serious adverse events (216 patients [14.5%] and 104 [14.0%], respectively) did not differ substantially between the two groups during the intervention period, but the incidence of adverse events leading to discontinuation of the regimen was higher in the bempedoic acid group than in the placebo group (162 patients [10.9%] vs. 53 [7.1%]), as was the incidence of gout (18 patients [1.2%] vs. 2 [0.3%]). At week 12, bempedoic acid reduced the mean LDL cholesterol level by 19.2 mg per deciliter, representing a change of −16.5% from baseline (difference vs. placebo in change from baseline, –18.1 percentage points; 95% confidence interval, –20.0 to –16.1; P

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). D‐4F was safe and well‐tolerated. Mean ± SD plasma D‐4F area under the curve (AUC, 0–8h) was 6.9 ± 5.7 ng/mL*h (100 mg), 22.7 ± 19.6 ng/mL*h (300 mg), and 104.0 ± 60.9 ng/mL*h (500 mg) among men, higher among women. Whereas placebo dropped HDL inflammatory index (HII) 28% 8 h postdose (range, 1.25–0.86), 300–500 mg D‐4F effectively halved HII: 1.35–0.57 and 1.22–0.63, respectively (P < 0.03 vs. placebo). Oral D‐4F peptide dose predicted HII suppression, whereas plasma D‐4F exposure was dissociated, suggesting plasma penetration is unnecessary. In conclusion, oral D‐4F dosing rendered HDL less inflammatory, affirming oral D‐4F as a potential therapy to improve HDL function.

Homozygous familial hypercholesterolemia is a genetic disorder characterized by low-density lipoprotein (LDL)-receptor dysfunction, markedly elevated levels of LDL-cholesterol (LDL-C) and premature atherosclerosis. Patients are often poorly responsive to conventional lipid-lowering therapies that upregulate LDL-receptor expression.1 Lomitapide inhibits microsomal triglyceride transfer protein, which lipidates nascent apolipoprotein (apo)B-containing lipoproteins. In a pivotal 78-week open-label trial, lomitapide, titrated to the maximal tolerable dose, decreased LDL-C by 50% at the end of the efficacy phase (week 26) in patients with homozygous familial hypercholesterolemia.2 The principal adverse events included gastrointestinal disturbances, hepatic enzyme elevations, and increased liver fat. Here we provide additional long-term efficacy and safety data, including an exploratory analysis of the potential metabolic consequences of hepatic fat accumulation from an extension trial (NCT00943306). Patients continued on lomitapide at the maximally tolerated dose until transition to commercial or compassionate lomitapide. Lipid-lowering therapies, including apheresis, could be modified at the investigator’s discretion if LDL-C was

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. Subjects A total of 130 healthy volunteers (114 subjects in study 1 and 16 subjects in study 2). Intervention In study 1, subjects were enrolled sequentially to one of the following eight open-label treatment arms (probe drug + lomitapide): atorvastatin 20 mg + lomitapide 10 mg, atorvastatin 20 mg + lomitapide 60 mg, simvastatin 20 mg + lomitapide 10 mg, rosuvastatin 20 mg + lomitapide 10 mg, rosuvastatin 20 mg + lomitapide 60 mg, fenofibrate 145 mg + lomitapide 10 mg, ezetimibe 10 mg + lomitapide 10 mg, and extended-release niacin 1000 mg + lomitapide 10 mg. Study 2 consisted of the ninth treatment arm: simvastatin 40 mg + lomitapide 60 mg. Subjects received one dose of the probe drug on the morning of day 1. On days 2–7, subjects took their dose of lomitapide once/day in the morning. On day 8, subjects received one dose of lomitapide simultaneously with the same probe drug they took on day 1. Subjects returned 1 week later (day 15) for a final visit to check safety laboratory parameters. Measurements and Main Results A full pharmacokinetic profile was performed for the probe drug on day 1 and day 8 (after 7 days of dosing with lomitapide [i.e., at steady state]). Pharmacokinetic parameters were calculated from the plasma concentration-time data for each day by using noncompartmental methods. Analysis of variance was applied to the ln-transformed maximum concentration (Cmax) and area under the plasma concentration-time curve from time 0–t (AUC0–t) values, and ratios of the means were compared for day 8 versus day 1. Lomitapide increased exposure to the statin medications. The percent least squares means ratios (LSMR%) (90% confidence intervals [CIs]) for AUC0–t of the statin medications with lomitapide at the 60 mg dose were as follows: 129 (115–144) for the sum of the active atorvastatin moieties, 168 (139–203) for simvastatin acid, and 132 (112–157) for rosuvastatin. The LSMR% (90% CI) for Cmax was 138 (120–160) for the sum of the active atorvastatin moieties, 157 (133–186) for simvastatin acid, and 104 (82–32) for rosuvastatin. The LSMRs were not appreciably altered for the other probe drugs. Conclusion This study shows that lomitapide is a weak inhibitor of CYP3A4 and increased the exposure of statin medications. Careful monitoring of adverse events of CYP3A4-metabolized statins should be used when initiating therapy with lomitapide.

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. In total, 26 and 31 subjects in the IY and EUC arms, respectively, completed the study. There were no differences in BP between the groups at 6 and 12 weeks. In the EUC group, 24-h systolic BP (SBP), diastolic BP (DBP) and mean arterial pressure (MAP) significantly decreased by 5, 3 and 3 mmHg, respectively, from baseline at 6 weeks (P< .05), but were no longer significant at 12 weeks. In the IY group, 24 h SBP was reduced by 6 mmHg at 12 weeks compared to baseline (P= .05). 24 h DBP (P< .01) and MAP (P< .05) decreased significantly each by 5 mmHg. No differences were observed in catecholamine or cortisol metabolism to explain the decrease in BP in the IY group at 12 weeks. Twelve weeks of IY produces clinically meaningful improvements in 24 h SBP and DBP. Larger studies are needed to establish the long term efficacy, acceptability, utility and potential mechanisms of IY to control BP.

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.A double-blind, placebo-controlled, randomized trial was conducted at a U.S. academic medical center. Sixty three patients with National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III)-defined metabolic syndrome were included. The primary end point was a change in the insulin sensitivity index derived from a frequently sampled intravenous glucose tolerance test. Prespecified secondary end points included changes in other measurements of glucose metabolism, oxidative stress, fasting serum lipids, and high sensitivity C-reactive protein.After 16 weeks of CrPic treatment, there was no significant change in insulin sensitivity index between groups (P = 0.14). However, CrPic increased acute insulin response to glucose (P 0.02). CrPic had no significant effect on other measures of glucose metabolism, body weight, serum lipids, or measures of inflammation and oxidative stress.CrPic at 1000 microg/day does not improve key features of the metabolic syndrome in obese nondiabetic 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. D-4F was detectable in plasma at all doses with a T(max) of 30 min, 1 h, and 2 h for 30, 100, and > or = 300 mg, respectively. The area under the curve((0-t)) was 27.81 ng/hr/ml and 54.71 ng/hr/ml for the 300 mg and 500 mg dose groups, respectively, and 17.96 ng/hr/ml for the 500 mg dose given with food. HDL from each time point for each subject was tested for its ability to inhibit LDL-induced monocyte chemotactic activity in cultures of human aortic endothelial cells. The values obtained were normalized to 1.0 for LDL alone to obtain the HDL inflammatory index. This index significantly improved at 4 h at the 300 mg dose and at 2 h at the 500 mg dose compared with placebo (P < 0.05). There were no changes in plasma lipid or lipoprotein levels. We conclude that unformulated D-4F has low bioavailability that is improved under fasting conditions, and that a single dose of D-4F is safe and well tolerated and may improve the HDL anti-inflammatory index.

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.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. Fasting lipoproteins, measures of insulin resistance, inflammation, oxidative stress, and safety were assessed at 0, 5 and 10 weeks.Flaxseed was well-tolerated, and increased serum levels of ALA (p0.001). Compared to wheat, flaxseed significantly reduced LDL-C at 5 weeks (-13%, p0.005), but not at 10 weeks (-7%, p = 0.07). Flaxseed reduced lipoprotein a (Lp[a]) by a net of 14% (p = 0.02), and reduced the homeostatic model assessment of insulin resistance (HOMA-IR) index by 23.7% (p = 0.03) compared to wheat at 10 weeks, but did not affect markers of inflammation (IL-6, Hs-CRP) or oxidative stress (ox LDL, urinary isoprostanes) at any time points. In men, flaxseed reduced HDL-C concentrations by a net of 16% (p = 0.03) and 9% (p = 0.05) at 5 and 10 weeks, respectively.Ground flaxseed has a modest but short lived LDL-C lowering effect, yet reduces Lp(a) and improves insulin sensitivity in hyperlipidemic adults. The HDL-C lowering effect of flaxseed in men warrants additional study.

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.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 [1.0 mmol per liter]), 9 of whom were also treated with 20 mg of atorvastatin daily. All the subjects received placebo for four weeks and then received 120 mg of torcetrapib daily for the following four weeks. Six of the subjects who did not receive atorvastatin also participated in a third phase, in which they received 120 mg of torcetrapib twice daily for four weeks.Treatment with 120 mg of torcetrapib daily increased plasma concentrations of HDL cholesterol by 61 percent (P0.001) and 46 percent (P=0.001) in the atorvastatin and non-atorvastatin cohorts, respectively, and treatment with 120 mg twice daily increased HDL cholesterol by 106 percent (P0.001). Torcetrapib also reduced low-density lipoprotein (LDL) cholesterol levels by 17 percent in the atorvastatin cohort (P=0.02). Finally, torcetrapib significantly altered the distribution of cholesterol among HDL and LDL subclasses, resulting in increases in the mean particle size of HDL and LDL in each cohort.In subjects with low HDL cholesterol levels, CETP inhibition with torcetrapib markedly increased HDL cholesterol levels and also decreased LDL cholesterol levels, both when administered as monotherapy and when administered in combination with a statin.

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. Limited data on resistance exercise suggest that this type of physical activity may reduce LDL cholesterol. Although these lipid effects are modest and variable, they are likely to be particularly important in reducing the morbidity and mortality from CHD on a population level, and may be especially important in patients with atherogenic dyslipidemia.

Background: Soy isoflavones are being evaluated as chemopreventive agents for breast and other cancers. Objective: The objective was to perform safety and pharmacokinetic studies of purified unconjugated isoflavone preparations containing genistein, daidzein, and glycitein in postmenopausal women. Design: Twenty-four healthy postmenopausal women ingested a single dose of 1 of 2 purified (from soybeans) isoflavone preparations that delivered a genistein dose of 2, 4, 8, or 16 mg/kg body wt. These doses were higher than those previously administered to human females. Toxicity studies were performed 24 h and 3, 6, 14, and 30 d after isoflavone administration. Kinetic studies were performed during the first 24 h. Results: We observed a 7% decrease in systolic and diastolic blood pressure and a 32% decrease in the neutrophil count 24 h after treatment with formulation A. Isolated episodes of nausea, pedal edema, and breast tenderness were judged to be possibly related to the study treatment. The terminal plasma half-lives for free genistein, daidzein, and glycitein averaged 3.8, 7.7, and 3.4 h, respectively. The terminal pseudo half-lives for total genistein and total daidzein in plasma averaged 10.1 and 10.8 h, respectively. The estimated bioavailabilities of both total genistein and total daidzein from each of the 2 formulations were not significantly different. Conclusions: A single-dose administration of purified unconjugated isoflavones at amounts that exceed normal dietary intakes had minimal clinical toxicity in healthy postmenopausal women. The pharmacokinetic data suggest that chronic dosing at 12‐24-h intervals would not lead to progressive accumulation of these isoflavones. Am J Clin Nutr 2002;76:1126‐37.

Background: Soy isoflavones are potential cancer chemoprevention treatments. Objective: We conducted safety studies of purified unconjugated genistein, daidzein, and glycitein, and defined pharmacokinetic parameters for their absorption and metabolism. Design: Thirty healthy men ingested a single dose of 1 of 2 isoflavone preparations purified from soy. The delivered doses of genistein (1, 2, 4, 8, or 16 mg/kg body wt) were higher than those previously administered to humans. Formulation A was composed of 90 ± 5% genistein, 10% daidzein, and 1% glycitein. Formulation B was composed of 43% genistein, 21% daidzein, and 2% glycitein. Results: We observed no clinically significant behavioral or physical changes after treatment. We observed elevations in lipoprotein lipase and hypophosphatemia that were possibly related to the treatment but that were associated with no clinical toxicity. Considerable quantities of isoflavones were excreted in urine as conjugates. The terminal elimination rate, elimination half-life, area under the curve, maximum plasma concentration, apparent systemic clearance, and volume of distribution were estimated for genistein and daidzein. The mean elimination halflives with both formulations were 3.2 h for free genistein and 4.2 h for free daidzein. The mean pseudo half-lives were 9.2 h for total genistein and 8.2 h for total daidzein. Conclusions: Dietary supplements of purified unconjugated isoflavones administered to humans in single doses exceeding normal dietary intake manyfold resulted in minimal clinical toxicity. Genistein and daidzein (free and total) were rapidly cleared from plasma and excreted in urine. Am J Clin Nutr 2002;75:126‐36.

Summary 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. Current lipid lowering therapy was maintained from 6 weeks before baseline through to at least week 26. Lomitapide dose was escalated on the basis of safety and tolerability from 5 mg to a maximum of 60 mg a day. The primary endpoint was mean percent change in levels of LDL cholesterol from baseline to week 26, after which patients remained on lomitapide through to week 78 for safety assessment. Percent change from baseline to week 26 was assessed with a mixed linear model. Findings 29 men and women with homozygous familial hypercholesterolaemia, aged 18 years or older, were recruited from 11 centres in four countries (USA, Canada, South Africa, and Italy). 23 of 29 enrolled patients completed both the efficacy phase (26 weeks) and the full study (78 weeks). The median dose of lomitapide was 40 mg a day. LDL cholesterol was reduced by 50% (95% CI −62 to −39) from baseline (mean 8·7 mmol/L [SD 2·9]) to week 26 (4·3 mmol/L [2·5]; p Interpretation Our study suggests that treatment with lomitapide could be a valuable drug in the management of homozygous familial hypercholesterolaemia. Funding FDA Office of the Orphan Product Development, Aegerion Pharmaceuticals.

Objective— The study of PPAR-α activation on apoA-I production in humans has been limited to fibrates, relatively weak PPAR-α agonists that may have other molecular effects. We sought to determine the effect of a potent and highly specific PPAR-α 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 μg) once daily (n=13) or placebo (n=15) for 8 weeks. Subjects underwent a kinetic study using a deuterated leucine tracer to measure apolipoprotein production and fractional catabolic rates (FCR) at baseline and after treatment. LY518674 significantly reduced VLDL-C (−38%, P =0.002) and triglyceride (−23%, P =0.002) levels whereas LDL-C and HDL-C levels were unchanged. LY518674 significantly reduced VLDL apoB-100 (−12%, P =0.01) levels, attributable to an increased VLDL apoB-100 FCR with no change in VLDL apoB-100 production. IDL and LDL apoB-100 kinetics were unchanged. LY518674 significantly increased the apoA-I production rate by 31% ( P P =0.002), resulting in no change in plasma apoA-I. There was a 71% increase in the apoA-II production rate ( P P Conclusions— Activation of PPAR-α with LY518674 (100 μg) in subjects with metabolic syndrome and low HDL-C increased the VLDL apoB-100 FCR consistent with enhanced lipolysis of plasma triglyceride. Significant increases in the apoA-I and apoA-II production rates were accompanied by increased FCRs resulting in no change in HDL-C levels. These data indicate a major effect of LY518674 on the production and clearance of apoA-I and HDL despite no change in the plasma concentration. The effect of these changes on reverse cholesterol transport remains to be determined.

Background Niacin and pioglitazone (PIO) increase HDL by uncertain mechanisms. Both increase adiponectin, whose effects on carbohydrate and fatty acid metabolism may benefit HDL indirectly. Little is known of the combined effects of the drugs on adiponectin and other adipokines. We hypothesized that PIO would complement changes in adipokines from niacin, and in turn, augment HDL. Methods In an open-label run-in, non-diabetics with low HDL titrated from 0 to 2 g extended-release niacin over 4 weeks, and were randomized to add PIO 30 mg or placebo in a double-blind manner. After 6 weeks, PIO was increased to 45 mg for another 6 weeks. We assessed changes in fasting adiponectin, resistin, complement C3 (the serum-detectable precursor of acylation stimulating protein), free fatty acids (FFA), hydroxy-butyrate (HBA), and triglycerides (TG), and their relationship to changes in HDL. Results Of 72 completers, 34 took niacin and placebo and 38 took niacin and PIO. The table shows absolute and relative change of each analyte from baseline to 16 weeks. Relative change in adiponectin was strongly correlated with change in HDL (Spearman’s rho +0.49, p Conclusion Pioglitazone augments niacin-induced changes in adiponectin and complement C3 thought to be favorable, and neutralizes niacin’s unfavorable increase in FFA. Adiponectin strongly predicted HDL after adjustment for TG. Since PIO had no independent effect on TG, we speculate that additional HDL-raising from PIO is mediated by the large increase in adiponectin. In summary, PIO enhances HDL-raising from niacin in proportion to increased adiponectin.

Many coronary heart disease patients fail to reach recommended LDL levels, either due to intolerance or inadequate response to available lipid-lowering therapy. Microsomal triglyceride transfer protein (MTP) inhibitors may provide a novel alternative pathway for LDL lowering. In this paper the authors tested the safety and LDL lowering efficacy of the MTP inhibitor, AEGR-733, alone and in combination with ezetimibe. 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., Bridgewater, NJ), alone and in combination with ezetimibe. Methods We performed a multicenter, double-blind, 12-week trial, which included 84 patients with hypercholesterolemia. Patients were randomly assigned ezetimibe 10 mg daily (n = 29); AEGR-733 5.0 mg daily for the first 4 weeks, 7.5 mg daily for the second 4 weeks and 10 mg daily for the last 4 weeks (n = 28); or ezetimibe 10 mg daily and AEGR-733 administered with the dose titration described above (n = 28). Results Ezetimibe monotherapy led to a 20–22% decrease in LDL-cholesterol concentrations. AEGR-733 monotherapy led to a dose-dependent decrease in LDL-cholesterol concentration: 19% at 5.0 mg, 26% at 7.5 mg and 30% at 10 mg. Combined therapy produced similar but larger dose-dependent decreases (35%, 38% and 46%, respectively). The number of patients who discontinued study drugs owing to adverse events was five with ezetimibe alone, nine with AEGR-733 alone, and four with combined ezetimibe and AEGR-733. Discontinuations from AEGR-733 were due primarily to mild transaminase elevations. Conclusions Inhibition of LDL production with low-dose AEGR-733, either alone or in combination with ezetimibe, could be an effective therapeutic option for patients unable to reach target LDL-cholesterol levels.

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(-/-)).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. Animals from each genetic background were then divided into 2 groups based on gender and mean plasma total cholesterol (TC). The hApoBtg and LDLr(-/-)/apobec(-/-) mice either continued on the control diet for a total of 31 and 35 days, respectively or were fed 20% w/w whole ground flaxseed (flax) with comparable caloric, macronutrient and fiber content for 21 days. Blood was obtained after a 4 hour fast from all mice prior to feeding both control and flax diets, after 10 days on the flax diet, and after 21 days on the flax at which time all mice were exsanguinated.The control diet increased TC by100 mg/dl in the hApoBtg with a greater increase observed in males and by 800 mg/dl in mice lacking the LDLr. After 3 weeks, the flax diet significantly reduced plasma TC by 19% and 22% in hApoBtg and LDLr(-/-)/apobec(-/-), respectively and non-high density lipoprotein cholesterol (non-HDL-C) by 24% in both models (p for all0.05). Flax significantly reduced hepatic cholesterol in hApoBtg by 32% and 47% in males and females, respectively and LDLr(-/-)/apobec(-/-) mice by 66%. Flax had no effect on the expression of the following hepatic genes: LDLr, 3-hydroxy-3-methylglutaryl (HMG) CoA reductase, phospholipid transfer protein, cholesterol 7alpha hydroxylase, fatty acid synthase, and acyl CoA oxidase in either mouse model.Flaxseed reduces plasma and hepatic cholesterol in hApoBtg mice, but had no effect on hepatic lipogenic genes and was equally effective in mice lacking LDLr. The combined data suggest that the lipid lowering effect of flax is not hepatic mediated and may be at the level of cholesterol absorption and/or bile acid reabsorption.

Background— PPAR-γ agonists improve insulin sensitivity and glycemic control in type 2 diabetes and may reduce atherosclerosis progression. Thus, PPAR-γ agonists may be an effective therapy for metabolic syndrome. However, the full spectrum of potentially antiatherogenic mechanisms of PPAR-γ agonists have not been fully tested in nondiabetic patients with metabolic syndrome. Methods and Results— We performed a prospective, double-blinded, placebo-controlled study of 60 nondiabetic subjects with low high-density lipoprotein cholesterol (HDL-C) level and metabolic syndrome to rosiglitazone 8 mg daily or placebo for 12 weeks. We found no significant effect of rosiglitazone on HDL-C (+5.5% versus +5.8%, P =0.89), and an increase in total cholesterol (+8% versus −1%; P =0.03). Nevertheless, rosiglitazone significantly increased adiponectin (+168% versus +25%; P P =0.009), C-reactive protein (−32% versus +36%, P =0.002), interleukin (IL)-6 (−22% versus +4%, P P Conclusions— These findings suggest that rosiglitazone, presumably through its PPAR-γ agonist properties, has direct effects on inflammatory markers and adipokines in the absence of favorable lipid effects. These findings may help explain the mechanism underlying the possible antiatherosclerotic effects of rosiglitazone.

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 r =0.34; P =0.01) but not to changes in insulin resistance. PIO did not affect serum triglycerides or low-density lipoprotein (LDL) cholesterol concentrations but reduced the number of small LDL particles by 18% ( P P P =0.02) while increasing mean serum levels of adiponectin by 111% ( P Conclusions— In nondiabetic patients with low HDL-C and MetSyn, PIO significantly raised HDL-C and favorably affected lipoprotein particle size, markers of inflammation, and adipokines without changes in triglycerides, LDL-C, or weight. These results suggest that PIO has direct effects on HDL, which may contribute to its antiatherogenic effects.

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. More research is needed to define the role of this functional food in reducing cardiovascular risk.

ContextHerbal 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.ObjectiveTo study the short-term safety and efficacy of 2 doses of a standardized guggul extract (guggulipid, containing 2.5% guggulsterones) in healthy adults with hyperlipidemia eating a typical Western diet.DesignDouble-blind, randomized, placebo-controlled trial using a parallel design, conducted March 2000-August 2001.Participants and SettingA total of 103 ambulatory, community-dwelling, healthy adults with hypercholesterolemia in the Philadelphia, Pa, metropolitan area.InterventionOral, 3 times daily doses of standard-dose guggulipid (1000 mg), high-dose guggulipid (2000 mg), or matching placebo.Main Outcome MeasuresPercentage change in levels of directly measured low-density lipoprotein cholesterol (LDL-C) after 8 weeks of therapy. Secondary outcome measures included levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C), triglycerides, and directly measured very low-density lipoprotein cholesterol (VLDL-C), as well as adverse events reports and laboratory safety measures including electrolyte levels and hepatic and renal function.ResultsCompared with participants randomized to placebo (n = 36), in whom levels of LDL-C decreased by 5%, both standard-dose guggulipid (n = 33) and high-dose guggulipid (n = 34) raised levels of LDL-C by 4% (P = .01 vs placebo) and 5% (P = .006 vs placebo), respectively, at 8 weeks, for a net positive change of 9% to 10%. There were no significant changes in levels of total cholesterol, HDL-C, triglycerides, or VLDL-C in response to treatment with guggulipid in the intention-to-treat analysis. While guggulipid was generally well tolerated, 6 participants treated with guggulipid developed a hypersensitivity rash compared with none in the placebo group.ConclusionsDespite plausible mechanisms of action, guggulipid did not appear to improve levels of serum cholesterol over the short term in this population of adults with hypercholesterolemia, and might in fact raise levels of LDL-C. Guggulipid also appeared to cause a dermatologic hypersensitivity reaction in some patients.