Search

A pilot randomized, double-blind placebo-controlled trial was conducted to assess the effects of orticumab, a monoclonal antibody that targets oxidized low-density lipoprotein (oxLDL), on coronary inflammation in patients with psoriasis. The study found that treatment with orticumab reduced the Fat Attenuation Index (FAI) score, a measure of coronary inflammation, in patients with high levels of inflammation but had no effect in those with low levels of inflammation. The study suggests that targeting oxLDL with orticumab may reduce coronary inflammation and potentially lower the risk of fatal cardiac events in patients with elevated inflammation. However, further research is needed to fully understand the mechanisms and clinical implications of this treatment. [Extracted from the article]

Objectives Changes in cIMT have not been consistently correlated with cardiovascular risk reduction in clinical studies. The variability of carotid intima media thickness (cIMT) changes in published statin LDL-C-lowering studies in relation to various baseline and study characteristics was assessed. Methods This was an exploratory analysis of study-level data pooled from statin-treatment arms of 13 studies conducted during 1988–2006. Baseline mean common carotid artery (CCA)/cIMT, maximum mean CCA/cIMT and LDL-C levels, and annualized cIMT changes were estimated for the overall studies, those conducted before/after 2000, and in risk-based subgroups. Potential relationships between prespecified covariates and cIMT changes were assessed. Results Baseline mean CCA/cIMT and LDL-C levels were higher in the combined studies conducted before year 2000 (0.8521 mm) than after 2000 (0.7458 mm), and somewhat higher in study populations of patients with coronary heart disease risk and those with greater LDL-C reductions. Mean CCA/cIMT changes were also larger for the studies conducted before 2000 (−0.0119 mm/year) than after 2000 (−0.0013 mm/year). Notably, studies conducted before 2000 were of longer duration (≥2 years) than after 2000 (<2 years). Heterogeneity in cIMT change was attributed to baseline and study-design characteristics. Longer study duration and greater LDL-C reductions were significantly related to larger annualized cIMT changes. Maximum cIMT results were similar. Conclusion Baseline cIMT and LDL-C levels were lower, and cIMT changes were smaller in statin cIMT trials conducted after 2000 than those before 2000. These trends are consistent with increased treatment and control of high LDL-C levels over recent years in clinical practice, and may influence the results of cIMT studies. [ABSTRACT FROM AUTHOR]

Triglycerides represent 1 component of a heterogeneous pool of triglyceride-rich lipoproteins (TGRLs). The reliance on triglycerides or TGRLs as cardiovascular disease (CVD) risk biomarkers prompted investigations into therapies that lower plasma triglycerides as a means to reduce CVD events. Genetic studies identified TGRL components and pathways involved in their synthesis and metabolism. We advocate that only a subset of genetic mechanisms regulating TGRLs contribute to the risk of CVD events. This “omic” approach recently resulted in new targets for reducing CVD events. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Reverse cholesterol transport (RCT) can be defined as a pathway of flux of cholesterol from peripheral tissues to the liver for potential excretion into feces. This prospective, placebo-controlled, double-blind crossover study assessed the effect of ezetimibe on several RCT parameters in hyperlipidemic patients. Methods: Following 7 weeks of treatment (ezetimibe 10 mg/day or placebo), 26 patients received 24-h continuous IV infusions of [3,4-13C2]-cholesterol, then took heavy water (2H2O) by mouth. Cholesterol excretion was measured by quantification of neutral/acid sterols in stool and blood samples during 7 days post-infusion with continued treatment. Plasma de novo cholesterol synthesis was assessed by 2H-labeling from 2H2O. Results: Ezetimibe significantly reduced levels of low-density lipoprotein cholesterol (22%, P < 0.001) without significant changes in triglycerides and high-density lipoprotein cholesterol and significantly increased the flux of plasma-derived cholesterol into fecal neutral sterols by 52% (P = 0.04) without change in flux into fecal bile acids. Total fecal neutral sterol output increased by 23% (P = 0.02). Plasma de novo cholesterol synthesis increased by 57% (P < 0.001). The fractional clearance rate (FCR) of plasma cholesteryl-ester trended higher (7%; P = 0.055) with a reduction in absolute cholesteryl-ester production rate (9%, P < 0.01). Whole-body free cholesterol efflux rate from extra-hepatic tissues into plasma was not measurably changed by ezetimibe. Conclusion: Ezetimibe treatment approximately doubled the flux of plasma-derived cholesterol into fecal neutral sterols, in association with increases in total fecal neutral sterol excretion, FCR of plasma cholesterol ester, and plasma de novo cholesterol synthesis. These effects are consistent with increased cholesterol transport through the plasma compartment and excretion from the body, in response to ezetimibe treatment in hyperlipidemic humans. Clintrials.gov: NCT00701727. [Copyright &y& Elsevier]

Objectives: The aim of this study was to assess the lipid-altering efficacy and safety of ETC-1002 in subjects with hypercholesterolemia. Background: ETC-1002 is a small molecule that modulates pathways of cholesterol, fatty acid, and carbohydrate metabolism and may have therapeutic benefits in treating hypercholesterolemia and other cardiometabolic risk factors. Methods: This multicenter, randomized, double-blind, placebo-controlled, parallel-group trial evaluated patients (n = 177) with elevated low-density lipoprotein cholesterol (LDL-C) (130 to 220 mg/dl), who were stratified by baseline triglycerides (not elevated [<150 mg/dl] or elevated [150–<400 mg/dl]) and randomized to receive 40, 80, or 120 mg of ETC-1002 or placebo once daily for 12 weeks. Outcomes included changes in LDL-C (primary endpoint), other lipids, and cardiometabolic risk factors; and safety. Results: ETC-1002 40, 80, and 120 mg lowered least-squares mean ± SE LDL-C levels by 17.9 ± 2.2%, 25.0 ± 2.1%, and 26.6 ± 2.2%, respectively, versus a reduction of 2.1 ± 2.2% with placebo (all, p < 0.0001); LDL-C lowering was similar between the subgroups with nonelevated and elevated triglycerides. ETC-1002 also lowered non–high-density lipoprotein cholesterol (non–HDL-C), apolipoprotein B, and LDL particle number (all, p < 0.0001) in a dose-dependent manner; HDL-C and triglyceride levels were relatively unchanged. Post-hoc analyses suggest that ETC-1002 may have favorable effects on other cardiometabolic risk factors. The ETC-1002 and placebo groups did not demonstrate clinically meaningful differences in adverse events or other safety assessments. Conclusions: ETC-1002 significantly lowered LDL-C levels up to 27% across a broad range of baseline triglycerides and was generally safe and well tolerated. ETC-1002 has a novel mechanism of action and may be useful for reducing LDL-C. (A Study to Assess the Efficacy and Safety of ETC-1002 in Subjects With Elevated Blood Cholesterol and Either Normal or Elevated Triglycerides; NCT01262638) [ABSTRACT FROM AUTHOR]

The aim of this analysis was to evaluate changes in cardiovascular risk factors in obese patients with dyslipidemia and/or hypertension receiving phentermine (PHEN) and top-iramate extended-release (TPM ER). In the 56-week, randomized, double-blind, placebo-controlled, multicenter CONQUER trial, PHEN/TPM ER demonstrated significant weight loss compared with placebo in overweight or obese participants with ≥2 weight-related co-morbidities. Participants with body mass indexes of 27 to 45 kg/m² were randomized to placebo, PHEN 7.5 mg/TPM ER 46 mg, or PHEN 15 mg/TPM ER 92 mg; participants also received lifestyle modification counseling. Primary end points were percentage weight loss and the proportion of participants achieving ≥5% weight loss. Additional end points were changes in lipid variables in the dyslipidemia population and blood pressure in the hypertensive population, stratified by treatment and magnitude of weight loss. PHEN/TPM ER produced significantly greater dose-related mean percentage weight loss compared with placebo in the subgroups of participants with dyslipidemia and those with hypertension. Regardless of treatment group assignment, participants with dyslipidemia who lost >5% of their baseline weight experienced significantly greater reductions in triglycerides (--14.5% to --39.8%), and in non--high-density lipoprotein cholesterol ( -- 9.4% to --14.8%) than those losing <5% of their weight (p <0.05). Similarly, participants with hypertension at baseline showed reduced systolic blood pressure by --7.5 to --11.8 mm Hg (p <0.001 vs those with <5% weight loss). In conclusion, the dose-related weight loss induced by PHEN/TPM ER treatment was accom-panied by significant improvements in cardiovascular disease risk factors in participants who had dyslipidemia or hypertension at baseline, suggesting that facilitating weight loss by augmenting lifestyle changes with pharmacotherapies may decrease the risk for cardiovascular disease in obese and overweight patients with co-morbidities. [ABSTRACT FROM AUTHOR]

Background: Statins are the standard-of-care therapy for reducing low-density lipoprotein cholesterol (LDL-C) levels; however, combination with other lipid-modifying agents may be necessary to normalize lipid profiles in patients with mixed dyslipidemia who, in addition to high LDL-C, also have high triglycerides (TG) and low levels of high-density lipoprotein cholesterol (HDL-C). Objective: This study aimed to evaluate the 1-year efficacy and safety of rosuvastatin in combination with fenofibric acid in a subgroup of patients treated for 12 weeks with rosuvastatin 10mg + fenofibric acid 135mg and subsequently treated for up to 52 weeks with rosuvastatin 20 mg+ fenofibric acid 135 mg. Methods: The efficacy and safety of combination therapy with rosuvastatin + fenofibric acid were demonstrated in a 12-week controlled study (NCT00300482) of patients with mixed dyslipidemia who were randomized to rosuvastatin 10, 20, or 40 mg, fenofibric acid 135 mg, or rosuvastatin 10 or 20mg + fenofibric acid 135 mg. All patients who completed the controlled study were eligible to enroll in a subsequent 52-week open-label extension study (NCT00300430) and received rosuvastatin 20mg + fenofibric acid 135 mg. The present post hoc analysis evaluated patients who were treated with rosuvastatin 10mg + fenofibric acid 135mg in the controlled study and received rosuvastatin 20mg + fenofibric acid 135mg in the open-label extension study. The study was carried out at investigative sites in the US (including Puerto Rico) and Canada. Patients included in the study were men and women ≥18 years of age with mixed dyslipidemia, defined as TG ≥150mg/dL, LDL-C ≥130mg/dL, and HDL-C <40/50mg/dL for men/women (at screening in the controlled trial). Efficacy variables included mean percentage changes in LDL-C, HDL-C, non-HDL-C, and apolipoprotein B (ApoB), andmedian percentage changes in TG and high-sensitivity C-reactive protein (hsCRP) from baseline (i.e. start of the open-label extension after 12 weeks of treatment with rosuvastatin 10mg + fenofibric acid 135 mg) to incremental time points up to 52 weeks in the extension study, and the proportion of patients achieving individual and combined goals for LDL-C and non-HDL-C. Adverse events (AEs) and clinical laboratory values were also assessed. Results: Of the 261 patients initially randomized to rosuvastatin 10mg + fenofibric acid 135 mg, 220 completed the controlled study and 187 continued treatment with rosuvastatin 20mg + fenofibric acid 135mg in the extension study. Increasing the rosuvastatin dose from 10mg to 20mg in combination with fenofibric acid 135mg for up to 52 weeks resulted in significant (p ≤ 0.005 for all comparisons) mean percentage changes from baseline in LDL-C (--9.5%), non-HDL-C (--6.0%), ApoB (--8.5%), and HDL-C (3.6%), while median TG levels remained largely unchanged (0.8%, p = 0.055) at the week 52 visit. Greater percentages of patients achieved their risk-stratified lipid goals at week 52 compared with baseline for LDL-C (89% vs 84%), non-HDL-C (50% vs 25%), and both LDL-C and non-HDL-C (50% vs 19%). Combination therapy was generally well tolerated. The incidence of muscle-, hepatic-, and renal-related AEs and laboratory values were within the expected range. Conclusion: This study demonstrates that 1-year therapy with rosuvastatin + fenofibric acid is well tolerated and that increasing the rosuvastatin dose from 10mg to 20 mg in the combination results in additional beneficial effects on key lipid parameters in patients with mixed dyslipidemia. [ABSTRACT FROM AUTHOR]

The present multicenter, 6-week, randomized, double-blind, parallel-group, clinical trial evaluated the safety and efficacy of ezetimibe (10 mg) added to stable rosuvastatin therapy versus up-titration of rosuvastatin from 5 to 10 mg or from 10 to 20 mg. The study population included 440 subjects at moderately high/high risk of coronary heart disease with low-density lipoprotein (LDL) cholesterol levels higher than the National Cholesterol Education Program Adult Treatment Panel III recommendations (<100 mg/dl for moderately high/high-risk subjects without atherosclerotic vascular disease or <70 mg/dl for high-risk subjects with atherosclerotic vascular disease). Pooled data demonstrated that ezetimibe added to stable rosuvastatin 5 mg or 10 mg reduced LDL cholesterol by 21%. In contrast, doubling rosuvastatin to 10 mg or 20 mg reduced LDL cholesterol by 5.7% (between-group difference of 15.2%, p <0.001). Individually, ezetimibe plus rosuvastatin 5 mg reduced LDL cholesterol more than did rosuvastatin 10 mg (12.3% difference, p <0.001), and ezetimibe plus rosuvastatin 10 mg reduced LDL cholesterol more than did rosuvastatin 20 mg (17.5% difference, p <0.001). Compared to rosuvastatin up-titration, ezetimibe add-on achieved significantly greater attainment of LDL cholesterol levels of <70 or <100 mg/dl (59.4% vs 30.9%, p <0.001), and <70 mg/dl in all subjects (43.8% vs 17.5%, p <0.001); produced significantly greater reductions in total cholesterol, non–high-density lipoprotein cholesterol, and apolipoprotein B (p <0.001); and resulted in similar effects on other lipid parameters. Adverse experiences were generally comparable among the groups. In conclusion, compared to up-titration doubling of the rosuvastatin dose, ezetimibe 10 mg added to stable rosuvastatin 5 mg or 10 mg produced greater improvements in many lipid parameters and achieved greater attainment of the National Cholesterol Education Program Adult Treatment Panel III recommended LDL cholesterol targets in subjects with elevated LDL cholesterol and at moderately high/high coronary heart disease risk. [Copyright &y& Elsevier]

Abstract: Prospective studies of coronary heart disease patients with disorders of insulin resistance, metabolic syndrome (MetSyn) and type 2 diabetes (T2DM), have shown that these patients usually display high levels of low-density lipoprotein particles (LDL-P) and low levels of high-density lipoprotein particles (HDL-P). In multiple prospective studies, high levels of LDL-P are more predictive of CHD risk than low-density lipoprotein cholesterol (LDL-C). The conventional goal of lipid lowering treatment is to lower LDL-C levels; however LDL-C is unrelated to the severity of insulin resistance. Among high cardiometabolic risk patients with LDL-C <100mg/dL, about two-thirds of patients have a high LDL-P (>1000nmol/L) despite this “optimal” level of LDL-C. For high cardiometabolic risk patients, LDL-P should be considered a primary goal of therapy due to its stronger association with cardiovascular risk. Further, we propose that certain lipid-altering therapies may be particularly useful in reducing cardiovascular events in statin-treated patients, not simply due to their improvement in LDL-C goal attainment, but due to their effects on lowering the number of low-density lipoprotein particles (LDL-P). [Copyright &y& Elsevier]

Background: Colesevelam is a bile acid sequestrant that differs structurally from traditional bile acid sequestrants, allowing it to bind bile acids with greater affinity. Studies have shown that colesevelam significantly reduces low-density lipoprotein cholesterol (LDL-C) levels and, in some cases, significantly increases high-density lipoprotein cholesterol (HDL-C) levels in adults with primary hypercholesterolemia. Objective: To investigate the safety and efficacy of colesevelam in adults with primary hypercholesterolemia. Study Design: This multicenter, open-label, titration-based extension study enrolled subjects who completed one of three multicenter, randomized, double-blind, placebo-controlled phase II studies with colesevelam. This study consisted of a 4-week washout/dietary stabilization period, a 50-week open-label treatment period, and a 2-week follow-up period. Setting: Ten clinical centers within the US. Subjects: Males and females 18 years of age or older who had completed a previous short-term (4- or 6-week) phase II clinical study with colesevelam. Intervention: At week 0 (following a 4-week washout of all lipid-lowering medication), subjects initiated treatment with colesevelam at a dosage of 1.5 g/day. Colesevelam was uptitrated to a maximum dosage of 3.75 g/day as necessary to achieve a 15-30% reduction from baseline in LDL-C level. At week 12, an HMGCoA reductase inhibitor (statin) or niacin (nicotinic acid) could be added if colesevelam 3.75 g/day was not sufficient to result in a 15-30% reduction from baseline in LDL-C level. Main Outcome Measure: The primary efficacy measure was the change in LDL-C level from baseline to week 50 across all treatment regimens. Secondary efficacy parameters included the change and percent change in total cholesterol, HDL-C, and triglyceride levels from baseline to week 50. There were three cohorts analyzed: (i) colesevelam monotherapy (included all subjects who received colesevelam monotherapy, regardless of dose); (ii) all treatment regimens (included all subjects who received colesevelam monotherapy or colesevelam plus low-dose statin or niacin therapy); and (iii) combination therapy (included only subjects who received colesevelam plus low-dose statin therapy). Two additional cohorts were also evaluated: (iv) maximum-dose colesevelam monotherapy (included only subjects who received colesevelam 3.75 g/day monotherapy); and (v) all maximum-dose colesevelam treatment regimens (included all subjects who received colesevelam 3.75 g/day, either as monotherapy or in combination with low-dose statin or niacin therapy). Results: In total, 272 subjects were screened, 260 enrolled, and 186 completed the study. In total, 255 subjects were included in the intent-to-treat population. The maximum dosage of colesevelam (3.75 g/day) was taken by 50% of subjects (n = 94/188) at week 50; only 38 subjects received low-dose statin or niacin by study end. At week 50, LDL-C levels were significantly (p < 0.001) reduced from baseline across all treatment regimens (by 29.6mg/dL [from 185.8 to 156.2 mg/dL; 15.0%]). Colesevelam also significantly reduced total cholesterol levels and significantly increased HDL-C and triglyceride levels across all treatment regimens (p < 0.001 for all). Drug-related adverse events were reported by 36.2% of subjects across all treatment regimens (and by 47.4% of subjects who received colesevelam plus low-dose statin or niacin therapy). Conclusion: In this study, colesevelam was found to be safe and effective for the management of LDL-C levels in adults with primary hypercholesterolemia. [ABSTRACT FROM AUTHOR]

Background: Coadministration of statin and fenofibrate monotherapies is frequently used to treat patients with dyslipidemia; however, a fixed-dose combination (FDC) tablet is not currently marketed. Objective: This study evaluates a new FDC tablet of atorvastatin 40 mg and fenofibrate 100 mg. Methods: This was a 12-week, multicenter, doubleblind, randomized, parallel-group Phase IIb study. Adults with dyslipidemia (non−HDL-C >130 mg/dL and triglycerides [TG] ≥150 but ≤500 mg/dL) were randomly assigned in a 1:1:1 ratio to receive the FDC, atorvastatin 40 mg, or fenofibrate 145 mg for 12 weeks. Study medication was taken once daily in the evening, without regard to meals. Patients attended follow-up visits after 4, 8, and 12 weeks of the double-blind treatment. The primary efficacy end points were the mean percentage changes from baseline to the final visit (week 12) in non−HDL-C, HDL-C, and TG. Secondary variables were LDL-C, VLDL-C particle concentration, total cholesterol, apolipoprotein B, lipoprotein (a), high-sensitivity C-reactive protein, fibrinogen, homocysteine, creatinine, myeloperoxidase, and lipoproteinassociated phospholipase A2. Tolerability was assessed by adverse events, laboratory parameters, vital signs, physical examinations, and ECGs. Results: Patients (n = 220) were aged 26 to 87 years; 115 (52.3%) were men and 105 (47.7%) were women; 189 (85.9%) were white, 17 (7.7%) were black, and 15 (6.8%) were Hispanic or Latino; and mean (SD) weight was 200.5 (40.85) lb (range, 103.5–367.4 lb). Previous treatments were statins (25.9% [57/220]), fibrates (1.8% [4/220]), and dietary supplements (25.5% [56/220]); 57.7% (127/220) of patients were treatment naive. Use of the FDC was associated with an improvement in non−HDL-C (−44.8%) that was significantly greater than with fenofibrate monotherapy (−16.1%; P < 0.001) but was not significantly different from that with atorvastatin monotherapy (−40.2%; P = NS). HDL-C increased significantly more in the FDC group (19.7%) than with atorvastatin (6.5%; P < 0.001) but was not significantly different from fenofibrate (18.2%; P = NS). TG lowering in the FDC group (−49.1%) was significantly greater than with both atorvastatin (−28.9%; P < 0.001) and fenofibrate (−27.8%; P = 0.001). LDL-C lowering in the FDC group (−42.3%) was significantly greater than with fenofibrate (−13.9%; P < 0.001) but not significantly different from atorvastatin (−43.1%; P = NS). The FDC had either comparable or significantly greater improvements in other lipid variables and multiple secondary variables. The FDC was generally well tolerated; the tolerability profile was consistent with those of atorvastatin and fenofibrate monotherapies. Treatment-emergent adverse events (ie, those occurring after the first dose of study medication) were recorded in 43 of 73 patients (58.9%) for the FDC, 49 of 74 (66.2%) for atorvastatin, and 48 of 73 (65.8%) for fenofibrate. Conclusions: In this 12-week study, patients with dyslipidemia treated with the 40/100-mg atorvastatin/ fenofibrate FDC had a significantly greater reduction in TG than those treated with atorvastatin 40 mg or higher-dose fenofibrate 145 mg. Treatment with the FDC was also associated with a significantly greater reduction in non−HDL-C compared with fenofibrate alone and a greater increase in HDL-C compared with atorvastatin alone. All treatments were generally well tolerated. [Copyright &y& Elsevier]

The article offers new information on the risk assessment methods for coronary heart disease (CHD) to family physicians in the U.S. The author highlights the significance of global risk prediction tools like the Framingham Risk Score (FRS) in determining risk and initiating preventive steps. FRS could provide CHD risk based on easily determined factors like age, gender and blood pressure. The author suggests that physicians should opt for a method that is within their range of practice.

This randomized, double-blind, parallel trial assessed the influence of pomegranate juice consumption on anterior and posterior carotid intima–media thickness (CIMT) progression rates in subjects at moderate risk for coronary heart disease. Subjects were men (45 to 74 years old) and women (55 to 74 years old) with ≥1 major coronary heart disease risk factor and baseline posterior wall CIMT 0.7 to 2.0 mm, without significant stenosis. Participants consumed 240 ml/day of pomegranate juice (n = 146) or a control beverage (n = 143) for up to 18 months. No significant difference in overall CIMT progression rate was observed between pomegranate juice and control treatments. In exploratory analyses, in subjects in the most adverse tertiles for baseline serum lipid peroxides, triglycerides (TGs), high-density lipoprotein (HDL) cholesterol, TGs/HDL cholesterol, total cholesterol/HDL cholesterol, and apolipoprotein-B100, those in the pomegranate juice group had significantly less anterior wall and/or composite CIMT progression versus control subjects. In conclusion, these results suggest that in subjects at moderate coronary heart disease risk, pomegranate juice consumption had no significant effect on overall CIMT progression rate but may have slowed CIMT progression in subjects with increased oxidative stress and disturbances in the TG-rich lipoprotein/HDL axis. [Copyright &y& Elsevier]

Abstract: Objective: To evaluate a new formulation of fenofibric acid (ABT-335) co-administered with 2 doses of rosuvastatin in patients with mixed dyslipidemia. Methods: In a phase 3, multicenter, randomized, double-blind, active-controlled study, a total of 1445 patients with LDL-C≥130mg/dL, TG≥150mg/dL, and HDL-C<40mg/dL (<50mg/dL for women) were randomized to either ABT-335 (135mg), rosuvastatin (10, 20, or 40mg), or ABT-335+rosuvastatin 10 or 20mg, and treated for 12 weeks. The primary efficacy comparisons were mean percent change in HDL-C and TG (ABT-335+rosuvastatin vs. corresponding dose of rosuvastatin), and LDL-C (ABT-335+rosuvastatin vs. ABT-335). Results: Combination therapy with ABT-335+rosuvastatin 10mg resulted in significantly (p <0.001) greater improvements in HDL-C (20.3% vs. 8.5%) and TG (−47.1% vs. −24.4%) compared to rosuvastatin 10mg; and LDL-C (−37.2% vs. −6.5%) compared to ABT-335. Similarly, significantly (p <0.001) greater improvements were observed with ABT-335+rosuvastatin 20mg in HDL-C (19.0% vs. 10.3%) and TG (−42.9% vs. −25.6%) compared to rosuvastatin 20mg; and LDL-C (−38.8% vs. −6.5%) compared to ABT-335 monotherapy. Greater improvements in multiple secondary endpoints were noted with combination therapy compared to prespecified monotherapies. Both combination therapy doses were generally well tolerated, with a safety profile consistent with ABT-335 and rosuvastatin monotherapies. No rhabdomyolysis or unexpected hepatic, renal, or muscle safety signals were identified. Conclusion: In patients with mixed dyslipidemia, combination therapy with ABT-335+rosuvastatin resulted in more effective control of multiple lipid parameters than either monotherapy alone, with a safety profile similar to both monotherapies. This combination may be an appropriate therapeutic option to treat mixed dyslipidemia. [Copyright &y& Elsevier]

OBJECTIVE: To compare changes in lipid levels (total cholesterol [total-C], low-density lipoprotein cholesterol [LDL-C], triglycerides [TG], and high-density lipoprotein cholesterol [HDL-C]) for patients who switched from standard fenofibrate 160 mg (requiring dosing with food) to fenofibrate 145 mg with no food effect (NFE). METHODS: The analyses were performed using an electronic medical records dataset from 1 January 2003 to 31 July 2005. Patients were eligible for the analysis if they had a diagnosis of hypertension, dyslipidaemia or diabetes mellitus, were written a prescription for standard fenofibrate 160 mg during the period 1 May 2004 to 30 April 2005, and were written a subsequent prescription for fenofibrate 145 mg NFE at least 60 days after first receiving the 160 mg dose. The outcomes measured were lipid levels: total-C, LDL-C, HDL-C and TG. RESULTS: 491 patients who switched from standard fenofibrate 160 mg to fenofibrate 145 mg NFE met all of the inclusion criteria. Patients who changed therapy to fenofibrate 145 mg NFE from standard fenofibrate 160 mg showed a beneficial response in lipid levels. Statistically significant patient-specific changes in lipid levels were observed for the change from baseline to standard fenofibrate 160 mg for three lipid levels (total-C, HDL-C and TG). Statistically significant changes were observed for the switch to fenofibrate 145 mg NFE for three lipid levels (total-C, LDL-C and TG). CONCLUSIONS: More patients treated in an outpatient clinical practice had better lipid results when prescribed fenofibrate 145 mg NFE than those prescribed standard fenofibrate 160 mg, suggesting that a less restrictive dosing regimen improves lipid outcomes. [ABSTRACT FROM AUTHOR]

The efficacy and safety of 2 regimens of a combination of a proprietary niacin extended release plus simvastatin (NER/S; 1,000/20 and 2,000/20 mg/day) were compared with simvastatin monotherapy (20 mg/day) for 24 weeks in 319 high-risk patients with predominantly mixed dyslipidemia who were already at National Cholesterol Education Program Adult Treatment Panel III risk-adjusted goals for low-density lipoprotein cholesterol. After a run-in on simvastatin 20 mg/day, both NER/S doses (1,000/20 and 2,000/20 mg/day) resulted in greater decreases in non–high-density lipoprotein (HDL) cholesterol vs simvastatin 20 mg/day (−13.9% and −22.5% vs −7.4%, respectively; p <0.01). Significant improvements in HDL cholesterol, triglycerides, apolipoprotein B, lipoprotein(a), and total/HDL cholesterol ratio were also observed. Patients with hypertriglyceridemia (triglycerides ≥200 mg/dl) typically had greater lipid responses to NER/S with the notable exception that HDL cholesterol responses to NER/S were similar in those with or without increased triglycerides. Treatment with both doses of NER/S was well tolerated; ≤60% of patients in any treatment group experienced flushing, >90% of flushing was mild or moderate in intensity, and only 7.5% of patients in both NER/S treatment groups discontinued because of flushing. The safety of NER/S was consistent with the safety profile of each individual component. In conclusion, this study showed that NER/S provided additional clinically relevant improvements in multiple lipid parameters and was safe and well tolerated. [Copyright &y& Elsevier]

The article outlines the implication of high-dose statin therapy in lowering the aggressive lipids of dyslipidemia patients in Illinois. Eventhough there are clear benefits obtained in lipid-modifying drugs, current management of dyslipidemia remains suboptimal. More often, patients failed to achieve guideline-recommended lipid goals due to the result of either no or suboptimal statin therapy. Research shows that the level of lipid lowering can be obtained safely in most patients by using a high-dose statin monotherapy.

A progressive accumulation of atherosclerotic lesions beginning early in life puts elderly persons at a greater absolute risk of cardiovascular disease and coronary events than other segments of the population. HMG-CoA reductase inhibitor (statin) therapy has been shown to be both efficacious and well tolerated in most elderly patients. Among the statins, rosuvastatin has advantages in treating older patients: at low starting doses it is very efficacious compared with other statins, and thus more likely to enable patients to reach their low-density lipoprotein-cholesterol goals without the need for titration or combination therapy. Lack of clinically significant interactions with most drugs metabolised by cytochrome P450 enzyme 3A4 may also make rosuvastatin safer for patients taking multiple medications. Furthermore, rosuvastatin has shown efficacy in treating patients with many of the co-morbidities common in the elderly, including renal impairment and diabetes mellitus. As yet, however, cardiovascular endpoint data for rosuvastatin are not available. [ABSTRACT FROM AUTHOR]

Abstract: Background: Patients with elevated serum triglyceride (TG) levels often have elevations in non-high-density lipoprotein cholesterol (non-HDL-C) levels as well. The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) has identified non-HDL-C as a secondary therapeutic target in these patients, but treatment goals may not be reached with statin monotherapy alone. Objective: This study evaluated the effects on non-HDL-C and other variables of adding prescription omega-3-acid ethyl esters (P-OM3; LovazaTM, formerly Omacor® [Reliant Pharmaceuticals, Inc., Liberty Corner, New Jersey]) to stable statin therapy in patients with persistent hypertriglyceridemia. Methods: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in adults who had received ≥8 weeks of stable statin therapy and had mean fasting TG levels ≥200 and <500 mg/dL and mean low-density lipoprotein cholesterol levels ⪯10% above their NCEP ATP III goal. The study regimen consisted of an initial 8 weeks of open-label simvastatin 40 mg/d and dietary counseling, followed by 8 weeks of randomized treatment with double-blind P-OM3 4 g/d plus simvastatin 40 mg/d or placebo plus simvastatin 40 mg/d. The main outcome measure was the percent change in non-HDL-C from baseline to the end of treatment. Results: The evaluable population included 254 patients, of whom 57.5% (146) were male and 95.7% (243) were white. The mean (SD) age of the population was 59.8 (10.4) years, and the mean weight was 92.0 (19.6) kg. At the end of treatment, the median percent change in non-HDL-C was significantly greater with P-OM3 plus simvastatin compared with placebo plus simvastatin (-9.0% vs -2.2%, respectively; P < 0.001). P-OM3 plus simvastatin was associated with significant reductions in TG (29.5% vs 6.3%) and very-low-density lipoprotein cholesterol (27.5% vs 7.2%), a significant increase in high-density lipoprotein cholesterol (HDL-C) (3.4% vs -1.2%), and a significant reduction in the total cholesterol:HDL-C ratio (9.6% vs 0.7%) (all, P < 0.001 vs placebo). Adverse events (AEs) reported by ≥1% of patients in the P-OM3 group that occurred with a higher frequency than in the group that received simvastatin alone were nasopharyngitis (4 [3.3%]), upper respiratory tract infection (4 [3.3%]), diarrhea (3 [2.5%]), and dyspepsia (3 [2.5%]). There was no significant difference in the frequency of AEs between groups. No serious AEs were considered treatment related. Conclusion: In these adult, mainly white patients with persistent hypertriglyceridemia, P-OM3 plus simvastatin and dietary counseling improved non-HDL-C and other lipid and lipoprotein parameters to a greater extent than simvastatin alone. [Copyright &y& Elsevier]

Data from recent clinical trials of high- versus moderate-dose statin therapy support the recommendation to achieve a low-density lipoprotein (LDL) <100 mg/dl in high-risk patients and reveal that many patients will require a high-dose statin to achieve this goal. Overall, low rates of serious musculoskeletal (<0.6%) and hepatic (<1.3%) toxicity have been observed with high-dose statin therapy. In the long-term trials, atorvastatin 80 mg had higher rates of persistent transaminase elevations but rates of myopathy and rhabdomyolysis similar to lower doses of statins. The rate of myopathy and rhabdomyolysis for simvastatin 80 mg, although still low, was about 4× higher than for atorvastatin 80 mg and lower doses of statin. A similar margin of safety would be expected in properly selected patients with characteristics similar to those who participated in the clinical trials. High-dose statin therapy or combination therapy will be required for the large majority of very high-risk patients to achieve the optional LDL goal of <70 mg/dl. While the combination of ezetimibe, bile-acid sequestering agents, niacin, and fenofibrate with moderate dose statins appears to be reasonably safe, the long-term safety of combination with high-dose statins remains to be established. In order to optimize patient outcomes, clinicians should be aware of specific patient characteristics, such as advancing age, gender, body mass index, or glomerular filtration rate, which predict muscle and hepatic statin toxicity. [Copyright &y& Elsevier]

It is well established that aggressive risk factor modification results in improved cardiovascular disease (CVD) outcomes. Yet, patients with type 2 diabetes mellitus have a much higher baseline risk for cardiovascular events. As type 2 diabetes and hypertension commonly coexist, achieving recommended targets for diabetes, hypertension, and CVD requires aggressive management. Global risk reduction with aggressive low-density lipoprotein reduction and through the additional normalization of glucose levels and blood pressure can help to reduce absolute risk in this very high-risk population. [Copyright &y& Elsevier]

Objectives: This study sought to evaluate the efficacy and safety of torcetrapib in patients with low high-density lipoprotein cholesterol (HDL-C) levels receiving background atorvastatin. Background: Elevating HDL-C levels may reduce the residual cardiovascular risk that is observed in patients treated with statin therapy. Torcetrapib (a cholesteryl ester transfer protein inhibitor) increases HDL-C and decreases low-density lipoprotein cholesterol (LDL-C). Methods: This was a multicenter, double-blind, randomized trial. Patients with below-average HDL-C (men <44 mg/dl; women <54 mg/dl) who were eligible for statin therapy according to National Cholesterol Education Program Adult Treatment Panel III guidelines or who had LDL-C >130 mg/dl at screening entered an 8-week run-in period with atorvastatin 20 mg/day before randomization (n = 174) to torcetrapib 10, 30, 60, or 90 mg/day or placebo for 8 weeks. Atorvastatin was continued during treatment with torcetrapib. Results: After 8 weeks, the percent change from baseline with torcetrapib (least-squares mean difference from placebo) ranged from 8.3% to 40.2% for HDL-C (p ≤ 0.0001 for 30-mg and higher doses) and from 0.6% to −18.9% for LDL-C (p < 0.01 for 60-mg and 90-mg doses). Particle size for both HDL and LDL increased with torcetrapib. The incidence of all-causality and treatment-related adverse events was similar across placebo and torcetrapib treatment groups with no evidence of a dose-related response. In some treatment groups, small increases in systolic and diastolic blood pressures were noted. Conclusions: In statin-eligible patients, torcetrapib plus background atorvastatin resulted in substantial, dose-dependent increases in HDL-C, accompanied by additional decreases in LDL-C beyond those seen with atorvastatin alone. Torcetrapib plus atorvastatin was generally well tolerated. [Copyright &y& Elsevier]

Objectives: This study was designed to evaluate the efficacy and safety of torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, in subjects with low high-density lipoprotein cholesterol (HDL-C) levels. Background: Evidence suggests HDL-C is atheroprotective. A proven mechanism for increasing the level of HDL-C is the inhibition of CETP. Methods: A total of 162 subjects with below-average HDL-C (men <44 mg/dl; women <54 mg/dl) who were not taking lipid-modifying therapy were randomized to double-blind treatment with torcetrapib 10, 30, 60, or 90 mg/day or placebo (∼30 subjects per group). Results: The percent change from baseline to Week 8 with torcetrapib (least-squares mean difference from placebo) was dose-dependent and ranged from 9.0% to 54.5% for HDL-C (p ≤ 0.0001 for 30 mg and higher doses) and from 3.0% to −16.5% for low-density lipoprotein cholesterol (LDL-C) (p < 0.01 for 90-mg dose). Low-density lipoprotein cholesterol lowering was less in subjects with higher (>150 mg/dl) versus lower levels of baseline triglycerides; at 60 mg, the change in LDL-C was 0.1% versus −22.2% (p < 0.0001), respectively. Particle size for both HDL and LDL increased with torcetrapib. There were no dose-related increases in the frequency of adverse events. Significant blood pressure increases were noted in 2 of 140 subjects. Conclusions: Torcetrapib resulted in substantial dose-dependent elevations in HDL-C, accompanied by moderate decreases in LDL-C at the higher doses. Torcetrapib was generally well tolerated. [Copyright &y& Elsevier]

A mechanism to explain the hypotriglyceridemic effects of marine omega-3 fatty acids in humans has not been clarified. A working model can be developed at the gene transcriptional level, which involves ?4 metabolic nuclear receptors. These include liver X receptor, hepatocyte nuclear factor–4? (HNF-4?), farnesol X receptor, and peroxisome proliferator–activated receptors (PPARs). Each of these receptors is regulated by sterol receptor element binding protein–1c (SREBP-1c), the main genetic switch controlling lipogenesis. Omega-3 fatty acids elicit hypotriglyceridemic effects by coordinately suppressing hepatic lipogenesis through reducing levels of SREBP-1c, upregulating fatty oxidation in the liver and skeletal muscle through PPAR activation, and enhancing flux of glucose to glycogen through downregulation of HNF-4?. The net result is the repartitioning of metabolic fuel from triglyceride storage toward oxidation, thereby reducing the substrate available for very-low-density lipoprotein (VLDL) synthesis. By simultaneously downregulating genes encoding proteins that stimulate lipid synthesis and upregulating genes encoding proteins that stimulate fatty acid oxidation, omega-3 fatty acids are more potent hypotriglyceridemic agents than are omega-6 fatty acids, on a carbon-for-carbon basis. Additionally, peroxidation of omega-3 fatty acids may reduce VLDL secretion through stimulating apolipoprotein B degradation. Omega-3 fatty acids may act by enhancing postprandial chylomicron clearance through reduced VLDL secretion and by directly stimulating lipoprotein lipase activity. These combined effects support the use of omega-3 fatty acids as a valuable clinical tool for the treatment of hypertriglyceridemia. [Copyright &y& Elsevier]

Despite the excellent benefit/risk profile of statins, their use is limited by a dose-related risk of adverse events, particularly those related to muscle toxicity. Ezetimibe/simvastatin (Vytorin) is a cholesterol-lowering therapy that inhibits the intestinal absorption (ezetimibe) and synthesis (simvastatin) of cholesterol. This analysis compared the muscle safety profiles of ezetimibe/simvastatin and simvastatin monotherapy. We reviewed muscle-related adverse event (AE) data from 17 randomized, blinded clinical trials (13 base and 4 extension studies), in which ezetimibe and simvastatin were either co-administered as separate entities or given as a combination tablet to 4,558 patients. The following AE categories were summarized: incidence of musculoskeletal or connective-tissue AEs (all and drug related); discontinuations due to musculoskeletal or connective-tissue AEs (all and drug related); incidence of AEs reported under the term “myalgia” (all and drug related); discontinuation due to myalgia (all and drug related); incidence of “myopathy” (all and drug related); increases in creatine kinase to 3 to <5, 5 to <10, and ≥10 times the upper limit of normal. For all AE categories examined, the incidence of muscle-related clinical and laboratory AEs or discontinuations due to muscle-related AEs was no more common in patients taking ezetimibe/simvastatin than in those taking simvastatin alone. Thus, the clinical trial experience with ezetimibe/simvastatin suggests that ezetimibe does not enhance or aggravate the muscle effects of simvastatin. [Copyright &y& Elsevier]

Cholesterol-lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, has been established as an effective method of reducing death and myocardial infarction among patients with coronary artery disease (CAD). However, a significant number of patients receiving statin therapy continue to have high residual risk. An important clinical challenge exists in reducing residual CAD risk with optimal therapies without increasing adverse effects. Combination therapy appears most appropriate for patients with a high rate of events of residual risk despite optimal statin therapy. This article discusses the role of combination therapy in managing CAD and in achieving optional targets in high-risk patient populations. [Copyright &y& Elsevier]

As the prevalence of the metabolic syndrome increases, 2 comorbid conditions—hepatic steatosis and human immunodeficiency virus (HIV) lipodystrophy—have become difficult clinical challenges. Dyslipidemia in patients with nonalcoholic fatty liver disease or nonalcoholic steatohepatitis may improve with use of statins, fibrates, niacin, and thiazolidinediones, but the data are presently very limited. HIV lipodystrophy is associated with a marked risk of coronary artery disease (CAD), and more aggressive management of the dyslipidemia is likely necessary to improve the prognosis. [Copyright &y& Elsevier]

The most recent national survey of compliance with the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) guidelines was completed before ATP III and showed significant underachievement of low-density lipoprotein (LDL) cholesterol goals. The NCEP Evaluation ProjecT Utilizing Novel E-Technology (NEPTUNE) II was a national survey conducted in 2003. Of the 4,885 patients, 67% achieved their LDL cholesterol treatment goal, including 89%, 76%, and 57%, respectively, in the 0 or 1 risk factor, ≥2 risk factors or coronary heart disease (CHD), and CHD risk equivalent categories. The percentage with triglyceride concentrations ≥200 mg/dl (2.25 mmol/L) in each risk category who achieved their LDL cholesterol and non-high-density lipoprotein cholesterol goals was 64%, 52%, and 27%, respectively. Patients with diabetes (55%) and other CHD risk equivalents (40%) were less likely to have achieved their LDL cholesterol targets than those with CHD (62%). Of the 1,447 patients with cardiovascular disease, 75% could be classified as very high risk according to the new July 2004 NCEP Writing Group recommendations, and 17.8% of those at very high risk had an LDL cholesterol level of &#60;70 mg/dl (&#60;1.81 mmol/L). In conclusion, these results suggest improved lipid management compared with previous surveys. The largest treatment gaps were found for features new to ATP III as of July 2004, including goal achievement for patients with CHD risk equivalents and for non-high-density lipoprotein cholesterol targets. Most of those (75%) with cardiovascular disease in NEPTUNE II would be considered very high risk and candidates for aggressive therapy to reach the new optional treatment goals. [Copyright &y& Elsevier]

Abstract: Background:: The limited bioavailability of certain fenofibrate formulations necessitates administration with food, raising concerns about efficacy and compliance. There is a need for new formulations that have improved bioavailability and eliminate the requirement for administration with food. Objective:: The aim of this study was to assess the food-related efficacy of a new formulation of micronized fenofibrate coated on inert microgranules (FF-μG) for the treatment of hypertriglyceridemia in patients exhibiting the metabolic syndrome. Methods:: This was a randomized, double-blind, placebo-controlled, double-dummy, parallel-group study in patients who had fasting triglyceride (TG) concentrations ≥300 mg/dL and &#60;1000 mg/dL and met National Cholesterol Education Program Adult Treatment Panel III criteria for the metabolic syndrome. A 6-week washout and diet lead-in period was followed by an 8-week treatment period. Eligible patients were randomized to receive either FF-μG 130 mg with food, FF-μG 130 mg without food, or placebo every day for 8 weeks. The primary end point was the mean percent change in TG levels from baseline to the end of treatment; changes in other lipid end points were also assessed. Safety profiles were assessed based on adverse-event reports, changes in clinical laboratory values and vital signs (including electrocardiography), and the findings of physical examinations. Results:: One hundred forty-six patients took part in the study: 54 received FF-μG 130 mg with food, 42 received FF-μG 130 mg without food, and 50 received placebo. The groups were similar in terms of mean age (56 years), sex (59.5%–63.0% men; 37.0%–40.5% women), race (83.3%–100% white), mean body weight (92 kg), mean height (172 cm), mean fasting baseline TG concentrations (480 mg/dL), and other components of the metabolic syndrome. The 2 FF-μG groups (with and without food) showed similar improvements in the dyslipidemia associated with the metabolic syndrome: TG levels decreased a mean of 36.7% and 36.6%, respectively (P &#60; 0.001 vs placebo). The overall frequency of adverse events was similar in the 2 FF-μG groups and did not differ significantly from placebo (63.0%, 61.9%, and 52.0%, respectively). Gastrointestinal disturbances (eg, diarrhea, dyspepsia) occurred more frequently in the 2 FF-μG groups compared with the placebo group (31.5%, 26.2%, and 12.0%; P = NS). Significant increases from baseline in alanine aminotransferase were seen in both FF-μG groups (mean [SEM], 3.77 [2.60] and 11.69 [7.42] U/L, respectively; P ≤ 0.05 vs placebo); however, these increases were considered clinically significant in only 5 cases, none of them requiring discontinuation of study drug. Conclusions:: This study found no inequivalence in the TG-lowering effects of the 2 fenofibrate regimens compared with placebo. Both regimens were well tolerated. Thus, FF-μG 130 mg administered without regard to meals appears to be efficacious and well tolerated for the treatment of hypertriglyceridemia in patients exhibiting the metabolic syndrome. [Copyright &y& Elsevier]

Biological therapies involve the utilization of proteins, DNA, antibodies, or other substances derived or synthesized from living tissue for therapeutic effects. There are several biological therapies in clinical development for the prevention and treatment of atherosclerosis. The most advanced in human trials are apolipoprotein mimetics, which include apolipoprotein A-1Milano and phospholipid complexes. Infusions of these apolipoprotein mimetics have been demonstrated to reduce atherosclerotic development in both animal models and humans over a relatively short period of time. Autoimmunization to create neutralizing antibodies to CETP is also in human trials. [Copyright &y& Elsevier]

Background: The available statin drugs have similar pharmacodynamic properties but are not equal in low-density lipoprotein cholesterol (LDL-C)—lowering efficacy.Objective: The aim of this study was to compare the effects of lovastatin and fluvastatin in lowering LDL-C.Methods: This was a prospective, randomized, double-blind study of patients aged >20 years with primary hypercholesterolemia conducted at 44 clinical sites across the United States. After a 6-week National Cholesterol Education Program (NCEP) Step I diet lead-in period in patients taking lipid-lowering drugs at screening, patients were randomized to receive lovastatin 10, 20, or 40 mg/d or fluvastatin 20 or 40 mg/d (the doses available at the time the study was conducted) for 6 weeks. Patients not taking lipid-lowering drugs at screening and who had been following the Step I diet for at least 6 weeks proceeded to the treatment phase. All patients received instruction for a Step I diet, which they followed throughout the treatment phase. After the treatment period, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), LDL-C, and triglycerides were measured, and TC:HDL-C and LDL-C:HDL-C ratios were calculated.Results: A total of 838 patients (476 men, 362 women; mean [SD] age, 59 [12] years) were included in the study. Lovastatin 20 and 40 mg/d significantly reduced mean LDL-C compared with the same dosages of fluvastatin. TC and the LDL-C:HDL-C ratio decreased more with lovastatin than with fluvastatin at a given dose level. Approximately 50% of patients treated with lovastatin 20 and 40 mg/d compared with ∼25% treated with fluvastatin 20 and 40 mg/d reached NCEP Adult Treatment Panel II LDL-C goals.Conclusion: In this small study population of patients with primary hypercholesterolemia taking lipid-lowering drugs, short-term (6-week) treatment with lovastatin was more efficacious than fluvastatin in lowering cholesterol levels and reaching LDL-C treatment goals. [Copyright &y& Elsevier]

This trial evaluated the efficacy of a ready-to-eat cereal containing beta-glucan, incorporated into a low saturated fat and cholesterol diet, for reducing LDL cholesterol levels in children and adolescents with mild-to-moderate primary hypercholesterolemia. Following diet lead-in and baseline assessment phases, 29 subjects (aged 6-14 years) were randomized to either control cereal or ready-to-eat cereal that provided 3 g/d of beta-glucan, for four weeks. Subjects then received the alternate product for an additional four weeks. Among subjects who were at least 80% compliant (n = 18), total and soluble dietary fiber intakes increased significantly (26.7%, p = 0.01 and 30.8%, p = 0.02, respectively) and LDL cholesterol was reduced by a mean of 5.3% (p = 0.03). The reduction in LDL cholesterol appeared to be most pronounced (9.2%, p = 0.001) among those with body mass index below the median (25.7 kg/m2). Thus, consumption of a beta-glucan containing cereal modestly lowers cholesterol levels in hypercholesterolemic children and adolescents. [Copyright &y& Elsevier]

The primary objective of this 6-week, parallel-group, open-label, randomized, multicenter trial was to compare rosuvastatin with atorvastatin, pravastatin, and simvastatin across dose ranges for reduction of low-density lipoprotein (LDL) cholesterol. Secondary objectives included comparing rosuvastatin with comparators for other lipid modifications and achievement of National Cholesterol Education Program Adult Treatment Panel III and Joint European Task Force LDL cholesterol goals. After a dietary lead-in period, 2,431 adults with hypercholesterolemia (LDL cholesterol ≥160 and <250 mg/dl; triglycerides <400 mg/dl) were randomized to treatment with rosuvastatin 10, 20, 40, or 80 mg; atorvastatin 10, 20, 40, or 80 mg; simvastatin 10, 20, 40, or 80 mg; or pravastatin 10, 20, or 40 mg. At 6 weeks, across-dose analyses showed that rosuvastatin 10 to 80 mg reduced LDL cholesterol by a mean of 8.2% more than atorvastatin 10 to 80 mg, 26% more than pravastatin 10 to 40 mg, and 12% to 18% more than simvastatin 10 to 80 mg (all p <0.001). Mean percent changes in high-density lipoprotein cholesterol in the rosuvastatin groups were +7.7% to +9.6% compared with +2.1% to +6.8% in all other groups. Across dose ranges, rosuvastatin reduced total cholesterol significantly more (p <0.001) than all comparators and triglycerides significantly more (p <0.001) than simvastatin and pravastatin. Adult Treatment Panel III LDL cholesterol goals were achieved by 82% to 89% of patients treated with rosuvastatin 10 to 40 mg compared with 69% to 85% of patients treated with atorvastatin 10 to 80 mg; the European LDL cholesterol goal of <3.0 mmol/L was achieved by 79% to 92% in rosuvastatin groups compared with 52% to 81% in atorvastatin groups. Drug tolerability was similar across treatments. [Copyright &y& Elsevier]

A cholesterol ester transfer protein (CETP) vaccine (CETi-1) that induces auto-antibodies that specifically bind and inhibit activity of endogenous CETP has been demonstrated in rabbits to significantly increase HDL-C and reduce the development of atherosclerosis. In a Phase I human trial with CETi-1, one patient at the highest dose (250 mg) out of a total of 36 patients who received a single injection developed anti-CETP antibodies. In an extension study of 23 patients, 53% (8/15) who received a second injection of the active vaccine developed anti-CETP antibodies compared with 0% (0/8) in the placebo group. The vaccine was well tolerated and no significant laboratory abnormalities occurred. CETi-1 is a feasible therapy in humans to induce CETP auto-antibodies. Future research will determine if repeat inoculations will induce a sufficient anti-CETP antibody response to inhibit CETP and increase HDL levels. [Copyright &y& Elsevier]

: ObjectivesThe purpose of this study was to assess the efficacy and safety of ezetimibe administered with simvastatin in patients with primary hypercholesterolemia.: BackgroundDespite the availability of statins, many patients do not achieve lipid targets. Combination therapy with lipid-lowering agents that act via a complementary pathway may allow additional patients to achieve recommended cholesterol goals.: MethodsAfter dietary stabilization, a 2- to 12-week washout period, and a 4-week, single-blind, placebo lead-in period, patients with baseline low-density lipoprotein cholesterol (LDL-C) ≥145 mg/dl to ≤250 mg/dl and triglycerides (TG) ≤350 mg/dl were randomized to one of the following 10 groups administered daily for 12 consecutive weeks: ezetimibe 10 mg; simvastatin 10, 20, 40, or 80 mg; ezetimibe 10 mg plus simvastatin 10, 20, 40, or 80 mg; or placebo. The primary efficacy variable was percentage reduction from baseline to end point in direct LDL-C for the pooled ezetimibe plus simvastatin groups versus pooled simvastatin groups.: ResultsEzetimibe plus simvastatin significantly improved LDL-C (p < 0.01), high-density lipoprotein cholesterol (HDL-C) (p = 0.03), and TG (p < 0.01) compared with simvastatin alone. Ezetimibe plus simvastatin (pooled doses) provided an incremental 13.8% LDL-C reduction, 2.4% HDL-C increase, and 7.5% TG reduction compared with pooled simvastatin alone. Coadministration of ezetimibe and simvastatin provided LDL-C reductions of 44% to 57%, TG reductions of 20% to 28%, and HDL-C increases of 8% to 11%, depending on the simvastatin dose. Ezetimibe 10 mg plus simvastatin 10 mg and simvastatin 80 mg alone each provided a 44% LDL-C reduction. The coadministration of ezetimibe with simvastatin was well tolerated, with a safety profile similar to those of simvastatin and of placebo.: ConclusionsWhen coadministered with simvastatin, ezetimibe provided significant incremental reductions in LDL-C and TG, as well as increases in HDL-C. Coadministration of ezetimibe with simvastatin was well tolerated and comparable to statin alone. [Copyright &y& Elsevier]

The use of combination therapy is an effective way to manage dyslipidemia in patients with coronary artery disease (CAD). However, combination therapy is not a frequently used strategy in the treatment of CAD. Aggressive lipid-altering therapy often requires the use of combination therapy involving statins in conjunction with niacin, fibric-acid derivatives, ezetimibe, or bile acid resins. Yet, safety concerns regarding the combination of statins with other lipid-altering drugs and patient acceptance of combination therapy have influenced its application in the treatment of CAD. This article discusses several safety and regulatory considerations for the use of combination therapy for dyslipidemia. [Copyright &y& Elsevier]

Background: Because lovastatin is efficiently extracted by the liver and because its administration in divided doses is associated with increased efficacy, an extended-release (ER) formulation may have the potential for a dose-sparing advantage relative to the immediate-release (IR) formulation in the treatment of hypercholesterolemia.Objective: This study compared the short-term pharmacodynamics, safety, and pharmacokinetics of multiple doses of lovastatin ER with those of lovastatin IR in patients with fasting low-density lipoprotein cholesterol (LDL-C) levels between 130 and 250 mg/dL and fasting triglyceride levels <350 mg/dL.Methods: The study had a randomized, single-blind, positive-controlled, 2-way crossover design, with a 4-week diet/placebo run-in period and two 4-week active-treatment periods. During period 1, patients received either lovastatin ER or lovastatin IR (both 40 mg OD). After 4 weeks of the initial study treatment and a 2-week washout period, patients were switched to the alternate treatment (period 2). Pharmacodynamic parameters (LDL-C, high-density lipoprotein cholesterol, total cholesterol, and triglyceride levels) were evaluated by combining data from weeks 3 and 4 of treatment. In a pharmacokinetic substudy, maximum plasma concentrations (Cmax) and area under the plasma concentration—time curve from zero to 24 hours (AUC0–24) were determined for lovastatin, lovastatin acid, and total and active inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase on days 1 and 28 of active treatment. The geometric mean ratio of AUC0–24 (lovastatin ER/lovastatin IR) was also calculated for each of these substances.Results: Of 76 patients who entered the run-in period, 26 (12 men, 14 women; mean age, 56.2 years) were randomized to receive active treatment and 24 were included in the efficacy analysis; 13 patients were included in the pharmacokinetic substudy, 12 of whom had complete pharmacokinetic data. Compared with lovastatin IR, lovastatin ER produced a 3.9% greater reduction in LDL-C (P = 0.044). Changes in other lipid parameters were not statistically significant. In the pharmacokinetic substudy, Cmax values for lovastatin, lovastatin acid, and inhibitors of HMG-CoA reductase were lower at day 28 with lovastatin ER than with lovastatin IR. The AUC0–24 ratio for lovastatin was 1.91 (90% CI, 1.77–3.35), reflecting higher bioavailability of the pro-drug with lovastatin ER; in contrast, the ratios for lovastatin acid and active and total inhibitors of HMG-CoA reductase were <1.Conclusions: In this short-term study in a small number of patients, lovastatin ER 40 mg produced significantly greater LDL-C lowering than did an equal dose of lovastatin IR, with a relatively low Cmax and comparable systemic exposure to lovastatin acid and active and total inhibitors of HMG-CoA reductase. Lovastatin ER was well tolerated, with no discontinuations due to adverse events. [Copyright &y& Elsevier]

Examines the use of surrogate markers of atherosclerosis for the clinical development of pharmaceutical agents in the United States. Lipoprotein metabolism; Status of potential therapeutic agents; Risk estimates for coronary artery disease.

Evaluates the influence of 2 continuous estrogen and estrogen-progestin replacement regimens on cardiovascular risk markers in postmenopausal women in the United States. Level of low-density lipoprotein cholesterol level in groups receiving active treatment; Profile of cardiovascular risk markers in group receiving 17-beta estradiol plus norethindrone.

Hydroxypropylmethylcellulose (HPMC) is a food gum that shares certain characteristics, such as high viscosity, with soluble fibers. In this trial, the safety and cholesterol-lowering efficacy of HPMC consumed with and between meals was evaluated in free-living male volunteers with mild-to-moderate hypercholesterolemia. After a 14-d baseline period, men (n = 51) with LDL cholesterol between 3.36 and 4.91 mmol/L and triglycerides <3.95 mmol/L were randomly assigned to consume 5.0 g/d HPMC in 240 mL of orange drink, taken either with or between meals, for a 2-wk treatment period. In the Between Meals group, total cholesterol was reduced by 8.0% vs. baseline in wk 1 of treatment (P < 0.05) and 5.1% in wk 2 (P < 0.01). LDL cholesterol concentrations fell by 12.0 and 7.7% (P < 0.01). In the With Meals group, reductions were 9.5 and 8.3% for total cholesterol, and 12.5 and 12.8% for LDL cholesterol (wk 1 and 2, respectively, P < 0.01). In both groups, HDL cholesterol decreased by approximately 5% during wk 1 of treatment (P < 0.01), but the wk 2 concentrations were not significantly different from baseline. There were no significant differences between groups in lipid responses, although there was a trend for a smaller LDL cholesterol-lowering effect during wk 2 of treatment in the Between Meals group (P < 0.06). Gastrointestinal-related adverse experiences (mostly mild) were twice as common among participants who ingested HPMC with meals (P < 0.05). These results suggest that HPMC has a lipid-lowering effect, which may be more consistent when taken with meals. [ABSTRACT FROM AUTHOR]

Examines the relation between hyperfibrinogenemia and small, dense low-density lipoprotein (LDL) subclass pattern in postmenopausal women. Correlation between the concentration of cholesterol carried in LDL particles and plasma fibrinogen concentration; Suggestion that hyperfibrinogenemia and LDL subclass pattern B may be 2 components of a common syndrome.

Obicetrapib is a selective inhibitor of cholesteryl ester transfer protein that is currently in phase 3 of development for the treatment of dyslipidemia as adjunct therapy. The purpose of this study was to comprehensively characterize the pharmacokinetic (PK) and pharmacodynamic (PD) disposition of obicetrapib. Data from 7 clinical trials conducted in healthy adults and those with varying degrees of dyslipidemia were included for model development. The structural model that best described obicetrapib PK was a 3‐compartment model with 4‐compartment transit absorption and first‐order elimination. Body weight was the only covariate found to significantly explain observed variability and was therefore included using allometric scaling on all disposition parameters. For a typical patient weighing 75 kg, the estimated apparent total body clearance and apparent volume of distribution of the central compartment was 0.81 L/h and 36.1 L, respectively. The final PK model parameters were estimated with good precision and were ultimately leveraged to sequentially inform 2 turnover models that describe obicetrapib's effect on low‐density lipoprotein cholesterol (LDL‐C) and high‐density lipoprotein cholesterol (HDL‐C) concentrations. The maximum stimulatory effect of obicetrapib on LDL‐C loss was estimated to be 1.046, while the maximum inhibitory effect of obicetrapib on HDL‐C loss was 0.691. This corresponds to a predicted typical maximum percent change from baseline LDL‐C and HDL‐C of 51.1% and 224%, respectively. The final sequential model described obicetrapib PKPD well and was ultimately able to both demonstrate evidence of internal consistency and support decision‐making throughout the development lifecycle. [ABSTRACT FROM AUTHOR]

Evaluates the lipid-lowering efficacy of colesevalam hydrochloride, a non-absorbed hydrogel with bile acid-sequestering properties. Decline in low-density lipoprotein cholesterol concentrations in response to colesevelam treatment; Percentage change in total cholesterol, low- and high-density lipoprotein, and triglyceride levels from baseline to the end of treatment.

Compares the long-term effects of lean red meat or lean white meat on serum lipid levels among free-living persons with hypercholesterolemia. Effect on serum lipids; Effect on body weight; Comparison of dietary data.

Reports the cholesterol-lowering efficacy of hydroxypropylmethylcellulose (HPMC). Characteristics of HPMC; Incorporation of HPMC into National Cholesterol Education Program Step 1 diet; Change in levels of high and low density lipoproteins; Suitability for inclusion in diets of patients with mild to moderate hypercholesterolemia.

Presents a randomized, multicenter, double-blind parallel-group study to evaluate the lipid-altering efficacy and safety of simvastatin 80/mg/day. Administration of a lipid-lowering diet and simvastatin to hypercholesterolemic patients in the United States; National Cholesterol Education Program low-density lipoprotein (LDL) cholesterol criteria for pharmacologic treatment.

Presents a study of orlistat, a gastrointestinal lipase inhibitor that reduces dietary fat absorption. Efforts to test the hypothesis that orlistat combined with dietary intervention is more effective than placebo plus diet for weight loss and maintenance over a two year period; Setting and participants; Intervention; Main outcome measures; Results; Conclusions.