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• Obicetrapib is a selective CETP inhibitor for reducing LDL-C and ASCVD. • Obicetrapib plus ezetimibe on top of high-intensity statin lowers LDL-C by 63%. • Obicetrapib monotherapy and with ezetimibe are both safe and well tolerated. Obicetrapib, a selective cholesteryl ester transfer protein (CETP) inhibitor, reduces low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein particles, and apolipoproteins, when added to high-intensity statin in patients with dyslipidemia. To evaluate the safety and lipid-altering efficacy of obicetrapib plus ezetimibe combination therapy as an adjunct to high-intensity statin therapy. This double-blind, randomized, phase 2 trial administered 10 mg obicetrapib plus 10 mg ezetimibe (n = 40), 10 mg obicetrapib (n = 39), or placebo (n = 40) for 12 weeks to patients with LDL-C >70 mg/dL and triglycerides (TG) <400 mg/dL, on stable high-intensity statin. Endpoints included concentrations of lipids, apolipoproteins, lipoprotein particles, and proprotein convertase subtilisin kexin type 9 (PCSK9), safety, and tolerability. Ninety-seven patients were included in the primary analysis (mean age 62.6 years, 63.9% male, 84.5% white, average body mass index of 30.9 kg/m2). LDL-C decreased from baseline to week 12 by 63.4%, 43.5%, and 6.35% in combination, monotherapy, and placebo groups, respectively (p <0.0001 vs. placebo). LDL-C levels of <100, <70, and <55 mg/dL were achieved by 100%, 93.5%, and 87.1%, respectively, of patients taking the combination. Both active treatments also significantly reduced concentrations of non-HDL-C, apolipoprotein B, and total and small LDL particles. Obicetrapib was well tolerated and no safety issues were identified. The combination of obicetrapib plus ezetimibe significantly lowered atherogenic lipid and lipoprotein parameters, and was safe and well tolerated when administered on top of high-intensity statin to patients with elevated LDL-C. [ABSTRACT FROM AUTHOR]

The 2013 American College of Cardiology/American Heart Association guidelines on cholesterol management placed greater emphasis on statin therapy given the well-established benefits in primary and secondary prevention of cardiovascular disease. Residual risk may remain after statin initiation, in part because of triglyceride-rich lipoprotein cholesterol. Several large trials have failed to show benefit with non-statin cholesterol-lowering medications in the reduction of cardiovascular events. Yet, subgroup analyses showed a benefit in those with hypertriglyceridemia and lower high-density lipoprotein cholesterol level, a high-risk pattern of dyslipidemia. This review discusses the benefits of omega-3 carboxylic acids, a recently approved formulation of omega-3 fatty acid with enhanced bioavailability, in the treatment of dyslipidemia both as monotherapy and combination therapy with a statin. [ABSTRACT FROM AUTHOR]

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]

Background: This study examined the effects of a mixture of highly bioavailable omega-3 carboxylic acids (OM3-CA) on nuclear magnetic resonance spectroscopy-assessed lipoprotein particle concentrations and sizes and other cardiovascular risk markers in statin-treated patients with fasting triglycerides (TG) ≥2.3 mmol/L (200 mg/dL) and <5.6 mmol/L (500 mg/dL) and at high cardiovascular risk. Methods: After a diet lead-in and statin-stabilization period, 647 patients were randomly assigned to receive capsules of control (olive oil, OO) 4 g/d, OM3-CA 2 g/d (plus OO 2 g/d), or OM3-CA 4 g/d for 6 weeks. Results: Compared with OO, low-density lipoprotein (LDL) particle size was increased with OM3-CA 2 g/d (p < 0.01) and 4 g/d (p < 0.001), and very low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) particle sizes were decreased with both OM3-CA dosages vs. OO (p < 0.001 and p < 0.05 for VLDL and HDL, respectively). Total VLDL/chylomicron remnant particle concentration was reduced by 8.5 and 16.0 % with OM3-CA 2 and 4 g/d, respectively, vs. a 6.9 % reduction with OO (p < 0.001 for OM3-CA 4 g/d vs. OO). Total HDL particle concentration was also reduced by 1.5 and 3.2 % with OM3-CA 2 and 4 g/d, respectively, vs. a 0.6 % increase with OO (at least p < 0.05 for both comparisons). Changes in total LDL particle concentration were not significantly different for OO vs. OM3-CA at either dosage. Apolipoprotein (Apo) CIII levels decreased by 7.6 and 13.1 % with OM3-CA 2 and 4 g/d, respectively, vs. 3.2 % with OO (p < 0.001 for OM3-CA 4 g/d vs. OO). Lipoprotein-associated phospholipase A2 (Lp-PLA2) mass was reduced by 6.2 and 10.7 % with OM3-CA 2 and 4 g/d, respectively, vs. a 0.1 % increase with OO (p < 0.001 for both vs. OO). There were no significant differences between treatments in high-sensitivity C-reactive protein responses. Conclusion: OM3-CA were associated with shifts in lipoprotein particle sizes and concentrations, and reductions in Apo CIII and Lp-PLA2, in patients with hypertriglyceridemia while taking a statin. [ABSTRACT FROM AUTHOR]

Statins are one of the most commonly prescribed drugs in clinical practice. They are usually well tolerated and effectively prevent cardiovascular events. Most adverse effects associated with statin therapy are musclerelated. The recent statement of the European Atherosclerosis Society (EAS) has focused on statin associated muscle symptoms (SAMS), and avoided the use of the term "statin intolerance'. Although muscle syndromes are the most common adverse effects observed after statin therapy, excluding other side effects might underestimate the number of patients with statin intolerance, which might be observed in 10-15% of patients. In clinical practice, statin intolerance limits effective treatment of patients at risk of, or with, cardiovascular disease. Knowledge of the most common adverse effects of statin therapy that might cause statin intolerance and the clear definition of this phenomenon is crucial to effectively treat patients with lipid disorders. Therefore, the aim of this position paper was to suggest a unified definition of statin intolerance, and to complement the recent EAS statement on SAMS, where the pathophysiology, diagnosis and the management were comprehensively presented. [ABSTRACT FROM AUTHOR]

Background: The occurrence of low rates of rhabdomyolysis among patients receiving lipid-lowering drugs (LLDs) in randomized clinical trials may be elucidated with population-based studies. Objective: To determine the risk of hospitalized rhabdomyolysis associated with LLD therapy. Methods: This observational study used claims data from 9 million members of five United States health plans to identify patients (≥18 years) who received >2 statin and nonstatin LLDs during July 2000 to December 2004. Inpatient International Classification of Diseases, Ninth Revision, Clinical Modification, codes for rhabdomyolysis (791.3, 728.89, and 728.88) were observed during the follow-up period; cases were confirmed with patients'' medical records. Rhabdomyolysis events were reported per 10,000 person-years of LLD exposure; multivariate analysis was conducted. Results: The study cohort (N = 473,343) received 490,988 and 11,624 person-years of LLD, and combination therapy, respectively. Medical charts were obtained for 104 of 144 eligible patients with rhabdomyolysis claims; 42 cases were confirmed. With atorvastatin as reference, rhabdomyolysis rates (95% confidence interval) were greatest for cerivastatin, 8.4 (2.3-21.7); no difference among available statins was observed. Rates for other LLD monotherapies were: niacin, 2.1 (0.3−7.7), ezetimibe, 2.1 (0.3−7.8), fenofibrate, 0 (0−1.7), and gemfibrozil, 2.0 (0.5−5.2). Multivariate analysis showed only cerivastatin with a significantly greater risk of rhabdomyolysis (odds ratio 4.74, 95% confidence interval 1.1-21.2, P = .041) versus atorvastatin among the statins. Combination therapies had increased rhabdomyolysis risk (OR 7.1, 1.6-31.6, P = .010) versus LLDs alone. Conclusion: The risk of habdomyolysis among hospitalized patients receiving statins was low; no difference among the available statins was evident. Further data are needed to establish the risk profile but current findings already offer guidance to physicians. [Copyright &y& Elsevier]

Abstract: The National Cholesterol Education Program Adult Treatment Panel guidelines have established low-density lipoprotein cholesterol (LDL-C) treatment goals, and secondary non-high-density lipoprotein (HDL)-C treatment goals for persons with hypertriglyceridemia. The use of lipid-lowering therapies, particularly statins, to achieve these goals has reduced cardiovascular disease (CVD) morbidity and mortality; however, significant residual risk for events remains. This, combined with the rising prevalence of obesity, which has shifted the risk profile of the population toward patients in whom LDL-C is less predictive of CVD events (metabolic syndrome, low HDL-C, elevated triglycerides), has increased interest in the clinical use of inflammatory and lipid biomarker assessments. Furthermore, the cost effectiveness of pharmacological intervention for both the initiation of therapy and the intensification of therapy has been enhanced by the availability of a variety of generic statins. This report describes the consensus view of an expert panel convened by the National Lipid Association to evaluate the use of selected biomarkers [C-reactive protein, lipoprotein-associated phospholipase A2, apolipoprotein B, LDL particle concentration, lipoprotein(a), and LDL and HDL subfractions] to improve risk assessment, or to adjust therapy. These panel recommendations are intended to provide practical advice to clinicians who wrestle with the challenges of identifying the patients who are most likely to benefit from therapy, or intensification of therapy, to provide the optimum protection from CV risk. [Copyright &y& Elsevier]

Background: Elevated levels of high-sensitivity C-reactive protein (hsCRP) correlate with an increased risk for cardiovascular events. Combination therapy with a statin and a fibrate may be more effective than statin monotherapy for reducing hsCRP, especially in patients with mixed dyslipidemia. Objective: To characterize the treatment effects of rosuvastatin and fenofibric acid combination therapy compared with individual monotherapies in mixed dyslipidemic patients with baseline hsCRP ≥2 mg/L versus <2 mg/L and to determine the effects of long-term treatment with rosuvastatin and fenofibric acid combination therapy on hsCRP and other lipids for patients with hsCRP ≥2 mg/L after treatment with rosuvastatin monotherapy. Methods: Data for the post hoc analysis were derived from two 12-week controlled studies and a 52-week extension study. Patients were treated with fenofibric acid 135 mg; rosuvastatin 5, 10, 20, or 40 mg; or rosuvastatin 5, 10, or 20 mg and fenofibric acid 135 mg in the controlled studies; and with rosuvastatin 20 mg and fenofibric acid 135 mg in the extension study. Results: In this analysis, 65% (1416/2182) of patients had pretreatment baseline hsCRP ≥2 mg/L. Among all treatment groups, larger decreases in hsCRP were observed in patients with greater baseline hsCRP; however, improvements in other lipids/apolipoprotein were comparable between the baseline hsCRP categories. Among patients with high hsCRP (≥2 mg/L) remaining after 12 weeks of rosuvastatin 10, 20, or 40 mg monotherapy, hsCRP was reduced by ∼36% after switching to rosuvastatin 20 mg and fenofibric acid 135 mg for up to 52 weeks, and ∼36% of patients shifted from hsCRP ≥2 mg/L to <2 mg/L. Conclusions: Combination therapy with rosuvastatin and fenofibric acid may be effective for improving the inflammatory biomarker, hsCRP as well as other lipid abnormalities in patients with mixed dyslipidemia and high hsCRP. [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]

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: Monotherapy with lipid-modifying medication is frequently insufficient to normalize lipid abnormalities in patients with mixed dyslipidemia and type 2 diabetes mellitus. Objective: To evaluate the efficacy and safety of fenofibric acid + statin combination therapy in this population. Study Design: A pooled, subgroup analysis of three randomized, controlled, double-blind, 12-week trials. Setting: Multiple clinical research facilities in the US and Canada. Patients: Patients with mixed dyslipidemia and type 2 diabetes (n = 586). Intervention: Fenofibric acid (Trilipix®) 135mg monotherapy; low-, moderate-, or high-dose statin monotherapy (rosuvastatin [Crestor®] 10, 20, or 40 mg; simvastatin [Zocor®] 20, 40, or 80 mg; or atorvastatin [Lipitor®] 20, 40, or 80 mg); or fenofibric acid + low- or moderate-dose statin. Main Outcome Measure: Mean percentage changes in lipid parameters, percentages of patients achieving optimal serum lipid/apolipoprotein levels, and incidence of adverse events. Results: Fenofibric acid + low-dose statin resulted in significantly (p < 0.001) greater mean percentage changes in high-density lipoprotein cholesterol (HDL-C) [16.8%] and triglycerides (-43.9%) than low-dose statin monotherapy (4.7% and -18.1%, respectively) and significantly (p < 0.001) greater reductions in lowdensity lipoprotein cholesterol (LDL-C) [-34.0%] than fenofibric acid monotherapy (-5.3%). Similarly, fenofibric acid + moderate-dose statin resulted in significantly (p < 0.011) greater mean percentage changes in HDL-C (16.3%) and triglycerides (-43.4%) than moderate-dose statin monotherapy (8.7% and -24.2%, respectively) and significantly (p < 0.001) greater reductions in LDL-C (-32.6%) than fenofibric acid monotherapy (-5.3%). Compared with low- or moderate-dose statin, fenofibric acid + low- or moderatedose statin resulted in over 5-fold higher percentages of patients achieving optimal levels of LDL-C, non- HDL-C, apolipoprotein B, HDL-C, and triglycerides simultaneously. Incidence of adverse events was generally similar among treatments. Conclusion: Fenofibric acid + statin combination therapy in patients with mixed dyslipidemia and type 2 diabetes was well tolerated and resulted in more comprehensive improvement in the lipid/apolipoprotein profile than either monotherapy. [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]

Background: Prescription omega-3-acid ethyl esters (P-OM3) often are used for hypertriglyceridemic patients receiving statin therapy who have residual increases in atherogenic lipoprotein lipid levels. To date, limited information has been published regarding the effects of omega-3 fatty acid consumption on lipoprotein particle concentrations. Objective: We evaluated the effects of adding P-OM3 4g/d to an ongoing regimen of simvastatin 40mg/d on lipoprotein particles (P) in subjects with hypertriglyceridemia. Methods: Data were analyzed from the multicenter, randomized, double-blind, placebo-controlled Combination of Prescription Omega-3s with Simvastatin (COMBOS) study. After an 8-week simvastatin lead-in, 254 subjects received P-OM3 (n=122) or placebo (n=132) for an additional 8 weeks. Nuclear magnetic resonance spectroscopy was used to assess lipoprotein concentrations and sizes. Remnant-like particle cholesterol, apolipoprotein (Apo) CIII, Apo AI, and lipoprotein-associated phospholipase A2 (Lp-PLA2) levels also were measured. Results: Compared with placebo, P-OM3 reduced mean very-low-density lipoprotein (VLDL-P) size and increased low-density lipoprotein particle (LDL-P) size (P < .006 for both) without altering high-density lipoprotein particle (HDL-P) size. P-OM3 did not significantly change total VLDL-P or LDL-P concentrations relative to placebo, but large VLDL-P and intermediate-density lipoprotein particle (IDL-P) concentrations were lowered (P < .01 for both), and the large LDL-P concentration was increased (P < .0001). HDL-P concentration was reduced (P < .0001) as the result of a decrease in medium HDL-P. Remnant-like particle cholesterol, Apo CIII, and Lp-PLA2 concentrations were reduced compared with placebo (all P < .003). Conclusions: P-OM3 induces changes in sizes, concentrations, and compositions of lipoproteins that may have relevance for the atherothrombotic process. [Copyright &y& Elsevier]

Objective: We sought to examine the diagnoses and medical management patterns of patients before the incidence of a cardiovascular (CV) event. Methods: A retrospective study of claims data from a national managed care plan was conducted. Eligible patients had a myocardial infarction, stroke, or revascularization between January 1, 2004 and December 31, 2005, and at least 3 years of continuous enrollment before the CV event. Patients were stratified by whether or not they had a diagnosis of atherosclerosis in the 3 years before the CV event. Diagnostic testing, lipid monitoring, and statin treatment patterns were assessed during the 3-year period before the CV event. Results: There were 16,543 patients with a CV event, and 65% had no previous diagnosis of atherosclerosis. For all patients, 58% were men, and mean age was 60 years. Angiography or cardiac imaging was performed in <3% of patients, and cardiac stress testing was performed in 13% of patients before the event. Only 19% of patients had ≥1 lipid test in the 12 months and 32% in the 3 years before the event, and their 12-month mean low-density lipoprotein cholesterol was 113 mg/dL. Thirty-four percent of patients were on statin therapy within the 3 years before event. The patient subgroup diagnosed with atherosclerosis had significantly more patients with cardiac testing, lipid monitoring, and statin therapy compared with patients with no previous diagnosis of atherosclerosis. Conclusion: These results from an actual clinical practice dataset indicate opportunities for improved detection and management of underlying atherosclerotic heart disease to avoid future cardiovascular events. [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]

Background: Patients may experience increased risk of adverse drug interactions when statins are administered concomitantly with cytochrome P450 3A4 (CYP3A4) inhibitors. Objective: To determine patient numbers in routine clinical practice with concomitant exposure to CYP3A4-metabolized statins and CYP3A4 inhibitors and highlight potential risk for adverse drug interaction. Methods: Exposure to prescription medications over 1 year (2005–2006) was evaluated from patient records: US PharMetrics Integrated Patient-Centric administrative claims database and the US General Electric Medical System (GEMS) database. Rates of concomitant prescribing of statins with CYP3A4 inhibitors (listed in United States of America product labels and all identified potential inhibitors) were examined in the cohort overall, in those aged ≥65 years, and in those receiving higher doses of statins. Results: Overall, 951,166 patient records were included (PharMetrics n = 650,825; GEMS, n = 300,341). Of these, 792,081 (83%) patients used a CYP3A4-metabolized statin as opposed to a non–CYP3A4-metabolized statin (17%). Findings from both databases were consistent. Overall, 25–30% of patients given a CYP3A4-metabolized statin were concomitantly exposed to a CYP3A4 inhibitor, including approximately 9% concomitantly exposed to a labeled inhibitor, findings consistent with those in patients aged ≥65 years, and patients on higher doses of statins. Conclusions: Clinicians frequently co-prescribe CYP3A4-metabolized statins with CYP3A4 inhibitors. Physician education regarding the impact of these inhibitors on the metabolism of lovastatin, simvastatin, and atrovastatin is needed. Further studies are also needed to determine whether concomitant administration of a non–CYP3A4-metabolized statin (such as fluvastatin, pravastatin, or rosuvastatin) with a CYP3A4 inhibitor, may reduce adverse event rates in routine clinical practice. [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.

Introduction: High-dose HMG-CoA reductase inhibitors (statins) fail to prevent approximately two-thirds of cardiovascular events. This fact has focused increased attention on treating abnormalities of non-high-density lipoprotein-cholesterol (non-HDL-C), HDL-C, and triglycerides in national guidelines and has intensified interest in combination therapy. Methods: The OCEANS study (Open-label evaluation of the safety and efficacy of a Combination of niacin ER and simvAstatin in patieNts with dySlipidemia; ClinicalTrials.gov identifier: NCT00080275) evaluated the safety and efficacy of a combination of niacin extended release and simvastatin (NER/S; SIMCOR®) over 52 weeks in 520 patients with mixed dyslipidemia. After a ≥4-week run-in phase of diet modification and simvastatin 40 mg/day, median baseline values (mg/dL) were: non-HDL-C = 141, low-density lipoproteincholesterol (LDL-C) = 110, HDL-C = 45, and triglyceride = 151. Patients were randomized to an 8- or 12-week niacin titration scheme to a maximum NER/S dosage of 2000/40 mg/day. Results: Differences between titration groups in tolerability, safety, and efficacy were minimal; therefore, all results are for pooled titration groups. The safety of NER/S was consistent with the safety profile of each individual component. Treatment with NER/S was well tolerated: 71% of patients experienced flushing and 92% of flushing episodes were mild or moderate in intensity. Overall, 61% of patients experienced flushing episodes that were rated as mild or moderate in intensity. Flushing decreased over time: <40% of those who had flushing during titration experienced flushing during the final 12 weeks. A total of 20% of patients discontinued treatment because of a treatment-related adverse event, including 7% who discontinued because of flushing. Median changes from baseline (following the simvastatin 40 mg/day run-in phase) to 24 weeks were: non-HDL-C = -27.3%, LDL-C = -25.0%, HDL-C = +23.9%, and triglycerides = -35.9% (all p < 0.0001 vs baseline). In lipidtreatment- naive patients, NER/S 2000/40 mg/day decreased non-HDL-C, LDL-C, and triglycerides by approximately 50% and increased HDL-C by approximately 25% when week-24 lipid values were compared with lipid values obtained prior to the simvastatin 40 mg/day run-in. All three therapeutic lipid targets (LDL-C [riskadjusted goal], HDL-C ≥40 mg/dL, and triglycerides <150 mg/dL) were achieved concurrently by 65% of patients treated with NER/S. Conclusion: Treatment with NER/S 2000/40 mg/day is well tolerated, has no unanticipated adverse events, and provides additional, clinically relevant improvements in multiple lipid parameters beyond statin monotherapy. [ABSTRACT FROM AUTHOR]

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]

Although the greatest burden of cardiovascular disease occurs after age 65 years, limited efficacy and safety data are available for cholesterol-lowering drugs in elderly patients. We undertook a pooled analysis of individual data from 13,282 patients aged 18-93 years in 16 published trials of ezetimibe and ezetimibe added on to or coadministered with a statin (ezetimibe/statin). Overall, ezetimibe reduced low-density lipoprotein cholesterol by 20% compared with placebo and ezetimibe/statin reduced low-density lipoprotein cholesterol by 17% compared with a statin alone, with consistent treatment effects across age groups (<65, 65-74 and =75 years). Rates of any adverse or drug-related adverse events were also similar across age groups. We conclude that the lipid efficacy and safety of ezetimibe and ezetimibe/statin in those aged 65-74 and 75 years and older are similar to those observed in patients aged under 65 years. [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]

Low high-density lipoprotein cholesterol (HDL-C) levels are associated with higher risk of cardiovascular disease, even in patients receiving statin therapy. HDL-C has a number of potential atheroprotective mechanisms, including reverse cholesterol transport. HDL-C also has antioxidant, anti-inflammatory, vasodilatory and antithrombotic effects. A number of targets with the potential to raise HDL-C levels and/or increase reverse cholesterol transport have been identified. Plasma concentrations of HDL-C are the net result of the de novo production, catabolism and recycling of HDL-C particles, as well as the contribution to HDL-C from components of other lipoproteins. HDL-C levels can be modified by increasing the production of apolipoprotein A-I or by delaying the clearance of HDL-C from the plasma. Whether manipulation of these drug targets to raise HDL-C will result in cardiovascular event reduction remains to be determined. [ABSTRACT FROM AUTHOR]

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]

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]

Emerging data suggest that the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) offer important benefits for the large population of individuals at high risk for coronary heart disease. This population encompasses a sizable portion of individuals who are also at high risk for drug-drug interactions due to their need for multiple medications. In general, statins are associated with a very small risk for myopathy (which may progress to fatal or nonfatal rhabdomyolysis); however, the potential for drug-drug interactions is known to increase this risk in specific high-risk groups. The incidence of myopathy associated with statin therapy is dose related and is increased when statins are used in combination with agents that share common metabolic pathways. Of particular concern is the potential for interactions with other lipid-lowering agents such as fibrates and niacin (nicotinic acid), which may be used in patients with mixed lipidemia, and with immunosuppressive agents, such as cyclosporine, which are commonly used in patients after transplantation. Clinicians should be alert to the potential for drug-drug interactions to minimize the risk of myopathy during long-term statin therapy in patients at high risk for coronary heart disease. [ABSTRACT FROM AUTHOR]

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]

With the aging of the population, death from coronary heart disease (CHD) and stroke has become more prevalent. Cardiovascular disease (CVD) risk factors, such as hypertension, obesity, and diabetes mellitus increase with age as well. Recent secondary-prevention studies have established the positive effect of statins in decreasing the risk of CHD mortality through the lowering of cholesterol. Statins have an excellent safety record, at least with users under age 65, and provide a cheaper alternative to more costly medical options. The most serious side effect associated with their use is myopathy, which is infrequent. Drug interactions have been found with drugs that compete for the same CYP450 isoenzymes as statins. Several drugs have been shown to significantly inhibit the CYP3A4 pathway; in combination with statins such as lovastatin, simvastatin, atorvastatin, and cerivastatin, they have been shown to elevate serum concentrations of these statins, or may increase the risk of myopathy. Alternatively, other drugs can inhibit the CYP2C9 pathway and may elevate serum concentration of fluvastatin. Due to the number of medications the elderly receive, an understanding of the various metabolic pathways is of vital importance to minimize the potential for drug interactions. The elderly population, while at high risk for CVD, is currently undertreated. Statins can effectively lower low-density lipoprotein cholesterol levels and lessen the risk of CVD for this population. [ABSTRACT FROM AUTHOR]

Assesses the lipid-lowering effect of atorvastatin (a new Hydroxy-3methyglutaryl coenzyme A reductase inhibitor) on levels of serum triglycerides and other lipoprotein fractions in patients with primary hypertriglyceridemia. Study design; Description of study participants; Interventions; Efficacy and safety measurements; Effect on serum lipids.

Elevated remnant lipoprotein cholesterol (RLP-C) levels increase cardiovascular disease risk. However, RLP-C measurement methods are not standardized, leading to variations across studies. To evaluate the effect of ezetimibe (Eze) + statins vs statin monotherapy on RLP-C using immunoseparation (IM), vertical auto profile (VAP) ultracentrifugation, and calculated RLP-C measurement methods. This post hoc analysis evaluated data pooled from 3 first-line (all-statin [simvastatin 10/20/40/80 mg] vs Eze + statin [Eze 10 mg + simvastatin]) and 2 second-line (statin [atorvastatin uptitrated to 40/80 mg] vs statin + Eze [atorvastatin 20/40 mg + Eze 10 mg]) studies. Similarity of RLP-C methods was evaluated using Pearson correlation coefficients and Bland-Altman plots. RLP-C changes and percent changes from baseline were measured by all 3 methods in first-line and VAP and calculated methods in second-line studies. Correlations between methods were generally moderate to strong for RLP-C levels, changes, and percent changes across treatment groups (r = 0.29–0.79) but with little evidence of agreement by Bland-Altman plots. Baseline RLP-C levels for Eze + statin vs all-statin groups were lower by IM (14.0 vs 14.0) compared with VAP (36.9 vs 35.9) and calculated (32.8 vs 33.3) methods. RLP-C changes (mg/dL) and percent changes from baseline were significantly greater (P <.01) with Eze + statins vs statins by VAP, calculated, and IM methods (between-treatment differences: −5.0 and −12.0, −2.0 and −5.4, and −1.5 and −12.1, respectively) in first-line, and VAP and calculated methods (between-treatment differences: −5.0 and −19.9 and −2.0 and −7.3) in second-line studies. Although the 3 methods showed little agreement, each supported Eze + statins for achieving greater RLP-C reductions vs statin monotherapy; variability of results reinforces urgent need to standardize RLP-C measurements. • Remnant lipoprotein cholesterol measurement methods showed little agreement. • Correlations between the measurement methods were generally moderate to strong. • Ezetimibe/statin showed greater remnant lipoprotein cholesterol reduction vs statin. • There is a need to standardize remnant lipoprotein cholesterol measurement methods. [ABSTRACT FROM AUTHOR]

There is an increasing trend among physicians to use 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) in combination with other antilipidemic agents. The complementary lipid-altering effects of statins and fibric acid derivatives (fibrates) have led to an increasing use of statin/fibrate combination therapy, particularly for patients who have mixed dyslipidemia. Clinical experience indicates that there may be an increased risk of myotoxicity associated with statin/fibrate combination therapy. However, it is not known whether there are differences in the rate of myotoxicity between the use of fenofibrate and gemfibrozil in combination with statins. To evaluate this question, data from the United States Food and Drug Administration''s Adverse Event Reporting System was reviewed to determine how many adverse events were reported for patients who were being treated concomitantly with statins and fibrates. The findings suggest that the use of fenofibrate in combination with statins results in fewer reports of rhabdomyolysis per million prescriptions dispensed than does the use of gemfibrozil. [Copyright &y& Elsevier]

The author comments on a meta-analysis of clinical trials that examined the association between high-dose statin therapy and increased risk of new-onset diabetes mellitus. According to the author, one possible explanation for statin-induced insulin resistance is inhibition of isoprenoid biosynthesis. He contends that statin monotherapy is effective in reducing low density lipoprotein regardless of the dosage. He points out that high-dose statin therapy is associated with toxicity risk.

Focuses on possible differences between fibrates in pharmacokinetic interactions with statins. Concerns of physicians about prescribing fibrates and statins concomitantly; Risk of myopathy with statin therapy; Potential differences between fibrates in their ability to affect the glucuronidation pathway.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein secreted by the hepatocyte that regulates the surface expression of low-density lipoprotein (LDL) receptors by targeting them for lysosomal degradation. Statins enhance PCSK9 synthesis, an effect that blunts the LDL-cholesterol (-C)–lowering effectiveness of statins. Loss-of-function mutations in the PCSK9 gene produce life-long low levels of LDL-C and reduce cardiovascular risk. Monoclonal antibodies to PCSK9, which mimic the effects of genetic mutations by inhibiting PCSK9, are in clinical trial development. Two different commercial development programs have demonstrated significant success in lowering LDL-C in phase 1 and 2 trials with similar agents: REGN727/SAR236553 (REGN727) and, more recently, AMG 145. When administered subcutaneously at doses ranging from 50 to 150 mg every 2 weeks or 200 to 400 mg every 4 weeks, these agents produced similar dose-responses in LDL-C lowering. In hypercholesterolemic patients, LDL-C reductions ranged up to 60%, and, as would be expected, an even greater response was reported for statin-treated hypercholesterolemic patients—up to 70% decrease. LDL-C has typically shown a gradual increase after the nadir as monoclonal antibodies are cleared from the circulation. Results to date indicate that the PCSK9 monoclonal antibody approach appears safe, well-tolerated, and profoundly lowers LDL-C levels while also favorably altering apolipoprotein B, triglycerides, lipoprotein (a), and high-density lipoprotein-C. It is expected to meet an important clinical need for patients unable to achieve adequate LDL-C-lowering with currently available therapies. [Copyright &y& Elsevier]

In patients with diabetes mellitus (DM), a cardiovascular event is of critical concern because of the impact on long-term survival. Cardiovascular disease (CVD) is the leading cause of death for patients with DM, which makes the modification of risk factors in the patient with DM and CVD a primary focus of the preventive cardiologist. Management of this patient population should include pharmacologic interventions, such as antidyslipidemics (mainly statins) and oral anti-DM (or insulin) agents, as well as diet control, physical exercise, and smoking cessation. It is hoped that focus on the ABCs of treatment—hemoglobin A1c, blood pressure, and cholesterol-lipid profile—along with ongoing and future studies on the effects of these interventions will help to reduce the significant morbidity and mortality from microvascular and macrovascular complications in these high-risk patients with DM. [ABSTRACT FROM AUTHOR]

As the significance of treating coronary artery disease (CAD) remains a high priority in reducing morbidity and mortality worldwide, newer treatment strategies continue to evolve. The efficacy of statin therapy in reducing low-density lipoprotein cholesterol and reducing cardiovascular events is well established. Yet, addressing residual macrovascular risk becomes a compelling rationale for proposing that pharmacologic therapy targeted at low concentrations of high-density lipoprotein (HDL) cholesterol is a rationale target for enhanced management of CAD. This article reviews current options for the therapeutic management of HDL cholesterol, including discussion of novel agents aimed at reducing cardiovascular disease risk in patients with low levels of HDL cholesterol. [Copyright &y& Elsevier]

Small, dense LDL are more atherogenic than larger LDL particles. It has been hypothesized that individuals shift from a predominance of larger (pattern A) to smaller LDL particles (pattern B) when the fasting triglyceride (TG) concentration exceeds a threshold, typically in the range of 100-250 mg/dL. The present investigation assessed the influence of TG-lowering with prescription omega-3-acid ethyl esters on LDL size in men and women with TG 200 to 499 mg/dL while on statin therapy. After 8 weeks on simvastatin 40 mg/d, 254 subjects were randomly assigned to 4 g/d of Omacor® (3.4 g/d EPA + DHA) or placebo for an additional 8 weeks. Median LDL particle size increased in the omega-3 treated group (19.90 to 20.20 nm, p=0.007 vs. placebo). Median changes from baseline were 0.60, 0.40, 0.15 and -0.20 nm, when the on-treatment TG concentrations were <150, 150-199, 200-249 and >250 mg/dL, respectively (p<0.001). In these on-treatment TG subsets, pattern B was present in 36, 50, 82 and 84% of subjects (p<0.001), compared to 68, 79, 93, and 73%, respectively, at baseline. The association of on-treatment TG category with the change in LDL particle size remained highly significant (p<0.001) after adjusting for the degree of TG-lowering. These results support the concept of a TG threshold for conversion from LDL subclass pattern B to A. [ABSTRACT FROM AUTHOR]

This article summarizes the final conclusions of the National Lipid Association (NLA) Statin Safety Task Force, based on a review and independent research of New Drug Application (NDA) information, US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) data, cohort and clinical trial results, and analysis of administrative claims database information and the assessment of its 4 Expert Panels, which focused on issues of statin safety with regard to liver, muscle, renal, and neurologic systems. Practical guidance in the form of recommendations to health professionals who manage the coronary artery disease risk of patients with statin therapy is provided. [Copyright &y& Elsevier]

The adverse event (AE) profiles of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) agents are of great interest, in particular the most recently approved statin, rosuvastatin. The forwarding of reports of AEs has been shown to be influenced by several reporting biases, including secular trend, the new drug reporting effect, product withdrawals, and publicity. Comparative assessments that use AE reporting rates are difficult to interpret under these circumstances, because such effects can themselves lead to marked increases in AE reporting. Consequently, many comparative reporting rate analyses are best carried out in conjunction with other metrics that put reporting burden into context, such as report proportion. All-AE reporting rates showed a temporal profile that resembled those of other statins when marketing cycle and secular trend were taken into account. A before-and-after cerivastatin withdrawal comparison showed a substantial increase in the reporting of AEs of interest for the statin class overall. Report proportion analyses indicated that the burden of rosuvastatin-associated AEs was similar to that for other statin agents. Analyses of monthly reporting rates showed that the reporting of rosuvastatin-associated rhabdomyolysis and renal failure have increased following AE-specific mass media publicity. Postrosuvastatin AE reporting patterns were comparable to those seen with other statins and did not resemble cerivastatin. [Copyright &y& Elsevier]

Presents a letter to the editor about Dr. Nissen's editorial on the benefits of statin therapy in ACS patients.

ETC-1002 is a new investigational low density lipoprotein cholesterol (LDL-C)-lowering agent (Esperion Therapeutics, Inc.). ETC-1002 is a dicarboxylic acid derivative with a novel mechanism of action targeting two hepatic enzymes – adenosine triphosphate-citrate lyase (ACL) and adenosine monophosphate-activated protein kinase (AMPK), inhibiting sterol and fatty acid synthesis and promoting mitochondrial long-chain fatty acid oxidation. This agent is currently in phase II clinical research. Available data report that ETC-1002 significantly decreased LDL-C levels (up to 32%) in both patients with normal and elevated baseline levels of triglycerides. Such beneficial effect is superior to currently approved non-statin lipid lowering agents. The levels of apolipoprotein B (apoB) and non-high density lipoprotein cholesterol (non-HDL-C) were also reduced with beneficial effect on other cardiometabolic factors such as inflammatory markers, blood pressure and body weight. Although, the safety and tolerability of ETC-1002 needs to be confirmed in ongoing and future, larger studies, this agent has, so far, been generally safe and well tolerated. This novel, oral, once-daily, small molecule may lead to effective LDL-C lowering treatment in hypercholesterolaemic subjects who are statin intolerant or as add-on therapy in those who are unable to reach the LDL-C goals despite being on statin therapy. This agent might not only exert lipid-lowering related benefits, but also favourable cardiometabolic effects. [ABSTRACT FROM AUTHOR]

The present post hoc analysis of data from the COMBination of prescription Omega-3 with Simvastatin (COMBOS) study investigated the predictors of the low-density lipoprotein (LDL) cholesterol response to prescription omega-3 acid ethyl ester (P-OM3) therapy in men and women with high (200 to 499 mg/dl) triglycerides during diet plus simvastatin therapy. Subjects (n = 256 randomized) received double-blind P-OM3 4 g/day or placebo for 8 weeks combined with diet and open-label simvastatin 40 mg/day. The percentage of changes from baseline (with diet plus simvastatin) in lipids was evaluated by tertiles of baseline LDL cholesterol and triglyceride concentrations. The baseline LDL cholesterol tertile was a significant predictor of the LDL cholesterol response (p = 0.022 for the treatment by baseline tertile interaction). The median LDL cholesterol response in the P-OM3 group was +9.5% (first tertile, <80.4 mg/dl), −0.9% (second tertile), and −6.4% (third tertile, ≥99.0 mg/dl). Non–high-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride responses did not vary significantly by baseline LDL cholesterol tertile. The reductions in very-low-density lipoprotein cholesterol concentrations were greater than the increases in LDL cholesterol, where present, resulting in a net decrease in the concentration of cholesterol carried by atherogenic particles (non–high-density lipoprotein cholesterol) in all baseline LDL cholesterol tertiles. In conclusion, these results suggest that the increase in LDL cholesterol that occurred with the addition of P-OM3 to simvastatin therapy in subjects with mixed dyslipidemia was confined predominantly to those with low LDL cholesterol levels while receiving simvastatin monotherapy. [Copyright &y& Elsevier]

Concomitant use of a fibrate and a statin may offer a therapeutic advantage to patients with dyslipidemia, especially in patients whose low-density lipoprotein cholesterol is controlled by statins but whose high-density lipoprotein cholesterol or triglycerides, or both, are not within goal. However, concern about drug–drug interactions may preclude optimal use of combination statin-fibrate therapy. This article reviews the pharmacokinetics between statins and fibrates, addressing risks associated with drug–drug interactions and combination therapy. [Copyright &y& Elsevier]

Purpose: Results from a Phase III, European, noninferiority trial in elderly (age ≥ 6 5 years) patients with primary hyperlipidemia or mixed (combined) dyslipidemia demonstrated significantly greater reductions in LDL-C for pitavastatin versus pravastatin across 3 pair-wise dose comparisons (1 mg vs 10 mg, 2 mg vs 20 mg, and 4 mg vs 40 mg, respectively). The present study investigated whether pitavastatin 4 mg is superior to pravastatin 40 mg in LDL-C reduction in adults (18-80 years old) with primary hyperlipidemia or mixed (combined) dyslipidemia. Methods: This was a Phase IV, multicenter, randomized, double-blind, double-dummy, active-control superiority study conducted in the United States. Patients with baseline LDL-C levels of 130 to 220 mg/dL (inclusive) and triglyceride levels ≤400 mg/dL after a 6-week washout/dietary stabilization period were randomized to 12 weeks of once-daily treatment with either pitavastatin 4 mg or pravastatin 40 mg. Findings: A total of 328 subjects (164 per treatment arm) were randomized (mean age, 57.9 years [76% were aged < 6 5 years]; 49.4% women; mean body mass index, 30.2 kg/m²) to treatment. The median percent change in LDL-C from baseline to the week 12 endpoint was -38.1% for pitavastatin 4 mg and -26.4% for pravastatin 40 mg; the difference in median percent change between treatments was -12.5% (P < 0.001). Differences between treatments in median percent reductions from baseline for apolipoprotein B, total cholesterol, and non-HDL-C were also significant in favor of pitavastatin (P < 0.001). Both treatments significantly (P < 0.001) increased HDL-C and decreased triglycerides, but the differences between treatments were not statistically significant. The overall rate of treatment-emergent adverse events was 47.6% (78 of 164) for pitavastatin and 44.5% (73 of 164) for pravastatin. Myalgia was reported by 3 patients (1.8%) in the pitavastatin group and by 4 patients (2.4%) in the pravastatin group. There were no reports of myositis or rhabdomyolysis. Implications: Pitavastatin 4 mg demonstrated superior LDL-C reductions compared with pravastatin 40 mg after 12 weeks of therapy in adults with primary hyperlipidemia or mixed (combined) dyslipidemia. There were no new safety findings in the trial. Clinical Trials.gov identifier: NCT01256476. [ABSTRACT FROM AUTHOR]

Background: A novel omega-3 formulation in free fatty acid form (OM3-FFA) has as much as 4-fold greater bioavailability than ethyl ester forms and reduces triglyceride (TG) levels in patients with severe hypertriglyceridemia. Objective: This study was designed to evaluate the efficacy of adding OM3-FFA (2 or 4 g/d) to statin therapy for lowering non-HDL-C and TG levels in subjects with persistent hypertriglyceridemia and at high risk for cardiovascular disease. Methods: In this double-blind, parallel-group study, 647 diet-stable patients with fasting TG levels ≥200 mg/ dL and <500 mg/dL (treated with a maximally tolerated dose of statin or statin with ezetimibe) and at high risk for cardiovascular disease were randomized to 6 weeks of treatment with capsules of control (olive oil [OO]) 4 g/d, OM3-FFA 2 g/d (plus 2 g/d OO), or OM3-FFA 4 g/d. Assessments included fasting serum levels of lipids and apolipoproteins (apo); plasma concentrations of eicosa-pentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, and arachidonic acid; and laboratory safety values and adverse events. Results: In the 627 subjects in the intention to treat sample, non-HDL-C levels were reduced with OM3-FFA 2 g/d and OM3-FFA 4 g/d (-3.9% and -6.9%, respec-tively) compared with OO (-0.9%) (both, P < 0.05), as were TG levels (-14.6% and -20.6%, respectively, vs -5.9%; both, P < 0.001). LDL-C levels increased with OM3-FFA 2 g/d (4.6%) compared with OO (1.1%) (P = 0.025) but not with OM3-FFA 4 g/d (1.3%). Total cholesterol and VLDL-C concentrations were reduced compared with OO with both OM3-FFA dosages, and the total cholesterol/HDL-C ratio and apo AI and apo B levels were significantly lowered with OM3-FFA 4 g/d only (all at least P < 0.05). Percent changes from baseline in HDL-C did not differ between OO and either OM3-FFA group. Plasma concentrations of docosahex-aenoic acid, eicosapentaenoic acid, and docosapentaenoic acid were significantly increased and arachidonic acid was significantly reduced in both OM3-FFA treatment groups compared with the OO responses (all, P < 0.001). Withdrawals related to treatment-emergent adverse events ranged from 0.9% with OO to 3.2% with OM3-FFA 4 g/d. Conclusions: OM3-FFA was well tolerated and low-ered non-HDL-C and TG levels at both 2- and 4-g/d dos-ages in patients with persistent hypertriglyceridemia taking a statin, with the 4-g/d dosage providing incremental im-provements compared with 2 g/d. ClinicalTrials.gov iden-tifier: NCT01408303. [ABSTRACT FROM AUTHOR]

It is well established that low high-density lipoprotein (HDL) cholesterol is a risk factor for coronary artery disease (CAD). Growing evidence from epidemiologic as well as intervention studies have identified that a low level of HDL cholesterol contributes to cardiovascular disease risk. In addition, a number of clinical trials have substantiated that an inverse association between HDL cholesterol concentrations and cardiovascular risk exists. Decreasing low-density lipoprotein cholesterol levels with statins has a major impact on cardiovascular risk reduction, and statin therapy plays a significant role in the management of CAD. However, low levels of HDL cholesterol remain as a cardiovascular risk factor despite statin therapy. This article presents an overview of statin clinical trials and discusses implications for the clinical management of patients with low HDL cholesterol levels and increased cardiovascular risk. [Copyright &y& Elsevier]

High-sensitivity assays that accurately measure levels of the inflammatory biomarker C-reactive protein have been proposed for use in assessments of risk for cardiovascular disease (CVD). A growing body of evidence supports recommendations for these tests in selected asymptomatic individuals deemed to be at intermediate risk of CVD according to traditional risk-factor assessments and who do not already warrant chronic treatment with aspirin and statin therapy. Data suggests that these high-sensitivity assays should be used in combination with measurements of LDL-cholesterol levels to assist risk stratification of selected patients for prevention of CVD. [ABSTRACT FROM AUTHOR]

Background: The enzyme acyl–coenzyme A:cholesterol acyltransferase (ACAT) esterifies cholesterol in a variety of tissues. In some animal models, ACAT inhibitors have antiatherosclerotic effects. Methods: We performed intravascular ultrasonography in 408 patients with angiographically documented coronary disease. All patients received usual care for secondary prevention, including statins, if indicated. Patients were randomly assigned to receive the ACAT inhibitor pactimibe (100 mg per day) or matching placebo. Ultrasonography was repeated after 18 months to measure the progression of atherosclerosis. Results: The primary efficacy variable analyzing the progression of atherosclerosis — the change in percent atheroma volume — was similar in the pactimibe and placebo groups (0.69 percent and 0.59 percent, respectively; P=0.77). However, both secondary efficacy variables assessed by means of intravascular ultrasonography showed unfavorable effects of pactimibe treatment. As compared with baseline values, the normalized total atheroma volume showed significant regression in the placebo group (−5.6 mm3, P=0.001) but not in the pactimibe group (−1.3 mm3, P=0.39; P=0.03 for the comparison between groups). The atheroma volume in the most diseased 10-mm subsegment regressed by 3.2 mm3 in the placebo group, as compared with a decrease of 1.3 mm3 in the pactimibe group (P=0.01). The combined incidence of adverse cardiovascular outcomes was similar in the two groups (P=0.53). Conclusions: For patients with coronary disease, treatment with an ACAT inhibitor did not improve the primary efficacy variable (percent atheroma volume) and adversely affected two major secondary efficacy measures assessed by intravascular ultrasonography. ACAT inhibition is not an effective strategy for limiting atherosclerosis and may promote atherogenesis. (ClinicalTrials.gov number, NCT00268515.) N Engl J Med 2006;354:1253-63. [ABSTRACT FROM AUTHOR]