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Background: Elevated remnant lipoprotein cholesterol (RLP-C) levels increase cardiovascular disease risk. However, RLP-C measurement methods are not standardized, leading to variations across studies., Objective: 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., 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., Results: 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., Conclusion: 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., (Copyright © 2019. Published by Elsevier Inc.)

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., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Context: In animal and observational studies, adiponectin is associated with lipoprotein risk factors for cardiovascular disease., Objective: We analyzed data from a randomized clinical trial to evaluate the relationship between changes in adiponectin to changes in lipoprotein risk factors after an intervention that alters adiponectin levels., Design and Setting: Adiponectin levels were measured at baseline and follow-up, as were lipoprotein risk factors for cardiovascular disease, at academic medical centers and ambulatory care centers., Patients and Other Participants: Participants included 361 men and women with type 2 diabetes., Intervention: Intervention included randomization to treatment with glimepiride or pioglitazone for 72 wk., Main Outcome Measure: The relationship of treatment-related differences in adiponectin level to treatment-related differences in lipoprotein cardiovascular risk factors at 72 wk was evaluated., Results: Pioglitazone led to an increase in adiponectin compared with glimepiride. Compared with baseline, pioglitazone treatment at 72 wk led to an increase in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particle size and a decrease in very-low-density lipoprotein (VLDL) particle size and LDL particle number. Glimepiride treatment more modestly decreased LDL particle number and increased LDL particle size. At 72 wk, there were significant treatment group differences for HDL, LDL, and VLDL particle size, and triglyceride and HDL cholesterol level. The increase in adiponectin predicted treatment-related improvement for triglyceride and HDL cholesterol level and LDL and HDL particle size., Conclusion: Increased adiponectin contributed to treatment-related benefit in lipoprotein cardiovascular disease risk factors in obese diabetic subjects treated with pioglitazone. These results provide support for a model that mechanistically links changes in adiponectin level to changes in lipoprotein composition in humans.

Objective: Insulin resistance and type 2 diabetes are associated with an atherogenic lipoprotein profile. We examined the role of visceral and subcutaneous fat depots, independent of BMI, on the dyslipidemia associated with type 2 diabetes., Research Design and Methods: A total of 382 subjects with type 2 diabetes underwent abdominal computed tomography to evaluate subcutaneous (SAT) and visceral adipose tissue (VAT) distribution and had anthropometric measurements to determine BMI and waist and hip circumference. Fasting blood was obtained for lipoprotein particle number and size using nuclear magnetic resonance spectroscopy. The relationship of lipoprotein particle number and size with BMI, SAT, and VAT was examined using multivariable regression models adjusted for age, sex, diabetes therapy, duration of diabetes, smoking, statin use, and A1C levels. The relation of VAT to lipoprotein particle number and size was further evaluated after the addition of BMI, BMI plus SAT, or BMI plus homeostatis is model assessment of insulin resistance (HOMA-IR) to the model., Results: VAT was positively related to VLDL particle number (P < 0.0001), LDL particle number (P < 0.01), and VLDL size (P < 0.0001) and negatively related to LDL size (P < 0.0001) and HDL size (P < 0.0001). These relationships remained unchanged after addition of BMI and SAT to the model. After addition of HOMA-IR, VAT remained positively related to VLDL particle number (P < 0.0001) and size (P < 0.01) and negatively related to LDL and HDL particle size (P < 0.0001 for both comparisons). Neither BMI nor SAT was independently related to lipoprotein parameters., Conclusions: In patients with type 2 diabetes, higher VAT independent of BMI was associated with higher VLDL and LDL particle number, larger VLDL particles, and smaller LDL and HDL particles. This lipoprotein pattern has been associated with increased risk for atherosclerosis and cardiovascular disease.

Purpose of Review: Patients with dyslipidemias continue to be undertreated in both the primary and secondary prevention settings. Many patients have therapeutic needs that exceed simple reductions in low-density lipoprotein levels using statins. This review discusses the need for comprehensive management of all abnormalities in a given patient's lipoprotein profile and for the use of combinations of anti-lipidemic medications, when indicated., Recent Findings: The majority of high-risk patients with manifestations of atherosclerotic disease or who have a coronary artery disease risk equivalent are not meeting their various lipoprotein targets. There is considerable reluctance to titrate statins and to use combinations of anti-lipidemic medications in patients not reaching their various lipoprotein targets. Combinations of anti-lipidemic medications can be specifically tailored to address abnormalities in multiple lipoprotein fractions. Recent clinical trials clearly demonstrate that combination therapy is well tolerated and facilitates lipoprotein goal attainment., Summary: Therapeutic approaches that incorporate the use of multiple anti-lipidemic medications should be more widely adopted in order to increase the number of patients able to meet their lipoprotein goals and to produce more substantially reduced risks for acute cardiovascular events.

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]

Lipoprotein X (LpX) is an abnormal lipoprotein found in conditions such as lecithin:cholesterol acyltransferase deficiency and cholestatic states (e.g., primary biliary cirrhosis and primary sclerosing cholangitis). Management of severe hypercholesterolemia due to LpX with drugs and physical removal methods is not well established in the literature. A case is discussed of a 51-year-old woman who presented with multiple electrolyte abnormalities, xanthomas and neuropathy found to be secondary to LpX in the setting of primary sclerosing cholangitis. This case highlights that oral medications, including statins, may be insufficient to normalize lipid levels or improve clinical symptoms of LpX and presents therapeutic plasma exchange as a safe and effective therapeutic option to treat the morbid sequela of LpX hyperlipidemia. [ABSTRACT FROM AUTHOR]

Lowering serum lipid levels is part of the foundation of treating and preventing clinically significant cardiovascular disease. Recently, the American Heart Association/American College of Cardiology released cholesterol guidelines which advocate for high efficacy statins rather than LDL-c goals for five patient subgroups at high risk for cardiovascular disease. Therefore, it is critical that clinicians have an approach for managing side-effects of statin therapy. Statins are associated with myopathy, transaminase elevations, and an increased risk of incident diabetes mellitus among some patients; connections between statins and other processes, such as renal and neurologic function, have also been studied with mixed results. Statin-related adverse effects might be minimized by careful assessment of patient risk factors. Strategies to continue statin therapy despite adverse effects include switching to another statin at a lower dose and titrating up, giving intermittent doses of statins, and adding non-statin agents. Non-statin lipid-lowering drugs have their own unique limitations. Management strategies and algorithms for statin-associated toxicities are available to help guide clinicians. Clinical practice should emphasize tailoring therapy to address each individual's cholesterol goals and risk of developing adverse effects on lipid-lowering drugs. [Copyright &y& Elsevier]

Abstract: An international panel of the International Atherosclerosis Society has developed a new set of recommendations for the management of dyslipidemia. The panel identifies non—high-density lipoprotein cholesterol as the major atherogenic lipoprotein. Primary and secondary prevention are considered separately. Optimal levels for atherogenic lipoproteins are derived for the two forms of prevention. For primary prevention, the recommendations emphasize lifestyle therapies to reduce atherogenic lipoproteins; drug therapy is reserved for subjects at greater risk. Risk assessment is based on estimation of lifetime risk according to differences in baseline population risk in different nations or regions. Secondary prevention emphasizes use of cholesterol-lowering drugs to attain optimal levels of atherogenic lipoproteins. [Copyright &y& Elsevier]

Background: Goal/desirable lipid levels are underachieved in patients with mixed dyslipidemia. These patients may have substantial residual risk of cardiovascular disease even while receiving optimal LDL-C-lowering therapy and may require additional therapy to improve multiple lipid/lipoprotein levels. Objective: To evaluate attainment of goal/desirable levels of lipids/lipoproteins after 12-week treatment with combination rosuvastatin + fenofibric acid versus rosuvastatin monotherapy. Methods: This was a post hoc analysis of patients with mixed dyslipidemia who enrolled in one of two randomized controlled trials, and were treated (N = 2066) with rosuvastatin (5, 10, or 20 mg), fenofibric acid 135 mg, or rosuvastatin + fenofibric acid for 12 weeks. Data were pooled across doses of rosuvastatin as monotherapy and combination therapy. Results: Compared with rosuvastatin monotherapy, combination therapy had comparable effects in achieving risk-stratified LDL-C goals; however, measures of total atherogenic burden were improved because significantly greater percentages of patients attained non-HDL-C goal in high- (62.9% vs 50.4%, P = .006) and moderate-risk groups (87.6% vs 80.4%, P = .016) and apolipoprotein B (ApoB) <90 mg/dL in high-risk group (59.8% vs 43.8%, P < .001). In the overall population, more patients treated with the combination therapy achieved desirable levels of HDL-C >40/50 mg/dL in men/women (P < .001), triglycerides <150 mg/dL (P < .001), and ApoB <90 mg/dL (P < .001), compared with rosuvastatin monotherapy. Furthermore, combination therapy resulted in significantly greater percentages of patients achieving simultaneous specified levels of LDL-C + non-HDL-C (P < .015); LDL-C + HDL-C + TG (P < .001); and LDL-C + HDL-C + triglycerides + non-HDL-C + ApoB (P < .001), compared with rosuvastatin monotherapy. Conclusion: Rosuvastatin + fenofibric acid may be more efficacious than rosuvastatin alone in patients with mixed dyslipidemia. [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: 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: 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]

Background: The number of patients with multiple lipid abnormalities is increasing. Lipid treatment guidelines are established for low-density lipoprotein cholesterol (LDL-C) and non–high-density lipoprotein cholesterol (non–HDL-C). The importance of treating HDL-C and triglycerides is gaining recognition. Objective: To determine, in patients who had been treated previously with simvastatin 40 mg/day, the efficacy, safety, and tolerability of two regimens of a combination of proprietary niacin, extended-release core, coated with 40 mg/day simvastatin (NER/S), compared to 80 mg/day simvastatin monotherapy (S80). Methods: High-risk patients (n = 343) with dyslipidemia were treated for 24 weeks with NER/S (1000/40 mg/day or 2000/40 mg/day) or S80. Results: Median percentage change from baseline to week 24 in non–HDL-C in either NER/S group was noninferior to S80 (−11.3%, −17.1%, and −10.1%, respectively). Changes in LDL-C were comparable (−8.6%, −11.6%, and −12.7%, respectively). Doubling the dose of simvastatin (S80) did not alter HDL-C, triglycerides, or lipoprotein(a); however, both NER/S doses resulted in significant improvements in all three parameters (+21.9%, −31.8%, and −21.0%, respectively, for NER/S 2000/40 mg/day). The safety of NER/S was consistent with the safety profile of each individual component. Treatment with both doses of NER/S was well tolerated; 59% of patients experienced flushing, 78% of flushing was mild or moderate in intensity, 49% of those who flushed during dose titration did not flush during weeks 13 to 24, and only 4.6% of patients discontinued because of flushing. Conclusion: NER/S provides similar reductions in non–HDL-C and LDL-C compared to doubling the simvastatin dose to 80 mg; however, only NER/S resulted in improvements in HDL-C, triglycerides, and lipoprotein(a). [Copyright &y& Elsevier]

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]

Abstract: Background: AGI-1067 (succinobucol) is a phenolic derivative of probucol that inhibits the vascular oxidative-inflammatory cascade and is intended to have an improved clinical profile. Objective: The Assessment of Lipoprotein Profiles (ALPS) study evaluated the effects of AGI-1067 on lipid, antioxidant, antiinflammatory and safety profiles in healthy subjects. Methods: This was a double-blind, placebo-controlled, 12-week, multicenter trial. Eligible subjects, aged 18 to 65 years, had low-density lipoprotein cholesterol (LDL-C) ≤ 190 mg/dL, triglyceride (TG) ≤ 600 mg/dL and Framingham risk <10%. Subjects were randomized 1:1 to oral 300 mg AGI-1067 (n = 127) or matching placebo (n = 127) once daily. Results: AGI-1067 and placebo treatment had small changes (mean) in: LDL-C (+2.98 vs −1.52 mg/dL, respectively; P = 0.057), apolipoprotein B (+1.48 vs −1.91 mg/dL; P = 0.267), high-density lipoprotein cholesterol (HDL-C) [−3.69 vs −0.29 mg/dL; P < 0.001], and apolipoprotein (Apo) A-I (−10.43 vs −6.14 mg/dL; P = 0.021). Subjects with baseline LDL-C > 130 mg/dL showed the largest decreases in HDL-C and ApoA-I, while subjects with LDL-C ≤130 mg/dL had insignificant changes in both parameters. Changes in cholesteryl ester transfer protein mass were significantly correlated (P < 0.0001) with LDL-C changes, but not HDL-C. Paraoxonase activity increased with AGI-1067 vs little change in placebo (+1.78 vs +0.15 U/L, respectively; P = 0.077). HDL particles isolated from AGI-1067 treated subjects showed significant antioxidant potency vs HDL particles from placebo subjects (thiobarbituric acid reactive substances in a LDL oxidation assay decreased −25.88% vs +7.88, respectively; P = 0.011). Conclusion: The ALPS study demonstrated that AGI-1067 had minor effects on LDL and HDL cholesterol. More dramatic effects were observed for HDL-associated paraoxonase and thiobarbituric acid reactive substances activity, suggesting that the antiatherosclerotic properties of AGI-1067 may involve an HDL antioxidant mechanism consistent with inhibition of the oxidative-inflammatory cascade, rather than involving a lipid regulating pathway. [Copyright &y& Elsevier]

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]

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]

Advancing age is an independent risk factor for the development of coronary heart disease. However, the significance of hypercholesterolemia as a cardiovascular risk factor in the elderly, has been widely debated. While no large-scale, randomized clinical trial has been conducted to evaluate cholesterol lowering solely in the elderly, evidence from older subgroups in several intervention trials supports the efficacy of lowering elevated low-density lipoprotein cholesterol for reducing cardiovascular risk in the elderly. Furthermore, although the relative risk of hypercholesterolemia for coronary heart disease incidence may be attenuated with advancing age, the population-wide impact of treating elevated cholesterol levels in the elderly would be large, due to the high frequency of coronary heart disease in the elderly. This article reviews key issues in the management of hypercholesterolemia with respect to coronary heart disease risk reduction in the elderly. [ABSTRACT FROM AUTHOR]

Background: Plant sterol esters reduce cholesterol absorption and lower circulating blood cholesterol concentrations when incorporated into the habitual diet. Objective: This randomized, double-blind, 3-group parallel, controlled study evaluated the influence of esterified plant sterols on serum lipid concentrations in adults with mild-to-moderate primary hypercholesterolemia. Design: Subjects incorporated a conventional 50%-fat spread into a National Cholesterol Education Program Step I diet for a 4-wk lead-in period, followed by a 5-wk intervention period of the diet plus either a control reduced-fat spread (40% fat; n = 92) or a reduced-fat spread enriched with plant sterol esters to achieve intakes of 1.1 g/d (n = 92; low-sterol group) or 2.2 g/d (n = 40; high-sterol group). Results: Subjects in the low- and high-sterol groups who consumed > 80% of the scheduled servings (per-protocol analyses) had total cholesterol values that were 5.2% and 6.6% lower, LDL-cholesterol values that were 7.6% and 8.1% lower, apolipoprotein B values that were 6.2% and 8.4% lower, and ratios of total to HDL cholesterol that were 5.9% and 8.1% lower, respectively, than values for the control group (P < 0.001 for all). Additionally, triacylglycerol concentrations decreased by 10.4% in the high-sterol group. Serum concentrations of fat-soluble vitamins and carotenoids were generally within reference ranges at baseline and postintervention. Serum plant sterol concentrations increased from baseline (0.48% of total sterol by wt) to 0.64% and 0.71% by wt for the low- and high-sterol groups, respectively (P < 0.05 compared with control). Conclusion: A reduced-fat spread containing plant sterol esters incorporated into a low-fat diet is a beneficial adjunct in the dietary management of hypercholesterolemia. [ABSTRACT FROM AUTHOR]

Inulin is a carbohydrate belonging to a class of compounds known as fructans. Because inulin is resistant to digestion in the upper gastrointestional tract it reaches the large intestine essentially intact, where it is fermented by indigenous bacteria. Thus, it may be classified as a soluble dietary fiber. Soluble fibers have been shown to modulate serum lipids. A recent study examined the effect of consuming three servings per day of inulin-containing foods, compared with the effect of similar foods without inulin, on serum lipid profiles among hypercholesterolemic men and women. In addition, the practicality of including 18 g/d of inulin in a low fat diet was investigated. The recent study randomized, double-blind, crossover trial with two 6-wk treatment periods, separated by a 6-wk washout. Men and women (n = 21) with baseline LDL increased significantly (7.4 and 12.3%, respectively) during the control phase. There were small, nonsignificant declines in total (1.3%) and LDL-C (2.1%) during the inulin phase. Thus, differences in response between periods (inulin - control) were significant (P < 0.05) for LDL-C (-14.4%) and total cholesterol (-8.7%). Mild gastrointestinal discomfort was more common during the inulin than the control food phase; however, the gastrointestinal side-effect profile of inulin was similar to that of other soluble fibers. Although it was not possible to draw firm conclusions, inulin may have blunted the hypercholesterolemic effects observed during consumption of control foods. Additional research will be required to confirm the possible lipid-modulating properties of dietary inulin in humans. [ABSTRACT FROM AUTHOR]

An abstract of the conference paper "Lipid sub-fractionation predicts worsening myocardial perfusion reserve in patients with low-density lipoprotein less than 100mg/dL: a regadenoson dardiac magnetic resonance study," by Amit R. Patel, and colleagues is presented.

Abstract: The digestive tract plays a key role in lipid metabolism and in cardiovascular risk through the physiology of bile acids on lipid absorption, enterohepatic recycling of bile acids, and cholesterol oxidation in synthesis of bile acids. Recent evidence associates the activation of farnesoid X receptor by bile acids with alterations in high-density lipoprotein cholesterol, triglyceride metabolism, and glucose metabolism. Bile-acid sequestrants augment cholesterol excretion via enhanced conversion to bile acids to lower low-density lipoprotein cholesterol. Several recent studies have demonstrated a role for the bile-acid sequestrant colesevelam hydrochloride in improving glycemic control as well as lipid profiles in subjects with type 2 diabetes. This work reviews the mechanisms of action of colesevelam hydrochloride in interrupting bile acid reabsorption and in lipid transport and glucose control. [Copyright &y& Elsevier]

Patients with type 2 diabetes (T2D) manifest a form of dyslipidemia typified by high LDL particle concentration (PC), small LDL particle size (PS), and high triglyceride and low HDL-C levels. This diabetic dyslipidemia may contribute to the excess cardiovascular events seen in T2D. In CHICAGO, a randomized, double-blind, multicenter, 72-week study, pioglitazone (PIO) was associated with less CIMT progression compared to glimepiride (GLM) in patients with T2D (N=462). We also observed significant improvements in TG and HDL-C levels with PIO vs GLM, with no difference in LDL-C levels. Here we report the results of the lipoprotein subfraction analysis. Blood samples were obtained at baseline and weeks 24, 48, and 72 (or time of withdrawal) for determination of PC and PS of VLDL, LDL, and HDL, measured by NMR spectroscopy. At Final Visit, PIO therapy produced a significant reduction in VLDL PS due to significant decreases in large and medium VLDL PC and increases in small VLDL PC. LDL PS significantly increased due to a significant reduction in small LDL and increase in large LDL PC. HDL PS also significantly increased due to a reduction in small and an increase in large HDL PC. In aggregate, the changes in lipoprotein subfraction distribution would be predicted to produce a reduction in CVD risk with PIO vs GLM and may contribute to beneficial effects of PIO on CIMT. [ABSTRACT FROM AUTHOR]

The article presents an answer to a clinical question related to the comparison of the effectiveness of intensive atorvastatin therapy in patients with coronary heart disease (CHD), with moderate atorvastatin therapy for reducing major cardiovascular events. This study included 10,001 patients 35 to 75 years of age who had clinically evident CHD and low-density lipoprotein. Exclusion criteria included hypersensitivity to statins, active liver disease, pregnancy, and uncontrolled diabetes mellitus.

The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) has acknowledged mounting evidence of an independent association between hypertriglyceridemia and coronary artery disease risk by issuing guidelines that identify non–high-density lipoprotein (HDL) cholesterol as a secondary target for therapy in patients with elevated triglyceride levels. In 2003, a national survey of outpatient lipid management was conducted for patients undergoing treatment by physicians who were high prescribers of lipid-altering drugs. Results of the NCEP Evaluation Project Utilizing Novel E-Technology II (NEPTUNE II) survey indicated much higher frequencies of low-density lipoprotein (LDL) cholesterol goal achievement compared with frequencies observed in a similarly designed survey in 1997. However, non–HDL cholesterol treatment success in the NEPTUNE II survey was markedly lower than that for LDL cholesterol overall and across risk categories. More aggressive therapy is therefore needed to achieve non–HDL cholesterol goals than LDL cholesterol goals. After achievement of LDL cholesterol goals, non–HDL cholesterol can be managed more aggressively by lowering LDL cholesterol or by using strategies that target a reduction in very-low-density lipoprotein cholesterol. Because the prevalence of hypertriglyceridemia in the United States is high and increasing, enhanced efforts to improve non–HDL cholesterol goal achievement have the potential to produce a substantial effect on public health. [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]

Elevated lipoprotein(a) [Lp(a)] levels are considered a causal factor for cardiovascular disease. In phase 3 ODYSSEY trials, alirocumab reduced levels of low-density lipoprotein cholesterol (LDL-C) and Lp(a), with concomitant reductions in the risk of major adverse cardiovascular events (MACE). We assessed whether lower on-study and greater percentage reductions in Lp(a) are associated with a lower risk of MACE. Post-hoc analysis of data pooled from 10 phase 3 ODYSSEY trials comparing alirocumab with control (placebo or ezetimibe) in patients (n = 4983) with cardiovascular disease and/or risk factors, and hypercholesterolemia despite statin/other lipid-lowering therapies. Median (Q1, Q3) baseline Lp(a) levels were 23.5 (8.0, 67.0) mg/dL. Median Lp(a) changes from baseline with alirocumab were −25.6% vs. −2.5% with placebo (absolute reductions 6.8 vs. 0.5 mg/dL) in placebo-controlled trials, and −21.4% vs. 0.0% with ezetimibe (4.5 vs. 0.0 mg/dL) in ezetimibe-controlled trials. During follow-up (6699 patient-years), 104 patients experienced MACE. A 12% relative risk reduction in MACE per 25% reduction in Lp(a) (p= 0.0254) was no longer significant after adjustment for LDL-C changes: hazard ratio per 25% reduction: 0.89 (95% confidence interval, 0.79–1.01; p= 0.0780). In subgroup analysis, the association between Lp(a) reduction and MACE remained significant in a fully adjusted model among participants with baseline Lp(a) ≥50 mg/dL (p -interaction vs. Lp(a) < 50 mg/dL: 0.0549). In this population, Lp(a) reductions were not significantly associated with MACE independently of LDL-C reductions. Reducing the risk of MACE by targeting Lp(a) may require greater reductions in Lp(a) with more potent therapies and/or higher initial Lp(a) levels. Image 1 • Analysis of 10 phase 3 ODYSSEY trials, alirocumab (ALI) vs. placebo or ezetimibe. • Median lipoprotein(a) [Lp(a)] reductions: ALI (21.4–25.6%) vs. control (0.0–2.5%). • Adjusted by baseline characteristics, 12% RRR in MACE per 25% reduction in Lp(a); p = 0.0254. • Adjusted by LDL-C reductions, RRR was not significant; hazard ratio = 0.89, p = 0.0780. • Fully adjusted RRR significant if baseline Lp(a) ≥ vs. < 50 mg/dL; p -interaction 0.0549. [ABSTRACT FROM AUTHOR]