Lipid-modifying Effects Research Articles

Niacin receptor activation improves human microvascular endothelial cell angiogenic function during lipotoxicity

Objective: Niacin (nicotinic acid) as a monotherapy can reduce vascular disease risk, but its mechanism of action remains controversial, and may not be dependent on systemic lipid modifying effects. Niacin has recently been shown to improve endothelial function and vascular regeneration, independent of correcting dyslipidemia, in rodent models of vascular injury and metabolic disease. As a potential biosynthetic precursor for NAD+, niacin could elicit these vascular benefits through NAD+-dependent, sirtuin (SIRT) mediated responses. Alternatively, niacin may act through its receptor, GPR109A, to promote endothelial function, though endothelial cells are not known to express this receptor. We hypothesized that niacin directly improves endothelial cell function during exposure to lipotoxic conditions and sought to determine the potential mechanism(s) involved. Methods and results: Angiogenic function in excess palmitate was assessed by tube formation following treatment of human microvascular endothelial cells (HMVEC) with either a relatively low concentration of niacin (10 μM), or nicotinamide mononucleotide (NMN) (1 μM), a direct NAD+ precursor. Although both niacin and NMN improved HMVEC tube formation during palmitate overload, only NMN increased cellular NAD+ and SIRT1 activity. We further observed that HMVEC express GRP109A. Activation of this receptor with either acifran or MK-1903 recapitulated niacin-induced improvements in HMVEC tube formation, while GPR109A siRNA diminished the effect of niacin. Conclusion: Niacin, at a low concentration, improves HMVEC angiogenic function under lipotoxic conditions, likely independent of NAD+ biosynthesis and SIRT1 activation, but rather through niacin receptor activation.

A simple and effective approach for the treatment of dyslipidemia using anionic nanoliposomes

The present study was undertaken to evaluate the anti-dyslipidemic effects of nanoliposomes with different phospholipid compositions. Three sets of liposomal formulations (20Mm; 100nM in size) were prepared with low (SPC), medium (POPC) and high (HSPC) phase transition temperature values with and without cholesterol and anionic phosphatidyl glycerol (HSPC/DSPG; POPC/DMPG; SPC/EPG). The liposomal preparations were characterized for their size and zeta potential (dynamic light scattering), J774A.1 macrophages uptake (flow cytometry) and lipid-modifying effects (tyloxapol-induced hyperlipidemic mouse model). Anionic formulations displayed the highest rate of uptake by macrophages. Among them, HSPC/DSPG and SPC/EPG liposomes had the best lipid-modifying activity. These two formulations exerted favorable impact on all lipid profile parameters by reducing LDL-C (by up to 76% [HSPC/DSPG] and 86% [SPC/EPG]), total cholesterol (by up to 52% [HSPC/DSPG] and 68% [SPC/EPG]), triglycerides (by up to 88% [HSPC/DSPG] and 73% [SPC/EPG]), apoB (by up to 44% [HSPC/DSPG] and 35% [SPC/EPG]) and elevating HDL-C (by up to 85% [HSPC/DSPG] and 75% [SPC/EPG]) concentrations. Atherogenic indices were also effectively reduced following HSPC/DSPG (by up to 69%) and SPC/EPG (by up to 79%) injections. Empty, cholesterol-free nanoliposomal formulations containing 75% anionic phospholipid (PG) might serve as effective and rapid acting anti-dyslipidemic agents. Further research is warranted to confirm the observed anti-dyslipidemic effects of anionic nanoliposomes in diet-induced hyperlipidemic models, and also to evaluate the potential protective effects in regressing atheromatous lesions.

Lipid-modifying effects of adjunctive therapy with curcuminoids–piperine combination in patients with metabolic syndrome: Results of a randomized controlled trial

Dyslipidemia is an established feature of metabolic syndrome (MS) that is associated with an increased risk of atherosclerotic cardiovascular disease. Curcuminoids are natural products with anti-atherosclerotic and lipid-modifying effects but their efficacy in patients with MS has not yet been tested. To investigate the effects of bioavailability-enhanced curcuminoids, as adjunctive to standard of care, on serum lipid concentrations in patients with MS. Patients diagnosed with MS according to the NCEP-ATPIII criteria who were receiving standard of care were assigned to either curcuminoids (C3 complex(®); 1000 mg/day; n=50) or placebo (n=50; matched with drug capsules in shape and color) for 8 weeks. In order to improve the oral bioavailability, curcuminoids were co-administered with piperine (bioperine(®)) in a ratio of 100:1. Serum concentrations of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, small dense LDL (sdLDL), lipoprotein(a) [Lp(a)], and non-HDL-C were determined at baseline and at the end of 8-week treatment period. Curcuminoids were more effective than placebo in reducing serum LDL-C, non-HDL-C, total cholesterol, triglycerides and Lp(a), and elevating HDL-C concentrations. However, changes in serum sdLDL levels were found to be comparable between the study groups. The effects of curcuminoids on triglycerides, non-HDL-C, total cholesterol and Lp(a) remained significant after adjustment for baseline values of lipids and body mass index. Curcuminoids-piperine combination is an efficacious adjunctive therapy in patients with MS and can modify serum lipid concentrations beyond what is achieved with standard of care.

Abstract 228: Niacin Improves Human Microvascular Endothelial Cell Angiogenic Function Under Lipotoxic and Hypoxic Conditions

Niacin (nicotinic acid) can reduce vascular disease risk, but its mechanism of action is controversial, and may not be dependent on systemic lipid modifying effects. It has recently been shown to improve endothelial function and vascular regeneration, independent of correcting dyslipidemia, in rodent models of vascular injury and ischemia, and metabolic disease. As a potential biosynthetic precursor for NAD + , niacin could elicit vascular benefits through NAD + -dependent, sirtuin (SIRT) mediated responses. Or, it may act through its receptor, GPR109A, to promote endothelial function, though endothelial cells are not known to express this protein. We tested the hypothesis that niacin directly improves endothelial cell function under lipotoxic and low oxygen conditions, and investigated the potential mechanism(s) involved. We measured human microvascular endothelial cell (HMVEC) angiogenic function, by tube formation on Matrigel (18 h), during fatty acid overload (0.5 mM palmitate, oleate, or palmitate plus oleate) under either normoxic (20% O 2 ) or low oxygen (2% O 2 ) conditions. Both supplementation with excess palmitate and incubation at 2% O 2 inhibited tube formation compared to control conditions (-38% and -44%, respectively, n=5, p<0.05). Although niacin (10 μM) improved tube formation in the presence of excess palmitate, during both normoxia (35%, n=5, p<0.05) and hypoxia (34%, n=5, p<0.05), it did not increase [NAD + ]/[NADH] ratios or SIRT1 activity. Gene expression microarray analyses further showed that niacin did not induce expression of known SIRT1 regulated genes. However, we made the novel observation that HMVEC express GRP109A. Selective activation of the receptor with acifran recapitulated niacin induced improvements in tube formation during palmitate overload in 20% O 2 (53%, n=3, p<0.05), while GPR109A siRNA diminished the effect (16%, n=3, p<0.05). We concluded that niacin improves HMVEC angiogenic function under lipotoxic and hypoxic conditions. During normoxia, this effect appears to be independent of NAD+ synthesis and SIRT1 activation, but likely occurs through activation of GPR109A. These findings may have implications for the use of niacin in ischemic vascular disease associated with metabolic disease.

Lipids, safety parameters, and drug concentrations after an additional 2 years of treatment with anacetrapib in the DEFINE study.

Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor that has previously been shown to reduce low-density lipoprotein cholesterol (LDL-C) and raise high-density lipoprotein cholesterol (HDL-C) in patients with or at high risk of coronary heart disease in the 76-week, placebo-controlled, Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib (DEFINE) trial. Here, we report the results of the 2-year extension to the DEFINE study where patients (n = 803) continued on the same assigned treatment as in the original 76-week study. Treatment with anacetrapib during the 2-year extension was well tolerated with a safety profile similar to patients on placebo. No clinically important abnormalities in liver enzymes, blood pressure, electrolytes, or adverse experiences were observed during the extension. At the end of the extension study, relative to the original baseline value, anacetrapib reduced Friedewald-calculated LDL-C by 39.9% and increased HDL-C by 153.3%, compared to placebo. The apparent steady state mean plasma trough concentration of anacetrapib was ∼640 nmol/L. Geometric mean plasma concentrations of anacetrapib did not appear to increase beyond week 40 of the 2-year extension of the 76-week DEFINE base study. In conclusion, an additional 2 years of treatment with anacetrapib were well tolerated with durable lipid-modifying effects on LDL-C and HDL-C.

Cholesteryl Ester Transfer Protein Inhibitors in the Treatment of Dyslipidemia: A Systematic Review and Meta-Analysis

Cholesteryl ester transfer protein (CETP) inhibitors are gaining substantial research interest for raising high density lipoprotein cholesterol levels. The aim of the research was to estimate the efficacy and safety of cholesteryl ester transfer protein inhibitors as novel lipid modifying drugs. Systematic searches of English literature for randomized controlled trials (RCT) were collected from MEDLINE, EBASE, CENTRAL and references listed in eligible studies. Two independent authors assessed the search results and only included the double-blind RCTs by using cholesteryl ester transfer protein inhibitors as exclusively or co-administrated with statin therapy irrespective of gender in enrolled adult subjects. Two independent authors extracted the data by using predefined data fields. Of 503 studies identified, 14 studies met the inclusion criteria, and 12 studies were included into the final meta-analysis. Our meta-analysis revealed that CETP inhibitors increased the HDL-c levels (n = 2826, p<0.00001, mean difference (MD) = 20.47, 95% CI [19.80 to 21.15]) and total cholesterol (n = 3423, p = 0.0002, MD = 3.57, 95%CI [1.69 to 5.44] to some extent combined with a reduction in triglyceride (n = 3739, p<0.00001, MD = −10.47, 95% CI [−11.91 to −9.03]) and LDL-c (n = 3159, p<0.00001, MD = −17.12, 95% CI [−18.87 to −15.36]) irrespective of mono-therapy or co-administration with statins. Subgroup analysis suggested that the lipid modifying effects varied according to the four currently available CETP inhibitors. CETP inhibitor therapy did not increase the adverse events when compared with control. However, we observed a slight increase in blood pressure (SBP, n = 2384, p<0.00001, MD = 2.73, 95% CI [2.14 to 3.31], DBP, n = 2384, p<0.00001, MD = 1.16, 95% CI [0.73 to 1.60]) after CETP inhibitor treatment, which were mainly ascribed to the torcetrapib treatment subgroup. CETP inhibitors therapy is associated with significant increase in HDL-c and decrease in triglyceride and LDL-c with satisfactory safety and tolerability in patients with dyslipidemia. However, the side-effect on blood pressure deserves more consideration in future studies.

The high-fat high-fructose hamster as an animal model for niacin’s biological activities in humans

ObjectiveNiacin has been used for more than 50years to treat dyslipidemia, yet the mechanisms underlying its lipid-modifying effects remain unknown, a situation stemming at least in part from a lack of validated animal models. The objective of this study was to determine if the dyslipidemic hamster could serve as such a model. Materials/MethodsDyslipidemia was induced in Golden Syrian hamsters by feeding them a high-fat, high-cholesterol, and high-fructose (HF/HF) diet. The effect of high-dose niacin treatment for 18days and 28days on plasma lipid levels and gene expression was measured. ResultsNiacin treatment produced significant decreases in plasma total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and free fatty acids (FFA), but had no measureable effect on high-density lipoprotein cholesterol (HDL-C) in the dyslipidemic hamster. Niacin treatment also produced significant increases in hepatic adenosine ATP-Binding Cassette A1 (ABCA1) mRNA, ABCA1 protein, apolipoprotein A-I (Apo A-I) mRNA, and adipose adiponectin mRNA in these animals. ConclusionsWith the exception of HDL-C, the lipid effects of niacin treatment in the dyslipidemic hamster closely parallel those observed in humans. Moreover, the effects of niacin treatment on gene expression of hepatic proteins related to HDL metabolism are similar to those observed in human cells in culture. The HF/HF-fed hamster could therefore serve as an animal model for niacin’s lowering of proatherogenic lipids and mechanisms of action relative to lipid metabolism.

The dual PPAR-alpha/gamma agonist aleglitazar increases number and function of endothelial progenitor cells: implications for vascular function and atherogenesis

Background: Endothelial progenitor cells (EPC) improve endothelial function and promote vascular repair. Aleglitazar combines lipid-modifying effects of PPAR-α agonists (fibrates) and insulin-sensitizing effects of PPAR-γ agonists (thiazolidinediones). We studied the effects of the novel dual peroxisome proliferator-activated receptor (PPAR)-α/γ agonist aleglitazar on glucose tolerance, EPC, endothelial function, neoangiogenesis and atherosclerosis in mice. Methods and results: C57Bl/6 wild-type (WT, normal chow), ApoE-/- mice (Western-type diet) and eNOS-/- mice were treated with aleglitazar (10 mg/kg/d, i.p.) or vehicle. Aleglitazar enhanced the expression of both the PPAR-α and PPAR-γ target genes and normalized glucose tolerance in cholesterol-fed ApoE-/- mice. In WT mice, aleglitazar treatment upregulated sca-1/VEGFR-2-positive EPC in the blood (153±10%) and bone marrow (197±22%), and upregulated spleen-derived diLDL/lectin-positive EPC (182±8%). Furthermore, aleglitazar augmented EPC migration (186±6% vs. controls) and enhanced neoangiogenesis (vascularized disk area 178±18% vs. controls). The effects of the dual PPAR-α/γ agonist on EPC number and function were abolished in eNOS knock-out mice. In ApoE-/- mice, aleglitazar upregulated EPC number and function, potently improved endothelium-dependent vasodilation and markedly reduced the formation of atherosclerotic plaques (plaque area/total lumen area 2.3±0.8% vs. 10.1±1.9% after 6 weeks and 22±2.2% vs. 36±2.1% after 8 weeks treatment). OilRed staining of hepatic sections showed a profound reduction of liver steatosis in ApoE-/- mice. In cultured human EPC, aleglitazar increased migration and colony forming units in a concentration-dependent manner. Furthermore, oxidative stress-induced EPC apoptosis and protein expression of p53 were reduced, while telomerase activity and expression of phospho-eNOS (S1177) and phospho-Akt were elevated. Comparative and inhibitor experiments revealed that aleglitazar's effects on EPC migration and colony forming units (CFU) were mediated by both PPAR-α and -γ signaling. E.g., aleglitazar treatment (10nM/l) induced EPC migration (304±21% vs. controls) and CFU (300±67% vs. controls) comparably to a co-stimulation of EPC with pioglitazone 10μM/l+fenofibric acid (150μM/l) (Migration: 332±28%; CFU: 289±72%). Conclusions: The dual PPAR-α/γ agonist aleglitazar augments number, function and survival of endothelial progenitor cells in an Akt- and eNOS-dependent fashion. The effects on EPC correlate with improved neoangiogenesis, restored endothelial function and prevention of atherosclerosis.

Lipid-modifying effects of nicotinic acid with laropiprant in Hong Kong Chinese patients with dyslipidaemia

Lipid-modifying effects of nicotinic acid with laropiprant in Hong Kong Chinese patients with dyslipidaemia

Anacetrapib: potential for the prevention and treatment of coronary heart disease

Anacetrapib: potential for the prevention and treatment of coronary heart disease Dylan L Steen,1 Amit V Khera,2 Christopher P Cannon1 1TIMI Study Group, Cardiovascular Division, 2Department of Medicine, Brigham and Women&rsquo;s Hospital, Boston, MA, USA Abstract: Despite major advances in cardiovascular care in recent decades, atherosclerotic cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Statins have been shown to reduce cardiovascular events by 25%&ndash;40% in a dose-dependent fashion; yet additional therapies are needed to reduce vascular disease progression and acute thrombotic events. In addition to low-density lipoprotein cholesterol (LDL-C) reduction, other lipid risk factors, such as low high-density lipoprotein cholesterol (HDL-C), have created interest as therapeutic targets to lower cardiovascular risk. However, the absence of compelling data for incremental benefit of non-LDL-centric therapies in the statin era has limited their clinical use. A novel class of compounds, cholesteryl ester transfer protein (CETP) inhibitors, has demonstrated many potentially beneficial lipid-modifying effects. While in vitro and animal data for CETP inhibition have been encouraging, the initial enthusiasm for the class has been tempered by the failure of two CETP inhibitors (torcetrapib and dalcetrapib) in Phase III trials to reduce cardiovascular outcomes. Anacetrapib, a compound that causes near-complete CETP inhibition, has among its effects, robust reductions in LDL-C and lipoprotein(a) as well as dramatic increases in HDL-C. The ability of anacetrapib to reduce coronary disease events is being tested in the Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (REVEAL) trial (NCT01252953). Keywords: anacetrapib, cholesteryl ester transfer protein, cholesteryl ester transfer protein inhibitor, atherosclerosis

Efficacy of a combination of cholesterol absorption and synthesis inhibitors in the correction of hyperlipidemia and dietary fat intolerance in patients with coronary heart disease (ESTHETICS trial)

Objective: to study the lipid-modifying effects of the selective intestinal cholesterol absorption inhibitor ezetimibe as monotherapy and in combination with simvastatin, an inhibitor of hydroxy methyl glutaryl coenzyme A (HMG-CoA) reductase, a key enzyme in cholesterol synthesis, which is given on an empty stomach and after single dietary fat intake (FI) that modulates postprandial hyperlipidemia (HL) in coronary heart disease (CHD) patients with baseline HL. Subjects and method. The trial covered 30 patients aged 43–75 years with CHD and baseline HL of Types IIa and IIb (Fredrickson classification) who were, after 4-week therapy, randomized to 2 groups: 1) 15 patients took ezetimibe 10 mg/day and 2) 15 received simvastatin 20 mg/day (the total duration of monotherapy was 12 weeks), then its half dose (from 20 to 10 mg/day) added by ezetimibe 10 mg/day (the duration of the combination therapy was 12 weeks). All the patients underwent standard FI test before and after a 12-week monotherapy period and 24 weeks (i.e. after 12-weel combination therapy). A standard FI test was carried out by the modified procedure described by J. Patsch (1983); the cutoffs for blood sampling for analysis were on an empty stomach (before FI) and 3 and 6 hours after FI. Results. The patients with CHD treated with ezetimibe 10 mg showed a significant reduction in the fasting levels of total cholesterol (TC) by 20% (p

Pitavastatin

Pitavastatin (Livazo®, Livalo®), an inhibitor of HMG-CoA reductase (statin), is indicated for the reduction of elevated total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels, in adult patients with primary hypercholesterolaemia and mixed dyslipidaemia, when response to diet and other non-pharmacological measures is inadequate. Pitavastatin has a favourable pharmacological profile following oral administration, including its long half-life (up to 12 hours), selective uptake into hepatocytes and minimal metabolism by cytochrome P450 (CYP) enzymes. This latter property decreases the likelihood of drug-drug interactions with agents that are metabolized by, inhibit or induce CYP enzymes. Pitavastatin improved the lipid profile (including LDL-C, TC and high-density lipoprotein cholesterol levels) in patients with hypercholesterolaemia and mixed dyslipidaemia, according to large, pivotal phase III studies of up to 60 weeks' duration. In these trials, pitavastatin for 12 weeks was noninferior to simvastatin and atorvastatin in terms of the improvement from baseline in LDL-C levels. In similarly designed trials, pitavastatin improved lipid profiles and was noninferior to simvastatin in patients with high cardiovascular risk and demonstrated significantly greater LDL-C reduction than pravastatin in elderly patients. Furthermore, in patients with type 2 diabetes mellitus, although noninferiority criteria for the comparison with atorvastatin were not met in terms of the improvement from baseline in LDL-C levels, pitavastatin was associated with some improvements in the lipid profile. Pitavastatin also demonstrated substantial lipid-modifying effects in exclusively Asian populations in well designed clinical trials. Pitavastatin was generally well tolerated in clinical trials of up to 60 weeks' duration, with a tolerability profile generally similar to that of atorvastatin and simvastatin. Therefore, pitavastatin appears to be an attractive alternative for the treatment of patients with primary hyperlipidaemia or mixed dyslipidaemia who have not responded adequately to diet and other non-pharmacological measures, and may present a useful treatment option in patients requiring polypharmacy, such as those at high risk of cardiovascular disease. Further studies evaluating the effects of pitavastatin on clinical endpoints, such as cardiovascular morbidity and mortality, are required to confirm the longer-term benefits of pitavastatin.

Lipid-altering efficacy and safety profile of co-administered extended release niacin/laropiprant and simvastatin versus atorvastatin in patients with mixed hyperlipidemia

BackgroundExtended-release niacin/laropiprant (ERN/LRPT) reduces flushing and preserves the lipid-modifying effects of ERN. This study compared the efficacy and safety of ERN/LRPT plus simvastatin (ERN/LRPT+SIMVA) with atorvastatin (ATORVA) in patients with mixed hyperlipidemia. MethodsAfter a 4-week placebo run-in, 2340 patients (LDL-C ≥130 and ≤190mg/dL, TG≥150 and ≤500mg/dL and above NCEP ATP III risk-based LDL-C goal) were randomized to 1 of 6 treatment arms: ERN/LRPT 1g/20mg+SIMVA (10 or 20mg), or ATORVA (10, 20, 40, or 80mg) once daily. ResultsAt Week 12, ERN/LRPT+SIMVA was superior to ATORVA in decreasing LDL-C/HDL-C (primary endpoint) at each pre-specified dose comparison: ERN/LRPT+SIMVA 20mg vs. ATORVA 10mg (−13.2%; p<0.001); ERN/LRPT+SIMVA 40mg vs. ATORVA 20mg (−10.8%; p<0.001); ATORVA 40mg (−5.1%; p<0.001); and ATORVA 80mg (−4.2%; p=0.007). At Week 12, ERN/LRPT+SIMVA was superior to ATORVA in increasing HDL-C and reducing TG for all pre-specified treatment comparisons, and reducing non-HDL-C and LDL-C for the ERN/LRPT+SIMVA 20mg versus ATORVA 10mg and ERN/LRPT+SIMVA 40mg versus ATORVA 20-mg dose comparisons, but not the ERN/LRPT+SIMVA 40mg versus ATORVA 40- and 80-mg dose comparisons. Adverse experiences (AEs) typically associated with niacin (flushing, pruritus, increased glucose, increased uric acid) were more common with ERN/LRPT+SIMVA, and hepatic-related laboratory AEs were more common with ATORVA. ConclusionERN/LRPT+SIMVA was generally superior to ATORVA in improving lipid parameters after 12weeks and was generally well tolerated in patients with mixed hyperlipidemia.

Abstract 9649: Lipid-modifying Effects of Anacetrapib in Patients with Lower versus Higher Baseline Levels Of HDL-C, LDL-C, And TG: Pre-Specified Subgroup Analyses of the DEFINE (Determining the Efficacy and Tolerability of CETP INhibition with AnacEtrapib) Trial

Purpose : Low HDL-C is a risk factor for coronary heart disease which partly accounts for residual risk despite statin therapy. After 24 weeks of treatment, the addition of anacetrapib (ANA), a cholesteryl ester transfer protein (CETP) inhibitor to statin therapy increased HDL-C by 138% and reduced LDL-C by 40% in a 1623 patient safety and lipid efficacy Phase III trial (DEFINE). Sub-group analyses were performed to determine the degree to which ANA raises HDL-C and lowers LDL-C in patients with low baseline HDL-C and in patients with diabetes and other subgroups. Methods: Percent placebo-corrected HDL-C increases and LDL-C decreases from baseline after 24 weeks of ANA, 100 mg/day, were compared among patients according to baseline HDL-C, LDL-C, and TG levels above or below the median and in patients with diabetes. Results: Median baseline HDL-C, LDL-C, and TG were 40 mg/dL, 81 mg/dL, and 128 mg/dL, respectively. ANA produced robust increases in HDL-C in patients with baseline HDL-C below (152%) and above (127%) the median. In the lowest baseline quartile of HDL-C (15 to 34 mg/dL) levels also increased to a mean on-treatment HDL-C of 85 mg/dL. The percent increase in HDL-C was similar in patients with lower vs. higher baseline TG levels. ANA increased HDL-C similarly in diabetics compared to non-diabetics (130% vs 150%) with a mean on-treatment HDL-C of 100 vs. 102 respectively. The percent reduction in LDL-C with ANA was generally similar in patients with lower vs higher baseline LDL-C, HDL-C or TG levels and in patients with or without diabetes. Conclusion: ANA robustly increased HDL-C in all patients especially those with low HDL-C. Reductions in LDL-C with ANA were independent of baseline LDL-C, HDL-C, or TG levels. The clinical impact of these lipid-modifying effects of ANA in these sub-groups will be assessed in REVEAL-HPS3/TIMI55, a 30,000 patient clinical outcomes trial.

Abstract P264: The Health and Economic Impact of Switching From Atorvastatin to Generic Simvastatin in the Netherlands

OBJECTIVES Since January 2009, Dutch clinicians have been required to rationalize the prescription of branded statins using an authorization form. This has led to significant switching of patients from atorvastatin to generic simvastatin. However, data from Q1 2009 indicated that 34% of this switching occurred at less than equipotent doses. We sought to assess the potential impact of this. METHODS A Markov micro-simulation model was populated with 1046 Dutch patients drawn from the PHARMO Institute database who were being prescribed atorvastatin in December 2008. Risks of cardiovascular disease (CVD) were estimated from a calibrated Framingham risk equation. Follow-up occurred for 20 years or until age 100. Decision analysis estimated the marginal effects of switching all patients to generic simvastatin. Dose-specific, lipid-modifying effects of the two statins and CVD costs were sourced from published data. Annual discount rates of 4% and 1.5% were applied to costs and health effects, respectively. RESULTS Of the 1046 subjects on atorvastatin, 207 (19.8%) were predicted to develop CVD over 20 years. In the switched-to-simvastatin group, the predicted number was 229 (21.9%), equating to a ‘number needed to harm’ of 48. Although switching led to a net cost saving of 549 Euro per subject, each also lost 0.015 life-years and 0.029 QALYs. These equated to ICERs of 36,653 Euro and 18,716 Euro per life-year and QALY gained, respectively (atorvastatin vs simvastatin). Sensitivity analyses, which included a 20% decrease in the percentage of switches to less potent simvastatin doses, indicated the results to be robust. CONCLUSIONS In the Netherlands, many patients are being switched from atorvastatin to generic simvastatin at inferior doses, which may be increasing CVD risk. Maintaining patients on atorvastatin is sound from a health economic perspective. [ Disclaimer: the views expressed in this abstract are only those of the authors, and not necessarily those of the PHARMO Institute.]

Fenofibrate

Fenofibrate is a fibric acid derivative indicated for the treatment of severe hypertriglyceridaemia and mixed dyslipidaemia in patients who have not responded to nonpharmacological therapies. The lipid-modifying effects of fenofibrate are mediated by the activation of peroxisome proliferator-activated receptor-α. Fenofibrate also has nonlipid, pleiotropic effects (e.g. reducing levels of fibrinogen, C-reactive protein and various pro-inflammatory markers, and improving flow-mediated dilatation) that may contribute to its clinical efficacy, particularly in terms of improving microvascular outcomes. Fenofibrate improves the lipid profile (particularly triglyceride [TG] and high-density lipoprotein-cholesterol [HDL-C] levels) in patients with dyslipidaemia. Compared with statin monotherapy, fenofibrate monotherapy tends to improve TG and HDL-C levels to a significantly greater extent, whereas statins improve low-density lipoprotein-cholesterol (LDL-C) and total cholesterol levels to a significantly greater extent. Fenofibrate is also associated with promoting a shift from small, dense, atherogenic LDL particles to larger, less dense LDL particles. Combination therapy with a statin plus fenofibrate generally improves the lipid profile to a greater extent than monotherapy with either agent in patients with dyslipidaemia and/or type 2 diabetes mellitus or the metabolic syndrome. In the pivotal FIELD and ACCORD trials in patients with type 2 diabetes, fenofibrate did not significantly reduce the risk of coronary heart disease events to a greater extent than placebo, and simvastatin plus fenofibrate did not significantly reduce the risk of major cardiovascular (CV) events to a greater extent than simvastatin plus placebo. However, the risk of some nonfatal macrovascular events and the incidence of certain microvascular outcomes were reduced significantly more with fenofibrate than with placebo in the FIELD trial, and in the ACCORD trial, patients receiving simvastatin plus fenofibrate were less likely to experience progression of diabetic retinopathy than those receiving simvastatin plus placebo. Subgroup analyses in the FIELD and ACCORD Lipid trials indicate that fenofibrate is of the greatest benefit in decreasing CV events in patients with atherogenic dyslipidaemia. Fenofibrate is generally well tolerated when administered alone or in combination with a statin. Thus, in patients with dyslipidaemia, particularly atherogenic dyslipidaemia, fenofibrate is a useful treatment option either alone or in combination with a statin.

Fenofibrate

Fenofibrate is a fibric acid derivative with lipid-modifying effects that are mediated by the activation of peroxisome proliferator-activated receptor-α. Fenofibrate also has a number of nonlipid, pleiotropic effects (e.g. reducing levels of fibrinogen, C-reactive protein, and various pro-inflammatory markers, and improving flow-mediated dilatation) that may contribute to its clinical efficacy, particularly in terms of improving microvascular outcomes. The beneficial effects of fenofibrate on the lipid profile have been shown in a number of randomized controlled trials. In primary dyslipidemia, fenofibrate monotherapy consistently decreased triglyceride (TG) levels to a significantly greater extent than placebo; significantly greater increases in high-density lipoprotein cholesterol (HDL-C) levels and significantly greater reductions in low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels were also seen in some trials. Monotherapy with fenofibrate or gemfibrozil had generally similar effects on TG and HDL-C levels, although in one trial, TC and LDL-C levels were reduced to a significantly greater extent with fenofibrate than with gemfibrozil. Fenofibrate monotherapy tended to improve TG and HDL-C levels to a significantly greater extent than statin monotherapy in primary dyslipidemia, whereas statin monotherapy decreased LDL-C and TC levels to a significantly greater extent than fenofibrate monotherapy. Fenofibrate also had a beneficial effect on atherogenic dyslipidemia in patients with the metabolic syndrome or type 2 diabetes mellitus, reducing TG levels, tending to increase HDL-C levels, and promoting a shift to larger low-density lipoprotein particles. In terms of cardiovascular outcomes, fenofibrate did not reduce the risk of coronary heart disease (CHD) events to a greater extent than placebo in patients with type 2 diabetes in the FIELD trial. However, the risk of some nonfatal macrovascular events (e.g. nonfatal myocardial infarction, revascularization) and certain microvascular outcomes (e.g. amputation, first laser therapy for diabetic retinopathy, progression of albuminuria) was reduced to a significantly greater extent with fenofibrate than with placebo. Subgroup analysis revealed a significant reduction in the cardiovascular disease (CVD) event rate among fenofibrate recipients in the subgroup of patients with marked hypertriglyceridemia or marked dyslipidemia at baseline. In the ACCORD Lipid trial, there were no significant differences between patients with type 2 diabetes and a high risk of CVD events who received fenofibrate plus simvastatin and those who received placebo plus simvastatin for any of the primary or secondary cardiovascular outcomes. However, fenofibrate plus simvastatin was of benefit in patients who had markedly high TG levels and markedly low HDL-C levels at baseline. In addition, fenofibrate plus simvastatin slowed the progression of diabetic retinopathy. Fenofibrate is generally well tolerated. Common adverse events included increases in transaminase levels that were usually transient, minor, and asymptomatic, and gastrointestinal signs and symptoms. In conclusion, monotherapy with fenofibrate remains a useful option in patients with dyslipidemia, particularly in atherogenic dyslipidemia characterized by high TG and low HDL-C levels.

Multimodale Therapie von Fettstoffwechselstörungen

In the multifactorial process of atherogenesis not only increased LDL-cholesterol but also decreased HDL-cholesterol and raised triglycerides correlate closely to cardiovascular events. Multiple studies have demonstrated a high prevalence of dyslipidemia and the metabolic syndrome in Germany.Statins remain first-line therapy for the treatment of dyslipidemia. However, despite therapy a relevant cardiovascular risk remains. Therefore, it is important to also aim for an adequate treatment of hypertriglyceridemia and also to raise HDL-levels. Many combination therapies have been shown to be effective in treating dyslipidemia. Adding Omega-3-fatty acids, nicotinic acid/laropiprant or a fibrate to statin monotherapy provide additional beneficial lipid-modifying effects for combined dyslipidemia. In the future a recommendation for the treatment of mixed hyperlipoproteinemia with decreased HDL, raised triglycerides and LDL-cholesterol shall have to be added to our guidelines.

Nicotinic Acid Has Anti-atherogenic and Anti-inflammatory Properties on Advanced Atherosclerotic Lesions Independent of its Lipid-modifying Capabilities

Inflammation contributes to atherosclerotic plaque initiation and progression. Recent studies suggest that nicotinic acid has anti-inflammatory effects independent of its lipid-modifying capabilities. We assessed the hypothesis that administration of nicotinic acid to older apolipoprotein E (apoE)-deficient mice with established lesions will reduce lesion size and plaque inflammation independent of its lipid-modifying effects. Therefore nicotinic acid was administered to 27-week-old apo E-deficient mice exhibiting advanced atherosclerotic lesions within the innominate artery. After 27 weeks of treatment both animal groups had no significant changes in plasma lipid levels. Mice treated with nicotinic acid (n = 22) demonstrated a 30% reduction in total lesion area compared with controls (n = 20). Furthermore, they revealed a more stable plaque composition with an increase in fibrous cap thickness and a reduction in the size of the necrotic core. Immunohistochemistry demonstrated a reduced accumulation of macrophages and a reduced expression of vascular cell adhesion molecule-1 and tissue factor. Additionally, administration of nicotinic acid significantly reduced tumor necrosis factor alpha expression in the thoracic aorta as demonstrated by real-time PCR. In conclusion, these data suggest that long-term administration of nicotinic acid has anti-atherogenic and anti-inflammatory properties on advanced atherosclerotic lesions, which are independent of its lipid-modifying actions.

Important Considerations for Treatment with Dietary Supplement versus Prescription Niacin Products

Niacin is a water-soluble B vitamin (B3) known to have favorable effects on multiple lipid parameters, including raising high-density lipoprotein cholesterol (HDL-C) levels and lowering triglycerides (TGs), lipoprotein(a), and low-density lipoprotein cholesterol (LDL-C). Although LDL-C remains the primary target of lipid-altering therapy, current guidelines emphasize HDL-C and other modifiable lipid factors as key secondary targets. Thus, niacin is considered an important therapeutic option to help reduce the risk of cardiovascular disease in patients with mixed dyslipidemia who, in addition to high LDL-C, have elevated TGs and low HDL-C. Although available prescription niacin products, including immediate-release niacin (IR; Niacor) and an extended-release niacin formulation (Niaspan), have demonstrated safety and efficacy in randomized clinical trials, confusion remains among health care providers and their patients regarding the various commercially available nonprescription dietary supplement niacin products. These dietary supplements, which include IR, sustained-release (SR), and “no-flush” or “flush-free” niacin products, are not subject to the same stringent US Food and Drug Administration regulations as prescription drugs. In fact, both the American Heart Association and the American Pharmacists Association recommend against the use of dietary supplement niacin as a substitute for prescription niacin. Although some dietary supplement IR and SR niacin products have demonstrated a lipid response in clinical trials, products labeled as “no-flush” or “flush-free” that are intended to avoid the common niacin-associated adverse effect of flushing generally contain minimal or no free, pharmacologically active niacin and therefore lack beneficial lipid-modifying effects. To clarify important differences between available prescription and dietary supplement niacin products, this article contrasts current regulatory standards for dietary supplements and prescription drugs and provides an overview of available clinical data from key trials of niacin.