Effects Of Extended-release Niacin Research Articles

Effect of extended-release niacin on plasma lipoprotein(a) levels: A systematic review and meta-analysis of randomized placebo-controlled trials

AimLipoprotein(a) (Lp(a)) is a proatherogenic and prothrombotic lipoprotein. Our aim was to quantify the extended-release nicotinic acid Lp(a) reducing effect with a meta-analysis of the available randomized clinical trials. MethodsA meta-analysis and random-effects meta-regression were performed on data pooled from 14 randomized placebo-controlled clinical trials published between 1998 and 2015, comprising 17 treatment arms, which included 9013 subjects, with 5362 in the niacin arm. ResultsThe impact of ER niacin on plasma Lp(a) concentrations was reported in 17 treatment arms. Meta-analysis suggested a significant reduction of Lp(a) levels following ER niacin treatment (weighted mean difference – WMD: −22.90%, 95% CI: −27.32, −18.48, p<0.001).Results also remained similar when the meta-analysis was repeated with standardized mean difference as summary statistic (WMD: −0.66, 95% CI: −0.82, −0.50, p<0.001). When the studies were categorized according to the administered dose, there was a comparable effect between the subsets of studies with administered doses of <2000mg/day (WMD: −21.85%, 95% CI: −30.61, −13.10, p<0.001) and ≥2000mg/day (WMD: −23.21%, 95% CI: −28.41, −18.01, p<0.001).The results of the random-effects meta-regression did not suggest any significant association between the changes in plasma concentrations of Lp(a) with dose (slope: −0.0001; 95% CI: −0.01, 0.01; p=0.983), treatment duration (slope: −0.40; 95% CI: −0.97, 0.17; p=0.166), and percentage change in plasma HDL-C concentrations (slope: 0.44; 95% CI: −0.48, 1.36; p=0.350). ConclusionIn this meta-analysis of randomized placebo-controlled clinical trials, treatment with nicotinic acid was associated with a significant reduction in Lp(a) levels.

Effects of extended-release niacin on the postprandial metabolism of Lp(a) and ApoB-100-containing lipoproteins in statin-treated men with type 2 diabetes mellitus.

The effects of extended-release niacin (ERN; 1-2 g/d) on the metabolism of lipoprotein(a) (Lp(a)) and apolipoprotein (apo) B-100-containing lipoproteins were investigated in 11 statin-treated white men with type 2 diabetes mellitus in a randomized, crossover trial of 12-weeks duration. The kinetics of Lp(a) and very low-density lipoprotein (VLDL), intermediate-density lipoprotein, and low-density lipoprotein (LDL) apoB-100 were determined following a standardized oral fat load (87% fat) using intravenous administration of D3-leucine, gas chromatography-mass spectrometry, and compartmental modeling. ERN significantly decreased fasting plasma total cholesterol, LDL cholesterol, and triglyceride concentrations. These effects were achieved without significant changes in body weight or insulin resistance. ERN significantly decreased plasma Lp(a) concentration (-26.5%) and the production rates of apo(a) (-41.5%) and Lp(a)-apoB-100 (-32.1%); the effect was greater in individuals with elevated Lp(a) concentration. ERN significantly decreased VLDL (-58.7%), intermediate-density lipoprotein (-33.6%), and LDL (-18.3%) apoB-100 concentrations and the corresponding production rates (VLDL, -49.8%; intermediate-density lipoprotein, -44.7%; LDL, -46.1%). The number of VLDL apoB-100 particles secreted increased in response to the oral fat load. Despite this, total VLDL apoB-100 production over the 10-hour postprandial period was significantly decreased with ERN (-21.9%). In statin-treated men with type 2 diabetes mellitus, ERN decreased plasma Lp(a) concentrations by decreasing the production of apo(a) and Lp(a)-apoB-100. ERN also decreased the concentrations of apoB-100-containing lipoproteins by decreasing VLDL production and the transport of these particles down the VLDL to LDL cascade. Our study provides further mechanistic insights into the lipid-regulating effects of ERN.

Effects of Extended-Release Niacin and Extended-Release Niacin/Laropiprant on the Pharmacokinetics of Simvastatin in Healthy Subjects

The use of multiple lipid-modifying agents with different mechanisms of action is often required to regulate lipid levels in patients with dyslipidemia. During combination therapy, alterations in the pharmacokinetics of any of the drugs used and their metabolites may occur. Three separate open-label, randomized, crossover studies evaluated the potential for pharmacokinetic interaction between extended-release niacin (with and without concomitant laropiprant) and simvastatin in healthy subjects. Study 1 used single doses of extended-release niacin and simvastatin; study 2 used multiple-dose coadministration of extended-release niacin/laropiprant and simvastatin in healthy subjects; and study 3 used single doses of both extended-release niacin and the coadministration of extended-release niacin/laropiprant and simvastatin in healthy Chinese subjects. During each treatment period, plasma samples were collected predose and at prespecified postdose time points for pharmacokinetic analyses. The safety and tolerability of simvastatin with and without coadministered extended-release niacin (or extended-release niacin/laropiprant) were assessed by clinical evaluation of adverse experiences. In 2 studies in healthy subjects, modest increases in exposure to simvastatin acid (by ∼60%) by extended-release niacin and extended-release niacin/laropiprant were observed. Based on the clinical experience with simvastatin, these effects are not believed to be clinically meaningful. In the third study on healthy Chinese subjects, no statistically meaningful increases in exposure to simvastatin by extended-release niacin and extended-release niacin/laropiprant were observed. In all populations examined in these studies, the coadministration of extended-release niacin and simvastatin was generally well tolerated.

Effect of extended-release niacin on cardiovascular events and kidney function in chronic kidney disease: a post hoc analysis of the AIM-HIGH trial

Chronic kidney disease (CKD) in patients is strongly associated with cardiovascular morbidity and mortality, and prevalent abnormal lipid metabolism. The AIM-HIGH trial examined the benefits of adding extended-release niacin (ERN) to simvastatin in patients with established coronary heart disease. Here we conducted a post-hoc analysis of the AIM-HIGH trial examining whether participants derived cardiovascular or renal benefits when stratified by renal function. Of 3414 participants, 505 had stage 3 CKD at baseline. Among the CKD subset, demographics and cardiovascular disease (CVD) risk factors were well balanced in the ERN and placebo arms. Compared to placebo, CKD participants receiving ERN had a significant decrease in triglycerides by a median of 59.0 mg/dL, and high density lipoprotein-cholesterol significantly increased by a mean of 11.3 mg/dL over a mean follow-up of 3 years. CVD events were similar between CKD participants in both arms. However, all-cause mortality was significantly higher in the ERN group (hazard ratio of 1.73). Mean change in eGFR among ERN-treated CKD participants was not significantly different between study arms. Thus, among AIM-HIGH participants with CKD, the addition of ERN to simvastatin for secondary prevention of CVD improved triglyceride and high density lipoprotein-cholesterol concentrations but did not improve cardiovascular outcomes or kidney function, and was associated with higher all-cause mortality.

ACP Journal Club: adding niacin plus laropiprant to statins did not reduce vascular events and increased serious adverse events.

Source Citation HPS2-THRIVE Collaborative Group, Landray MJ, Haynes R, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371:203-12. 25014686

Effects of Extended-Release Niacin with Laropiprant in High-Risk Patients

BackgroundPatients with evidence of vascular disease are at increased risk for subsequent vascular events despite effective use of statins to lower the low-density lipoprotein (LDL) cholesterol level. Niacin lowers the LDL cholesterol level and raises the high-density lipoprotein (HDL) cholesterol level, but its clinical efficacy and safety are uncertain.MethodsAfter a prerandomization run-in phase to standardize the background statin-based LDL cholesterol–lowering therapy and to establish participants' ability to take extended-release niacin without clinically significant adverse effects, we randomly assigned 25,673 adults with vascular disease to receive 2 g of extended-release niacin and 40 mg of laropiprant or a matching placebo daily. The primary outcome was the first major vascular event (nonfatal myocardial infarction, death from coronary causes, stroke, or arterial revascularization).ResultsDuring a median follow-up period of 3.9 years, participants who were assigned to extended-release niacin–laropiprant had an LDL cholesterol level that was an average of 10 mg per deciliter (0.25 mmol per liter as measured in the central laboratory) lower and an HDL cholesterol level that was an average of 6 mg per deciliter (0.16 mmol per liter) higher than the levels in those assigned to placebo. Assignment to niacin–laropiprant, as compared with assignment to placebo, had no significant effect on the incidence of major vascular events (13.2% and 13.7% of participants with an event, respectively; rate ratio, 0.96; 95% confidence interval [CI], 0.90 to 1.03; P=0.29). Niacin–laropiprant was associated with an increased incidence of disturbances in diabetes control that were considered to be serious (absolute excess as compared with placebo, 3.7 percentage points; P<0.001) and with an increased incidence of diabetes diagnoses (absolute excess, 1.3 percentage points; P<0.001), as well as increases in serious adverse events associated with the gastrointestinal system (absolute excess, 1.0 percentage point; P<0.001), musculoskeletal system (absolute excess, 0.7 percentage points; P<0.001), skin (absolute excess, 0.3 percentage points; P=0.003), and unexpectedly, infection (absolute excess, 1.4 percentage points; P<0.001) and bleeding (absolute excess, 0.7 percentage points; P<0.001).ConclusionsAmong participants with atherosclerotic vascular disease, the addition of extended-release niacin–laropiprant to statin-based LDL cholesterol–lowering therapy did not significantly reduce the risk of major vascular events but did increase the risk of serious adverse events. (Funded by Merck and others; HPS2-THRIVE ClinicalTrials.gov number, NCT00461630.)

Abstract 625: Niacin Improves Atherogenic Postprandial Lipemia in Patients at High Cardiovascular Risk Despite Reduced Cholesterol Efflux From Human Macrophages

Introduction: The role of niacin has been called into question by recent outcome trials showing no benefit on cardiovascular events. Still, for certain high risk patients not achieving their LDL-C target niacin remains a significant therapeutic option. Hypothesis: Although the effect of niacin on fasting lipids is well established, its impact on cholesterol efflux and lipoprotein metabolism during the atherogenic postprandial state remains indeterminate. Methods: We evaluated the effect of extended-release niacin with laropiprant (ERN/LRP) on postprandial lipoprotein metabolism in 10 subjects on stable statin therapy. All subjects received 1g/20mg ERN/LRP for 4 weeks and then 2 g/40mg ERN/LRP for 8 weeks. At each experimental period, all patients consumed a standardized test meal (1100kcal). Postprandial hypertriglyceridemia (HTG) and plasma efflux capacity through THP-1 macrophages and cellular models overexpressing ABCA1, ABCG1 and SR-BI were evaluated. Results: Compared with baseline, ERN/LRP significantly improved postprandial HTG by reducing the area under the curve AUC for chylomicrons (-50%, p=0.004), VLDL-1 (-43%, p=0.0001) and VLDL-2 (-28%, p=0.01). These latter reductions induce a concomitant decrease in CETP activity during the postprandial state (-11.7%;p=0.03, -12%;p=0.01, -18%;p=0.0003, -13%;p=0.0006, 2h, 4h, 6h and 8h respectively after fat load). Plasma cholesterol efflux capacity from human THP-1 macrophages was reduced throughout the postprandial phase (AUC:-20%, p=0.05) following ERN/LRP therapy as a result of a specific reduction in ABCA1 dependent efflux pathway (AUC:-10%; p&lt;0.05), whereas other efflux pathways such as SRBI and ABCG1 were not changed. Conclusions: ERN/LRP treatment reduces physiological triglyceride rich lipoproteins synthesis which indirectly results in a significant reduction in CETP activity. By this mechanism, intravascular remodeling of HDL is altered, thus affecting regeneration of ApoA1/preβ-HDL, the preferential cellular cholesterol acceptors via ABCA1 pathway. We conclude that Niacin therapy is associated with an overall reduction in the early step of RCT representing therefore one potential mechanistic hypothesis for the disappointing results in recent clinical trials

Effect of Extended-Release Niacin on Serum Lipids and on Endothelial Function in Adults With Sickle Cell Anemia and Low High-Density Lipoprotein Cholesterol Levels

Through bound apolipoprotein A-I (apoA-I), high-density lipoprotein cholesterol (HDL-C) activates endothelial nitric oxide synthase, inducing vasodilation. Because patients with sickle cell disease (SCD) have low apoA-I and endothelial dysfunction, we conducted a randomized, double-blinded, placebo-controlled trial to test whether extended-release niacin (niacin-ER) increases apoA-I-containing HDL-C and improves vascular function in SCD. Twenty-seven patients with SCD with levels of HDL-C <39 mg/dl or apoA-I <99 mg/dl were randomized to 12 weeks of niacin-ER, increased in 500-mg increments to a maximum of 1,500 mg/day, or placebo. The primary outcome was the absolute change in HDL-C level after 12 weeks, with endothelial function assessed before and at the end of treatment. Niacin-ER-treated patients trended to greater increase in HDL-C level compared with placebo treatment at 12 weeks (5.1 ± 7.7 vs 0.9 ± 3.8 mg/dl, 1-tailed p = 0.07), associated with significantly greater improvements in the ratios of low-density lipoprotein to HDL-C levels (1.24 vs 1.95, p = 0.003) and apolipoprotein B to apoA-I levels (0.46 vs 0.58, p = 0.03) compared with placebo-treated patients. No improvements were detected in 3 independent vascular physiology assays of endothelial function. Thus, the relatively small changes in HDL-C levels achieved by the dose of niacin-ER used in our study are not associated with improved vascular function in patients with SCD with initially low levels of apoA-I or HDL-C.

Search and rescue for hypotheses surviving AIM-HIGH, the niacin therapy earthquake: Still problematic after the primary publication

Search and rescue for hypotheses surviving AIM-HIGH, the niacin therapy earthquake: Still problematic after the primary publication

Effect of Extended-Release Niacin on New-Onset Diabetes Among Hyperlipidemic Patients Treated With Ezetimibe/Simvastatin in a Randomized Controlled Trial

OBJECTIVETo determine the effect of niacin on fasting glucose (FG) and new-onset diabetes in statin/ezetimibe-treated patients.RESEARCH DESIGN AND METHODSThis was a prespecified secondary analysis among 942 hyperlipidemic patients randomized to ezetimibe/simvastatin (E/S; 10/20 mg) or E/S + extended-release niacin (N; titrated to 2 g) over 64 weeks.RESULTSFG levels peaked by 8–12 weeks, then declined even without antidiabetic medication. At 64 weeks, 3.5% taking E/S+N versus 2.6% taking E/S met criteria for new-onset diabetes (P = 0.66). An additional 1.4% taking E/S+N versus 0.4% taking E/S transiently met criteria for diabetes and then remitted (P = 0.46). Of 28 new-diabetes diagnoses in the E/S+N group, 25 occurred by 24 weeks. Among patients with baseline diabetes, 13.9% taking E/S+N and 11.6% taking E/S underwent antidiabetic treatment modification.CONCLUSIONSIncreased FG and new-onset diabetes with E/S+N occurred mainly around the time of initial uptitration of N and often improved or remitted without specific treatment.

Short-term effects of extended-release niacin on endothelial function in HIV-infected patients on stable antiretroviral therapy

To assess the short-term effects of extended-release niacin (ERN) on endothelial function in HIV-infected patients with low high-density lipoprotein-cholesterol (HDL-c) levels. Randomized controlled study to determine the short-term effects of ERN on endothelial function, measured by flow-mediated vasodilation (FMD) of the brachial artery, in HIV-infected adults with low HDL-c. Participants on stable HAART with fasting HDL-c less than 40 mg/dl and low-density lipoprotein-cholesterol less than 130 mg/dl were randomized to ERN or control arms. ERN treatment started at 500 mg/night and titrated to 1500 mg/night for 12 weeks. Controls received the same follow-up but were not given ERN (no placebo). Participants were excluded if they had a history of cardiac disease, uncontrolled hypertension, diabetes mellitus, or were on lipid-lowering medications such as statins and fibrates. Change in FMD was compared between arms with respect to baseline HDL-c. Nineteen participants were enrolled: 89% men, median age 50 years, 53% white/non-Hispanic, median CD4 cell count 493 cells/microl, and 95% of them had HIV RNA below 50 copies/ml. Participants receiving ERN had a median HDL-c (interquartile range) increase of 3.0 mg/dl (0.75 to 5.0) compared with -1.0 mg/dl in controls (-6.0 to 2.5), a P value is equal to 0.04. The median change in FMD was 0.91% (-2.95 to 2.21) for ERN and -0.48% (-2.65 to 0.98) for controls (P = 0.67). However, end of study FMD for ERN was significantly different from controls after adjusting for baseline differences in FMD and HDL-c, 6.36% (95% confidence interval 4.85-7.87) and 2.73% (95% confidence interval 0.95-4.51) respectively, a P value is equal to 0.048. This pilot study demonstrated that short-term niacin therapy could improve endothelial function in HIV-infected patients with low HDL-c.

A 004 The Effects of Extended-release Niacin for Increasing High-Density Lipoprotein Cholesterol Levels: Effectiveness and Tolerability

A 004 The Effects of Extended-release Niacin for Increasing High-Density Lipoprotein Cholesterol Levels: Effectiveness and Tolerability

Blood pressure-lowering effects of extended-release niacin alone and extended-release niacin/laropiprant combination: A post hoc analysis of a 24-week, placebo-controlled trial in dyslipidemic patients

Background: Dyslipidemia and high blood pressure are both major cardiovascular disease risk factors. Niacin is an effective lipid-altering agent that has been reported to reduce the risk of cardiovascular disease. However, the more widespread use of niacin is limited, mainly due to the occurrence of flushing. Laropiprant (LRPT) is a selective antagonist of prostaglandin D 2 receptor subtype 1 that reduces extended-release niacin (ERN)-induced flushing without affecting its beneficial lipid effects. While the lipid effects of ERN are well known, the blood pressure effects are unclear. Objective: The aim of this analysis was to examine the blood pressure effects of ERN and ERN/LRPT. Methods: This was a post hoc analysis of a 24-week, worldwide, multicenter, double-blind, randomized, placebo-controlled, parallel, Phase III, previously published study of dyslipidemic patients, which examined the effect of ERN and ERN/LRPT on systolic blood pressure (SBP) and diastolic blood pressure (DBP). Results: A total of 1613 men and women, aged 21 to 85 years, with primary hypercholesterolemia or mixed dyslipidemia (66% on statins), were included in the original analysis. ERN alone, or in combination with LRPT, was associated with significant reductions in SBP and DBP at 24 weeks from baseline. The placebo-adjusted mean changes from baseline at week 24 in SBP were −2.2 and −3.1 mm Hg for the ERN and ERN/LRPT groups, respectively ( P < 0.05 and P < 0.001). Similar changes in DBP were observed; −2.7 and −2.5 mm Hg in the ERN and ERN/ LRPT groups, respectively (both, P < 0.001). Conclusion: This post hoc analysis of a 24-week trial found that ERN alone, or in combination with LRPT, was associated with significant placebo-adjusted reductions from baseline in blood pressure in these hyperlipidemic hypertensive or normotensive subjects.

Extended-release niacin reduces LDL particle number without changing total LDL cholesterol in patients with stable CAD

The importance of the number of circulating low-density lipoprotein (LDL) cholesterol particles, in addition to total LDL level, has been increasingly recognized. The effects of extended-release niacin (ERN) on LDL particle numbers have not been studied. To evaluate ERN's effects on LDL particle numbers. Fifty-four patients with stable coronary artery disease (CAD) and well-controlled LDL levels were randomly assigned to 3 months of ERN (1 g/day) or placebo in addition to their baseline medications. Lipoprotein particle number was analyzed by proton nuclear magnetic resonance spectroscopy at baseline and after 3 months. Compared to baseline, the addition of ERN had no significant effect on total LDL cholesterol levels; however, ERN decreased the number of medium and small LDL particles (P < .005). After 3 months, ERN decreased the number of medium and small LDL particles compared to placebo-treated patients (P < .05). ERN raised HDL cholesterol levels by 2.7%, significantly increased the number of large HDL particles (P < .001), and decreased the number of small HDL particles (P = .027) compared to placebo. There were no significant changes in lipid values or particle numbers in the placebo-treated patients. In patients with stable coronary artery disease and well-controlled LDL cholesterol levels, ERN reduced the number of circulating particles of the more atherogenic subtypes of LDL, despite having no effect on total LDL cholesterol levels. ERN also favorably altered the number of HDL particles. ERN-induced alterations in lipoprotein particle numbers may contribute to its anti-atherosclerotic effects, and these effects may not be evident from the standard lipid profile.

Effects of extended-release niacin on lipid profile and adipocyte biology in patients with impaired glucose tolerance

BackgroundLow high-density lipoprotein cholesterol (HDL-C) serum concentrations are independent risk factors for the development of coronary artery disease. In patients with the metabolic syndrome, low HDL-C can contribute to premature atherosclerosis. Extended-release (ER) niacin increases HDL-C and was shown to slow the progression of atherosclerosis. Adipose tissue is an important site of niacin action. Here we sought to determine potential pleiotropic effects of ER niacin on adipose tissue biology in patients with impaired glucose tolerance (IGT). Methods and resultsThirty patients with IGT (mean age=45.2±3.9 years), low HDL-C serum concentrations (HDL-C <1.0mmol/l), but no additional comorbidities were treated once-daily with ER niacin (1000mg) in a randomized open-label controlled (n=30) study for 6 months. During the first 4 weeks, daily dose was increased from 375 to 1000mg in weekly intervals. At baseline and after 6 months, subcutaneous adipose tissue biopsies were taken, body fat mass, insulin sensitivity (euglycemic–hyperinsulinemic clamp), and adipokine serum concentrations were measured. After 6 months of ER niacin treatment, HDL-C increased significantly by 24% and adiponectin by 35%. In addition, ER niacin significantly reduced circulating lipoprotein (a) by 38% (p<0.001) and fasting triglycerides by 12% (p<0.05). Whole-body insulin sensitivity increased in the ER niacin treatment group, although this trend was not statistically significant (p=0.085). Six months ER niacin led to a significant reduction in mean adipocyte size associated with increased insulin sensitivity in isolated adipocytes and gene expression changes including increased adiponectin, C/EBPα, C/EBPδ, PPARγ and decreased carnitine palmitoyl transferase 2, hormone sensitive lipase, nicotinic acid receptor (GPR109B) and fatty-acid synthase mRNA expression. ConclusionTreatment with ER niacin significantly improves atherogenic lipid profile in patients with IGT. These beneficial effects could at least in part be due to pleiotropic niacin effects in adipose tissue, characterized by decreased mean adipocyte size, increased insulin sensitivity and altered mRNA expression profile.

Effect of extended-release niacin on hormone-sensitive lipase and lipoprotein lipase in patients with HIV-associated lipodystrophy syndrome

HIV-associated lipodystrophy syndrome is strongly associated with antiretroviral treatment in patients with human immunodeficiency virus (HIV). Niacin is thought to affect hormone-sensitive lipase (HSL) and lipoprotein lipase (LPL) expression in peripheral and intra-abdominal fat (IAF). This study investigated the effect of extended-release niacin (ERN) on adipose HSL and LPL expression in patients with HIV-associated lipodystrophy syndrome. Changes in IAF and peripheral fat content and HSL and LPL expression were examined in 4 HIV-infected patients recruited from a prospective study treated with ERN. Patients underwent limited 8 slice computerized tomography abdominal scans, dual-energy X-ray absorptiometry scans, and skin punch biopsies of the mid-thigh at baseline and after 12 weeks of ERN. All subjects were on stable highly active antiretroviral therapy prior to and during the study. Changes in body habitus were self-reported. Normalized HSL expression decreased in 3 patients and normalized LPL expression increased in all 4 patients when comparing pre- and post-ERN treated samples. All subjects showed a decrease in total cholesterol (TC) and triglyceride (TG) levels. Preliminary analysis suggests ERN may induce changes in HSL and LPL expression. This method is a feasible approach to identify changes in adipose RNA expression involved with lipolysis.

Identifying the Vulnerable Patient with Rupture-Prone Plaque

Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality in the United States, and the obesity epidemic combined with aging of the population seems destined to increase the burden of this disease. Traditional cardiovascular risk assessment accounts for <50% of the variability in risk in the United States. Therefore, better and more effective identification of persons at high cardiovascular risk is needed. Our understanding of atherosclerosis has shifted from a focal disease whose hallmark is symptoms caused by a severe stenosis to a systemic disease characterized by endothelial dysfunction (ED) and plaque inflammation, with the potential for rupture and thrombosis mainly in those with subcritical stenosis. Under the new paradigm, clinicians require updated strategies to better assess the quality of arterial plaque. Effective tools for primary and secondary prevention of heart attack and stroke include intensive lifestyle modification, blood pressure reduction, and lipid-modifying therapies. These interventions are now understood to decrease plaque inflammation and thereby promote plaque stability. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) appears to be a specific marker of plaque inflammation that may play a direct role in the formation of rupture-prone plaque. In contrast, traditional risk factors, lipid measurement, and most vascular imaging modalities do not directly assess the acute ischemic potential in the arterial wall. Measuring Lp-PLA(2) levels in human serum or plasma is noninvasive and relatively inexpensive. Lp-PLA(2) may provide additional clinically relevant information that shows which patients have a high level of atherosclerotic disease activity as manifested by vascular inflammation, ED, and increased risk for progression toward rupture-prone plaque.

Effects of Laropiprant on Nicotinic Acid-Induced Flushing in Patients With Dyslipidemia

Niacin (nicotinic acid) is not optimally used mainly because of flushing, a process mediated primarily by prostaglandin D(2), which leads to poor patient compliance and suboptimal dosing. This phase II dose-ranging study was designed to assess whether the prostaglandin D(2) receptor 1 antagonist laropiprant (LRPT; MK-0524) would (1) reduce extended-release niacin (ERN)-induced flushing in dyslipidemic patients and (2) support a novel accelerated ERN dosing paradigm: initiating ERN at 1 g and advancing rapidly to 2 g. In part A of the study, 154 dyslipidemic patients were randomized to LRPT 150 mg/day or placebo in a 9-week, 2-period crossover study. Patients who completed part A (n = 122) entered part B (after a 2-week washout), together with additional patients who entered part B directly (n = 290). Part B patients were randomized to placebo, ERN 1 g (Niaspan, no previous titration), or ERN 1 g coadministered with LRPT 18.75, 37.5, 75, or 150 mg for 4 weeks, with doubling of the respective doses for the remaining 4 weeks. Patients treated with LRPT plus ERN experienced significantly less ERN-induced flushing than those treated with ERN alone during the initiation of treatment (ERN 1 g, week 1) and the maintenance treatment (ERN 1 to 2 g, weeks 2 to 8). All doses of LRPT were maximally effective in inhibiting niacin-induced flushing. LRPT did not alter the beneficial lipid effects of ERN. LRPT plus ERN was well tolerated. In conclusion, the significant reduction in ERN-induced flushing provided by LRPT plus ERN supports an accelerated ERN dose-advancement paradigm to achieve rapidly a 2-g dose in dyslipidemic patients.

Abstract 189: Extended-Release Niacin Improves Endothelial Function, Restores Re-Endothelialization Capacity of Endothelial Progenitor Cells and Augments Vasoprotective Properties of HDL in Patients with Metabolic Syndrome

Background: High density lipoprotein (HDL)-targeted therapies are currently evaluated as a novel therapeutic strategy for cardiovascular disease. However, recent data suggest that HDL may become dysfunctional in metabolic syndrome (MetS). We therefore evaluated the effect of extended-release niacin (ERN) on endothelial function, re-endothelialization capacity of endothelial progenitor cells (EPC) and HDL quality, i.e. the capacity of HDL to stimulate endothelial nitric oxide (NO) production and reduce superoxide (O 2 .− ) production. Methods and Results: Thirty MetS patients were randomized to 3 month treatment with ERN (1500 mg/d) or placebo. Flow-dependent, endothelium-mediated vasodilation (FDD) was characterized by high-resolution ultrasound, EPCs were cultured and HDL was isolated by ultracentrifugation before and after therapy. In vivo re-endothelialization capacity of EPCs was tested by transplantation of EPCs (5x10 5 cells) into nude mice using a carotid injury model. Furthermore, the effects of HDL on endothelial cell superoxide (O 2 . − ) and NO production were determined by electron spin resonance spectroscopy. ERN therapy significantly raised HDL levels (36.4±4.2 vs. 43.4±6.9 mg/dl, P &lt;0.01), whereas no change was observed after placebo (35.9±6.2 vs. 33.7±6.1 mg/dl, P n.s.). FDD was improved by ERN (5.2±1.8 vs 9.8±2.2%; P&lt;0.01), but not after placebo therapy (4.9±1.5 vs. 4.3±0.9 %; P n.s.). Moreover, the re-endothelialization capacity of EPCs was markedly increased after ERN, but not after placebo (REA-ERN: 34±9%; P&lt; 0.001 vs. placebo). Importantly, HDL isolated after ERN, but not after placebo therapy stimulated endothelial cell NO production and inhibited endothelial cell O 2 . − production, suggesting that improved vasoprotective properties of HDL contributed to beneficial effects of ERN therapy on endothelial function. Conclusions: The present study demonstrates that extended-release niacin improves endothelium-dependent vasodilation, restores re-endothelialization capacity of EPCs and importantly improves vasoprotective functions of HDL from patients with metabolic syndrome. These data suggest that extended-release niacin therapy has a beneficial effect on HDL vasoprotective qualities.

The effects of extended-release niacin on carotid intimal media thickness, endothelial function and inflammatory markers in patients with the metabolic syndrome

Niacin is an agent that significantly increases high-density lipoprotein cholesterol (HDL-C), but its effects on surrogate markers of atherosclerosis and inflammatory markers are less clear. We studied the effects of niacin on carotid intimal media thickness (IMT), brachial artery reactivity as well as markers of inflammation and the metabolic profile of patients with metabolic syndrome. Fifty patients with the metabolic syndrome (Adult Treatment Panel (ATP) III criteria) were randomised to either extended-release niacin (1000 mg/day) or placebo. After 52 weeks of treatment, there was a change of carotid IMT of +0.009 +/- 0.003 mm in the placebo group and -0.005 +/- 0.002 mm in the niacin group (p = 0.021 between groups). Endothelial function improved by 22% in the group treated with niacin (p < 0.001), whereas no significant changes were seen in the placebo group. High sensitivity C-reactive protein decreased by 20% in the group treated with niacin for 52 weeks (p = 0.013). Niacin increased HDL-C (p < 0.001) and decreased low-density lipoprotein cholesterol and triglycerides (p < 0.001) significantly, and there were no adverse effects on fasting glucose levels after 52 weeks of treatment. Extended-release niacin therapy effects a regression in carotid intimal medial thickness and improvement in metabolic parameters (increased HDL and reduced triglycerides). Furthermore, extended-release niacin may demonstrate an anti-atherogenic effect in the metabolic syndrome by improving endothelial function and decreasing vascular inflammation.