Nicotinic acid (niacin) induces beneficial changes in serum lipoproteins and has been associated with beneficial cardiovascular effects. Niacin reduces low-density lipoprotein, increases high-density ...lipoprotein, and decreases triglycerides. It is well established that activation of the seven-transmembrane G(i)-coupled receptor GPR109A on Langerhans cells results in release of prostaglandin D₂, which mediates the well-known flushing side effect of niacin. Niacin activation of GPR109A on adipocytes also mediates the transient reduction of plasma free fatty acid (FFA) levels characteristic of niacin, which has been long hypothesized to be the mechanism underlying the changes in the serum lipid profile. We tested this "FFA hypothesis" and the hypothesis that niacin lipid efficacy is mediated via GPR109A by dosing mice lacking GPR109A with niacin and testing two novel, full GPR109A agonists, MK-1903 and SCH900271, in three human clinical trials. In mice, the absence of GPR109A had no effect on niacin's lipid efficacy despite complete abrogation of the anti-lipolytic effect. Both MK-1903 and SCH900271 lowered FFAs acutely in humans; however, neither had the expected effects on serum lipids. Chronic FFA suppression was not sustainable via GPR109A agonism with niacin, MK-1903, or SCH900271. We conclude that the GPR109A receptor does not mediate niacin's lipid efficacy, challenging the long-standing FFA hypothesis.
Niacin (nicotinic acid) is not optimally used mainly because of flushing, a process mediated primarily by prostaglandin D2 , which leads to poor patient compliance and suboptimal dosing. This phase ...II dose-ranging study was designed to assess whether the prostaglandin D2 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 To assess the effects of anacetrapib added to statin ±other lipid-modifying therapies (LMT) in patients with hypercholesterolemia and not at their low density lipoprotein cholesterol (LDL-C) ...goal (as per NCEP ATP III guidelines) and in those with low high-density lipoprotein cholesterol (HDL-C). Patients on a stable dose of moderate/high-intensity statin ±other LMT with LDL-C ≥70 mg/dL, ≥100 mg/dL, ≥130 mg/dL, or ≥160 mg/dL for very high, high, moderate, and low coronary heart disease (CHD) risk, respectively, or at LDL-C goal with HDL-C ≤40 mg/dL, were randomized 1:1:1, stratified by background therapy use, to anacetrapib 100 mg (n=153), anacetrapib 25 mg (n=152), or placebo (n=154) for 24 weeks, followed by a 12-week off-drug reversal phase. The primary endpoints were % change from baseline in LDL-C (beta-quantification BQ method) and HDL-C, as well as the safety profile of anacetrapib. Both doses of anacetrapib reduced LDL-C, non-HDL-C, apolipoprotein (Apo) B, and lipoprotein a (Lp(a)) and increased HDL-C and ApoAI vs placebo (P<0.001 for all). There were no meaningful differences between the anacetrapib 25 mg, 100 mg and placebo groups in the proportions of discontinuations due to drug-related adverse events (0.7%, 1.3% vs. 1.3%) or in abnormalities in liver enzymes (0%, 0% vs. 0.7%), creatine kinase elevations overall (0%, 0.7% vs. 0%) or with muscle symptoms (none seen), blood pressure, electrolytes or adjudicated cardiovascular (CV) events (0.7%, 0.7% vs. 1.3%). In conclusion, treatment with anacetrapib resulted in substantial reductions in LDL-C and increases in HDL-C and was generally well tolerated. ClinicalTrials.gov number, NCT01717300.
High precision measurements of the polarized electron beam-spin asymmetry in semi-inclusive deep inelastic scattering (SIDIS) from the proton have been performed using a 10.6 GeV incident electron ...beam and the CLAS12 spectrometer at Jefferson Lab. We report here a high precision multidimensional study of single π^{+} SIDIS data over a large kinematic range in Bjorken x, fractional energy, and transverse momentum of the hadron as well as photon virtualities Q^{2} ranging from 1-7 GeV^{2}. In particular, the structure function ratio F_{LU}^{sinϕ}/F_{UU} has been determined, where F_{LU}^{sinϕ} is a twist-3 quantity that can reveal novel aspects of emergent hadron mass and quark-gluon correlations within the nucleon. The data's impact on the evolving understanding of the underlying reaction mechanisms and their kinematic variation is explored using theoretical models for the different contributing transverse momentum dependent parton distribution functions.
To assess the effect of simvastatin treatment on the risk of cardiovascular events in nondiabetic patients with coronary heart disease (CHD) with and without the metabolic syndrome, as defined by the ...National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP-III).
Subgroup analyses were performed on data from 3933 nondiabetic patients with clinically established CHD, serum total cholesterol level 5.5-8.0 mmol/l, and serum triglyceride level <or=2.5 mmol/l who were participating in the Scandinavian Simvastatin Survival Study (4S), a randomized, placebo-controlled trial. End points were total mortality, coronary mortality, major CHD event, myocardial revascularization, any CHD event, stroke, and any atherosclerotic event.
Over the 5.4-year median follow-up period, simvastatin produced similar changes in serum lipid levels in 893 patients with the metabolic syndrome and in 3040 patients without the metabolic syndrome. The relative risks of main end points in simvastatin-treated patients compared with placebo-treated patients with the metabolic syndrome were as follows: total mortality 0.54 (95% CI 0.36-0.82), coronary mortality 0.39 (0.23-0.65), major CHD event 0.59 (0.45-0.77), and any atherosclerotic event 0.69 (0.56-0.84). The corresponding RRs in patients without the metabolic syndrome were 0.72 (0.56-0.91), 0.62 (0.45-0.84), 0.71 (0.61-0.82), and 0.76 (0.68-0.85).
Nondiabetic CHD patients with or without the metabolic syndrome realize from simvastatin treatment a similar, substantial relative reduction in the risk of cardiovascular events. The absolute benefit may be greater in patients with the metabolic syndrome because they are at a higher absolute risk.
This phase 3, multiregional, randomized, double-blind, placebo-controlled study assessed the efficacy/safety profile of anacetrapib added to ongoing therapy with statin ± other lipid-modifying ...therapies in patients with hypercholesterolemia who were not at their low-density lipoprotein (LDL-C) goal (as per the National Cholesterol Education Program Adult Treatment Panel III guidelines) and in those with low high-density lipoprotein cholesterol (HDL-C). Patients on a stable dose of statin ± other lipid-modifying therapies and with LDL-C ≥70 to <115, ≥100 to <145, ≥130, or ≥160 mg/dl for very high, high, moderate, or low CHD risk or at LDL-C goal (per CHD risk category) with HDL-C ≤40 mg/dl were randomized in a ratio of 1:1 to anacetrapib 100 mg (n = 290) or placebo (n = 293) for 24 weeks, followed by a 12-week off-drug phase. The co-primary end points were % change from baseline in LDL-C and HDL-C and the safety profile of anacetrapib. Treatment with anacetrapib reduced LDL-C (BQ) by 37% (95% confidence interval −42.5, −31.0) and increased HDL-C by 118% (95% confidence interval 110.6, 125.7) relative to placebo (p <0.001 for both). Anacetrapib also reduced non-HDL-C, apolipoprotein B, and lipoprotein a and increased apolipoprotein AI versus placebo (p <0.001 for all). There were no clinically meaningful differences between the anacetrapib and placebo groups in the % patients who discontinued drug due to an adverse event or in abnormalities in liver enzymes, creatine kinase, blood pressure, electrolytes, or adjudicated cardiovascular events. Treatment with anacetrapib substantially reduced LDL-C and also increased HDL-C and was well tolerated over 24 weeks in statin-treated patients with hypercholesterolemia or low HDL-C.
To compare the efficacy and safety of 10 mg of ezetimibe coadministered with simvastatin with the safety and efficacy of simvastatin monotherapy for patients with hypercholesterolemia.
This ...multicenter double-blind, placebo-controlled, factorial study enrolled 887 patients with hypercholesterolemia (low-density lipoprotein cholesterol LDL-C, 145-250 mg/dL; triglycerides, ≤350 mg/dL). Patients were randomized to 1 of 10 treatments— placebo, ezetimibe at 10 mg/d, simvastatin at 10, 20, 40, or 80 mg/d, or simvastatin at 10, 20, 40, or 80 mg/d plus ezetimibe at 10 mg/d for 12 weeks. The study began March 13, 2001, and ended January 8, 2002. The primary efficacy end point was the mean percent change in LDL-C levels from baseline to study end point (last available postbaseline LDL-C measurement) for the pooled ezetimibe/simvastatin group vs the pooled simvastatin monotherapy group.
Coadministration of ezetimibe/simvastatin was significantly (P<.001) more effective than simvastatin alone in reducing LDL-C levels for the pooled ezetimibe/simvastatin vs pooled simvastatin analysis and at each specific dose comparison. The decrease in LDL-C levels with coadministration of ezetimibe and the lowest dose of simvastatin, 10 mg, was similar to the decrease with the maximum dose of simvastatin, 80 mg. A significantly (P<.001) greater proportion of patients in the ezetimibe/simvastatin group achieved target LDL-C levels compared with those in the monotherapy group. Treatment with ezetimibe/simvastatin also led to greater reductions in total cholesterol, triglyceride, non-high-density lipoprotein cholesterol, and apolipoprotein B levels compared with simvastatin alone; both treatments increased high-density lipoprotein cholesterol levels similarly. The safety and tolerability profiles for the ezetimibe/simvastatin and monotherapy groups were similar.
Through dual inhibition of cholesterol absorption and synthesis, coadministration of ezetimibe/simvastatin offers a highly efficacious and well-tolerated lipid-lowering strategy for treating patients with primary hypercholesterolemia.
Aims To examine the efficacy and safety of coadministered ezetimibe (EZE) with fenofibrate (FENO) in patients with mixed hyperlipidaemia. Methods and results This was a multicentre, randomized, ...double-blind, placebo-controlled, parallel arm trial in patients with mixed hyperlipidaemia LDL-cholesterol (LDL-C), 3.4–5.7 mmol/L (2.6–4.7 mmol/L for patients with type 2 diabetes); triglycerides (TG), 2.3–5.7 mmol/L and no history of coronary heart disease (CHD), CHD-equivalent disease (except for type 2 diabetes), or CHD risk score >20%. A total of 625 patients was randomized in a 1 : 3 : 3 : 3 ratio to one of four daily treatments for 12 weeks: placebo; EZE 10 mg; FENO 160 mg; FENO 160 mg plus EZE 10 mg (FENO+EZE). The primary endpoint compared the LDL-C lowering efficacy of FENO+EZE vs. FENO alone. LDL-C, non-HDL-cholesterol (non-HDL-C), and apolipoprotein B were significantly (P<0.001) reduced with FENO+EZE when compared with FENO or EZE alone. TG levels were significantly decreased and HDL-C was significantly increased with FENO+EZE and FENO treatments when compared with placebo (P<0.001). Coadministration therapy reduced LDL-C by 20.4%, non-HDL-C by 30.4%, TG by 44.0%, and increased HDL-C by 19.0%. At baseline, >70% of all patients exhibited the small, dense LDL pattern B profile. A greater proportion of patients on FENO+EZE and FENO alone treatments shifted from a more atherogenic LDL size pattern to a larger, more buoyant, and less atherogenic LDL size pattern at study endpoint than those on placebo or EZE. All three active therapies were well tolerated. Conclusion Coadministration of EZE with FENO provided a complementary efficacy therapy that improves the atherogenic lipid profile of patients with mixed hyperlipidaemia.
Abstract 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 D2 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.
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