Niacin extended release (ER)/simvastatin (Simcor®): a guide to its use in lipid regulation.
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ABSTRACT:
SUBMITTER: Lyseng-Williamson KA
PROVIDER: S-EPMC3586144 | biostudies-other | 2010
REPOSITORIES: biostudies-other
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Niacin extended release (ER)/simvastatin (Simcor®): a guide to its use in lipid regulation.
Lyseng-Williamson Katherine A KA
Drugs in R&D 20100101 4
Oral fixed-dose niacin extended release/simvastatin is associated with clinically relevant improvements in plasma lipid profiles, including lowering of non-high-density lipoprotein cholesterol levels, relative to simvastatin monotherapy in patients with mixed dyslipidemias who had not responded fully to simvastatin monotherapy, and is generally well tolerated. ...[more]
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Project description:Combination therapy with ezetimibe/simvastatin (E/S) and extended-release niacin (N) has been reported to be safe and efficacious in concomitantly reducing low-density lipoprotein cholesterol and increasing high-density lipoprotein cholesterol in hyperlipidemic patients at high risk for atherosclerotic cardiovascular events. This analysis evaluated the effect of E/S coadministered with N on low-density lipoprotein particle number (LDL-P) and high-density lipoprotein particle number (HDL-P) as assessed by nuclear magnetic resonance (NMR) spectroscopy in patients with type IIa or IIb hyperlipidemia.This was an analysis of a previously reported 24-week randomized, double-blind study in type IIa/IIb hyperlipidemic patients randomized to treatment with E/S (10/20 mg/day)+N (titrated to 2 g/day) or N (titrated to 2 g/day) or E/S (10/20 mg/day). Samples from a subset of patients (577 of 1220) were available for post hoc analysis of LDL-P and HDL-P by NMR spectroscopy. Increases in HDL-P (+16.2%) and decreases in LDL-P (-47.7%) were significantly greater with E/S+N compared with N (+9.8% for HDL-P and -21.5% for LDL-P) and E/S (+12.8% for HDL-P and -36.8% for LDL-P). In tertile analyses, those with the lowest baseline HDL-P had the greatest percent increase in HDL-P (N, 18.4/7.9/2.1; E/S, 19.3/12.2/5.3; and E/S+N, 26.9/13.8/6.9; all P<0.001). Individuals in the highest tertile of LDL-P had the greatest percent reduction in LDL-P (N, 18.3/23.1/24.6; E/S, 29.7/38.3/41.8; and E/S+N, 44.3/49.0/50.5; all P<0.001).These results suggest that E/S+N improves lipoprotein particle number, consistent with its lipid-modifying benefits in type IIa or IIb hyperlipidemia patients and may exert the greatest effect in those with high LDL-P and low HDL-P at baseline.
| S-EPMC3828803 | biostudies-literature
Project description:Niacin is an antidyslipidemic agent that may cause blood sugar elevation in patients with diabetes, but its effects on glucose and insulin values in nondiabetic statin-treated subjects with cardiovascular disease and at high risk for diabetes are less well known.This was a prespecified, intent-to-treat analysis of the Atherothrombosis Intervention in Metabolic syndrome with low high-density lipoprotein/high triglycerides: Impact on Global Health outcomes trial which randomized 3,414 participants at 92 centers in the US and Canada to extended-release niacin (ERN) plus simvastatin/ezetimibe (ERN) or simvastatin/ezetimibe plus placebo (Placebo). Baseline and annual fasting glucose and insulin values were measured. Those experiencing an adverse event indicative of diabetes or starting medications for diabetes were considered to have confirmed diabetes. In addition, nondiabetic subjects with 2 annual follow-up glucose measurements were categorized into normal, impaired fasting glucose or newly diagnosed diabetes (presumed or confirmed) states.Compared with placebo, ERN increased annual fasting glucose from baseline to 1 year in both those with normal (7.9 ± 15.8 vs 4.3 ± 10.3 mg/dL; P < .001) and impaired fasting glucose (4.1 ± 18.7 vs 1.4 ± 14.9; P < .02) and increased insulin levels. Both effects waned over the next 2 years. There were less consistent effects in those with baseline diabetes. There was an increased risk of progressing from normal to presumed or confirmed impaired fasting glucose (ERN 197/336) cases (58.6%) vs placebo 135/325 cases (41.5%; P < .001) over time, but no difference in diabetes development in the 2 treatment groups except in those with normal fasting glucose at baseline.The addition of ERN to simvastatin/ezetimibe had marginal effects on glycemia in those with diabetes at baseline, and there was a trend toward increased development of new-onset diabetes. In addition, ERN increased the risk of developing impaired fasting glucose, which may have deleterious consequences over time and warrants further study.
| S-EPMC4914402 | biostudies-literature
Project description:Postprandial triglyceridemia predicts cardiovascular events. Niacin might lower postprandial triglycerides by restricting free fatty acids. Immediate-release niacin reduced postprandial triglycerides, but extended-release niacin failed to do so when dosed the night before a fat challenge. The study aims were to determine whether extended-release niacin dosed before a fat challenge suppresses postprandial triglycerides and whether postprandial triglycerides are related to free fatty acid restriction.A double-blinded, placebo-controlled, random-order crossover experiment was performed, in which healthy volunteers took 2 g extended-release niacin or placebo 1 hour before heavy cream. We sampled blood over 12 hours and report triglycerides and free fatty acid as means ± standard deviation for incremental area under the curve (AUC) and nadir.By combining 43 fat challenges from 22 subjects, postprandial triglycerides incremental AUC was +312 ± 200 mg/dL*h on placebo versus +199 ± 200 mg/dL*h on extended-release niacin (33% decrease, P=.02). The incremental nadir for free fatty acid was -0.07 ± 0.15 mmol/L on placebo versus -0.27 ± 0.13 mmol/L on extended-release niacin (P<.0001), and free fatty acid incremental AUC decreased from +2.9 ± 1.5 mmol/L*h to +1.5 ± 1.5 mmol/L*h on extended-release niacin (20% decrease, P=.0015). The incremental AUC for triglycerides was strongly related to the post-dose decrease in free fatty acid (r = +0.58, P=.0007).Given right before a fat meal, even a single dose of extended-release niacin suppresses postprandial triglyceridemia. This establishes that postprandial triglycerides suppression is an acute pharmacodynamic effect of extended-release niacin, probably the result of marked free fatty acid restriction. Further study is warranted to determine whether mealtime dosing would augment the clinical efficacy of extended-release niacin therapy.
| S-EPMC4170918 | biostudies-literature
Project description:To determine the effect of niacin on fasting glucose (FG) and new-onset diabetes in statin/ezetimibe-treated patients.This 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.FG 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.Increased 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.
| S-EPMC3308290 | biostudies-literature
Project description:BackgroundStatins modify correlations between apolipoprotein B (apoB) and low-density lipoprotein cholesterol (LDL-C) and apoB and non-high-density lipoprotein cholesterol (non-HDL-C); however, it is not known whether niacin-based therapies have similar effects.ObjectiveTo evaluate the effects of extended-release niacin (ERN)/laropiprant (LRPT), simvastatin (SIMVA), and ERN/LRPT + SIMVA (pooled ERN/LRPT + SIMVA) on apoB:LDL-C and apoB:non-HDL-C correlations in dyslipidemic patients.MethodsThis post-hoc analysis of a 12-week study evaluated the apoB:LDL-C and apoB:non-HDL-C correlations in dyslipidemic patients randomized equally to double-blind ERN/LRPT 1 g/20 mg, SIMVA 10, 20, or 40 mg, or ERN/LRPT 1 g/20 mg + SIMVA (10, 20, or 40 mg) once daily for 4 weeks. At week 5, doses were doubled in all groups except SIMVA 40 mg (unchanged) and ERN/LRPT 1 g/20 mg + SIMVA 40 mg (switched to ERN/LRPT 2 g/40 mg + SIMVA 40 mg). Simple linear regression analyses were used to calculate LDL-C and non-HDL-C levels corresponding to known apoB baseline values (ie, in untreated patients) and following treatment.ResultsThe apoB:LDL-C and apoB:non-HDL-C correlations were higher and the predicted LDL-C and non-HDL-C levels for a known apoB value were considerably lower following treatment with ERN/LRPT, SIMVA and ERN/LRPT + SIMVA compared with untreated patients at baseline.ConclusionGreater dissociation of apoB, LDL-C, and non-HDL-C targets occur following treatment with ERN/LRPT, SIMVA, and ERN/LRPT + SIMVA in patients with dyslipidemia. The achievement of more aggressive LDL-C and non-HDL-C goals in patients receiving lipid-modifying therapy may further reduce coronary risk by normalizing apoB-containing atherogenic lipoproteins.
| S-EPMC4019613 | biostudies-literature
Project description:Coronary heart disease (CHD) remains the leading cause of death in Germany despite statin use to reduce low-density lipoprotein cholesterol (LDL-C) levels; improving lipids beyond LDL-C may further reduce cardiovascular risk. A fixed-dose combination of extended-release niacin (ERN) with laropiprant (LRPT) provides comprehensive lipid management. We adapted a decision-analytic model to evaluate the economic value (incremental cost-effectiveness ratio [ICER] in terms of costs per life-years gained [LYG]) of ERN/LRPT 2 g over a lifetime in secondary prevention patients in a German setting. Two scenarios were modelled: (1) ERN/LRPT 2 g added to simvastatin 40 mg in patients not at LDL-C goal with simvastatin 40 mg; (2) adding ERN/LRPT 2 g compared with titration to simvastatin 40 mg in patients not at LDL-C goal with simvastatin 20 mg. In both scenarios, adding ERN/LRPT was cost-effective relative to simvastatin monotherapy at a commonly accepted threshold of €30,000 per LYG; ICERs for ERN/LRPT were €13,331 per LYG in scenario 1 and €17,684 per LYG in scenario 2. Subgroup analyses showed that ERN/LRPT was cost-effective in patients with or without diabetes, patients aged ? 65 or >65 years and patients with low baseline high-density lipoprotein cholesterol levels; ICERs ranged from €10,342 to €15,579 in scenario 1, and from €14,081 to €20,462 in scenario 2. In conclusion, comprehensive lipid management with ERN/LRPT 2 g is cost-effective in secondary prevention patients in Germany who have not achieved LDL-C goal with simvastatin monotherapy.
| S-EPMC3343242 | biostudies-other
Project description:Niacin (nicotinic acid, NA) is administered orally as an antihyperlipidemic agent in extended-release (ER) tablets in high doses. Due to rapid absorption and extensive metabolism (non-linear pharmacokinetics), the drug plasma levels are highly variable, which may correlate with side effects. Interestingly, this erratic drug delivery behavior of niacin ER products cannot be clarified by compendial in vitro release testing. The standard dissolution tests do not allow to mimic the selected GI tract characteristics in order to estimate the robustness of formulation under the variability of the physiological conditions. These are characterized by the pH value, impact of motility forces and composition, as well as volume of GI liquids. Our paper demonstrates a comparison of a newly developed ER HPMC niacin formulation with an originator product. The research aimed to design a robust matrix tablet of comparable biopharmaceutical behavior, safety and efficacy. The extensive in vitro investigation, including dynamic studies in flow-through cell apparatus and stress test device, forms the basis for the evaluation of nicotinic acid plasma concentrations in vivo. The occurrence of erratic, multiple NA plasma peaks after the administration of both extended-release products is a result of its local input excess over the metabolic threshold (at the level corresponding to maximum 2% of the administered dose, i.e., 20 mg of drug) due to the mechanical stresses of physiological intensity. We demonstrate how this behavior is similar for both marketed and test products. In this context, we describe how a robust ER matrix and well-designed formulation does not guarantee the test product's bioequivalence to the comparator one out of reasons unrelated to technology and biopharmaceutical properties, but because of the active compound's intrinsic pharmacokinetic characteristics, i.e., highly variable, extensive metabolism of nicotinic acid.
| S-EPMC6985042 | biostudies-literature
Project description:BACKGROUND AND OBJECTIVES:Niacin downregulates intestinal sodium-dependent phosphate transporter 2b expression and reduces intestinal phosphate transport. Short-term studies have suggested that niacin lowers serum phosphate concentrations in patients with CKD and ESRD. However, the long-term effects of niacin on serum phosphate and other mineral markers are unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Trial was a randomized, double-blind, placebo-controlled trial testing extended release niacin in persons with prevalent cardiovascular disease. We examined the effect of randomized treatment with niacin (1500 or 2000 mg) or placebo on temporal changes in markers of mineral metabolism in 352 participants with eGFR<60 ml/min per 1.73 m2 over 3 years. Changes in each marker were compared over time between the niacin and placebo arms using linear mixed effects models. RESULTS:Randomization to niacin led to 0.08 mg/dl lower plasma phosphate concentrations per year of treatment compared with placebo (P<0.01) and 0.25 mg/dl lower mean phosphate 3 years after baseline (3.32 versus 3.57 mg/dl; P=0.03). In contrast, randomization to niacin was not associated with statistically significant changes in plasma intact fibroblast growth factor 23, parathyroid hormone, calcium, or vitamin D metabolites over 3 years. CONCLUSIONS:The use of niacin over 3 years lowered serum phosphorous concentrations but did not affect other markers of mineral metabolism in participants with CKD.
| S-EPMC5753310 | biostudies-other
Project description:BackgroundNiacin has multiple lipoprotein effects that may provide cardiovascular benefit when added to statin monotherapy.MethodsIn this randomized, placebo-controlled trial (n = 75) of magnetic resonance imaging of carotid atherosclerosis, we performed a secondary comparison of combination niacin-statin (simvastatin 20 mg/Niacin-ER 2G [S20/N]) to monotherapy with moderate (20 mg [S20]) and high-dose (80 mg [S80]) simvastatin on lipids, apolipoproteins (apo), low density lipoprotein (LDL) and high density lipoprotein (HDL) particle subclasses, and inflammatory markers.ResultsAt baseline, average age was 71, 72% were male, 62.5% used statins, and average LDL-cholesterol was 111 mg/dL. At 12 months, S20/N, compared to S80, significantly reduced apoB (-36.6% vs -11.9%; P = .05) and lipoprotein(a) (-18% vs +3.5%; P = .001) and had at least an equivalent effect on LDL-cholesterol (-39.3% vs -24.3%; P = .24). The combination reduced the proportion of subjects with atherogenic LDL pattern-B (50% to 11.5%) compared to S80 (56% to 56%) (P = .01). Despite increases in plasma free fatty acids (+62.4%; F = 5.65, P = .005 vs S20 and S80), plasma triglycerides (-29.4%; F = 6.88, P = .002 vs S20 and S80), and very-low-density lipoprotein (-44.2%; F = 7.94, P < .001 vs S20 and S80), levels were reduced by S20/N. S20/N increased HDL-cholesterol levels (+18.1%) as compared to S20 (0%) and S80 (+5.9%) (P < .001 vs both statin arms), largely due to an increase in HDL particle size (+4.6%; P = .01 vs both statin arms).ConclusionsWe demonstrate that full-dose niacin/moderate-dose simvastatin combination has sustained benefits on atherogenic apoB lipoproteins, at least comparable to high-dose simvastatin, while also raising HDL-cholesterol. Results of large clinical trials will inform whether niacin-statin combinations reduce cardiovascular disease events.
| S-EPMC3088112 | biostudies-literature
Project description:The progression of atherosclerosis remains a major cause of morbidity and mortality. Plaque formation is an immunological response driven by a number of risk factors, and reduction of risk is the primary goal of treatment. The role of LDL-C is well established and statins have proved effective drugs, although the relative risk reduction is only around 30%. The importance of other factors-notably low HDL-C and high TGs-has become increasingly clear and the search for alternative strategies continues. Niacin is particularly effective in achieving normalization of HDL-C but is clinically underutilized due to the side effect of cutaneous flushing. The discovery that flushing is mediated by mechanisms distinct from the lipid-lowering effects has led to the development of combination drugs with reduced side effects. This review considers the evidence regarding the clinical efficacy of extended-release niacin and the DP1 antagonist laropiprant in the treatment of hypercholesterolemia and mixed dyslipidemias.
| S-EPMC3201109 | biostudies-other