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Background and Objective: Niacin is a highly effective agent for increasing low high-density lipoprotein cholesterol (HDL-C) levels. It also has beneficial effects on key pro-atherogenic lipoprotein parameters. However, the side effect of flushing can challenge patient adherence to treatment. In this study, we pooled safety data from available trials of at least 16 weeks' duration to evaluate the impact of flushing on patient adherence to niacin extended-release (NER) therapy., Methods: Data were pooled from eight NER studies (administered as NER with a maximum dosage of 1000, 1500, and 2000 mg/day, either as monotherapy or in combination with simvastatin 20 or 40 mg/day [NER/S], or lovastatin 20 or 40 mg/day [NER/L]) to evaluate rates of study discontinuation due to flushing or any treatment-related adverse events., Results: While 66.6% of patients experienced flushing, only 5.2% of patients discontinued treatment due to flushing. Of the total number of patients treated with NER (n = 307), NER/S (n = 912), or NER/L (n = 928), 34 (11%), 105 (11%), and 127 (14%) patients discontinued due to any treatment-related adverse event, respectively, while 14 (5%), 43 (5%), and 55 (6%) discontinued due to flushing. Discontinuation for flushing did not differ with regard to maximum dose, or to the presence or type of statin combined with NER., Conclusion: Although flushing was common with NER treatment, discontinuation due to flushing occurred in only 5-6% of patients in this pooled analysis. This could be due to several factors, including the fact that all patients in the NER trials were educated about flushing and its management. Translation of methodology employed in these trials into clinical practice may improve long-term adherence to NER therapy, which would enhance the therapeutic benefit of NER for reducing cardiovascular risk.

Background: Niacin extended-release (NER) is safe and effective for treatment of dyslipidemia. However, some patients discontinue NER treatment because of flushing, the most common adverse event associated with niacin therapy., Objective: To evaluate the effect of daily oral acetylsalicylic acid (ASA) on NER-induced flushing in patients with dyslipidemia., Methods: A randomized, double-blind, placebo-controlled, multicenter, 5-week study was conducted (ClinicalTrials.gov identifier: NCT00626392). Patients (n = 277) were randomly assigned to one of six treatment arms and received a 1-week run-in with ASA 325 mg or placebo followed by 4 weeks of ASA 325 mg or placebo 30 minutes before NER at a starting dose of 500 mg or 1000 mg; all patients were titrated to NER 2000 mg at week 3. The primary endpoint was the maximum severity of flushing events during week 1., Results: In week 1, ASA run-in, ASA pretreatment, and a lower starting dosage of NER (500 mg/day) resulted in reductions in mean maximum severity of flushing; 48% fewer patients who received ASA experienced flushing episodes of moderate or greater intensity relative to placebo (absolute rates 15% vs 29%; p = 0.01). Over 4 weeks, ASA reduced the number of flushing episodes/patient/week by 42% relative to placebo. The discontinuation rate due to flushing was lower in the ASA group compared with placebo (1.8% vs 9.4%; p = 0.007). Overall safety was not different between groups., Conclusion: These data suggest that a clinically meaningful reduction in the severity and incidence of NER-induced flushing may be achieved with ASA use.

Introduction: High-dose HMG-CoA reductase inhibitors (statins) fail to prevent approximately two-thirds of cardiovascular events. This fact has focused increased attention on treating abnormalities of non-high-density lipoprotein-cholesterol (non-HDL-C), HDL-C, and triglycerides in national guidelines and has intensified interest in combination therapy., Methods: The OCEANS study (Open-label evaluation of the safety and efficacy of a Combination of niacin ER and simvAstatin in patieNts with dySlipidemia; ClinicalTrials.gov identifier: NCT00080275) evaluated the safety and efficacy of a combination of niacin extended release and simvastatin (NER/S; SIMCOR) over 52 weeks in 520 patients with mixed dyslipidemia. After a >or=4-week run-in phase of diet modification and simvastatin 40 mg/day, median baseline values (mg/dL) were: non-HDL-C = 141, low-density lipoprotein-cholesterol (LDL-C) = 110, HDL-C = 45, and triglyceride = 151. Patients were randomized to an 8- or 12-week niacin titration scheme to a maximum NER/S dosage of 2,000/40 mg/day., Results: Differences between titration groups in tolerability, safety, and efficacy were minimal; therefore, all results are for pooled titration groups. The safety of NER/S was consistent with the safety profile of each individual component. Treatment with NER/S was well tolerated: 71% of patients experienced flushing and 92% of flushing episodes were mild or moderate in intensity. Overall, 61% of patients experienced flushing episodes that were rated as mild or moderate in intensity. Flushing decreased over time: <40% of those who had flushing during titration experienced flushing during the final 12 weeks. A total of 20% of patients discontinued treatment because of a treatment-related adverse event, including 7% who discontinued because of flushing. Median changes from baseline (following the simvastatin 40 mg/day run-in phase) to 24 weeks were: non-HDL-C = -27.3%, LDL-C = -25.0%, HDL-C = +23.9%, and triglycerides = -35.9% (all p < 0.0001 vs baseline). In lipid-treatment-naive patients, NER/S 2,000/40 mg/day decreased non-HDL-C, LDL-C, and triglycerides by approximately 50% and increased HDL-C by approximately 25% when week-24 lipid values were compared with lipid values obtained prior to the simvastatin 40 mg/day run-in. All three therapeutic lipid targets (LDL-C [risk-adjusted goal], HDL-C >or=40 mg/dL, and triglycerides <150 mg/dL) were achieved concurrently by 65% of patients treated with NER/S., Conclusion: Treatment with NER/S 2,000/40 mg/day is well tolerated, has no unanticipated adverse events, and provides additional, clinically relevant improvements in multiple lipid parameters beyond statin monotherapy.

Plasma levels of high-density lipoprotein-cholesterol (HDL-C) are a powerful independent cardiovascular risk factor, bearing an inverse relationship with atherosclerotic cardiovascular disease (with risk rising sharply when levels are <1.04 mmol/L). Apart from its protective role in atherosclerosis, HDL-C increases fibrinolysis, is an antioxidant to low density lipoprotein-cholesterol (LDL-C), and decreases platelet aggregability. Up to a third of patients with atherosclerotic cardiovascular disease have 'desirable' plasma levels of total cholesterol but low HDL-C levels. Benefits of treating low plasma HDL-C levels were clearly demonstrated in the Veterans Affairs HDL Intervention Trial (VA-HIT) where gemfibrozil reduced nonfatal infarcts and coronary deaths by 22%. This was achieved by a 6% increase in plasma HDL-C levels, and a 24.5% decrease in plasma levels of triglycerides, without any significant decrease in LDL-C levels. Multivariate analyses revealed the rise in plasma HDL-C levels after treatment, but not decreases in plasma levels of triglycerides or LDL-C, predicted coronary artery disease events. The typical patient under consideration in this article is one with plasma levels of HDL-C <1 mmol/L, LDL-C <3.37 mmol/L [either receiving therapeutic lifestyle changes or or LDL-C-lowering therapy comprising a hydroxymethylglutaryl coenzyme-A (HMG-CoA) reductase inhibitor or bile acid sequestrant] and fasting triglycerides <2.26 mmol/L. We propose this dyslipidemia be classified as Type VI phenotype following the Frederickson and Lees classification. High-risk patients (with >/=2 risk factors for atherosclerotic cardiovascular disease, or 10-year cardiovascular risk >20%), patients with established atherosclerotic cardiovascular disease, or type 2 diabetes mellitus, or metabolic syndrome should receive pharmacotherapy. Plasma HDL-C levels >1.16 mmol/L may be considered optimal and between 1 and 1.16 mmol/L as desirable. Fibric acid derivatives, nicotinic acid, HMG-CoA reductase inhibitors, estrogens, and ethanol (not recommended as therapy) increase plasma HDL-C levels. Nicotinic acid is the most potent agent and recent reports indicate that, in contrast to gemfibrozil, it selectively increases antiatherogenic HDL subfraction, lipoprotein (Lp) AI (without apolipoprotein AII), in patients with low plasma HDL-C levels. An extended-release formulation, administered once daily, has improved the tolerability of nicotinic acid. Recent evidence also indicates that nicotinic acid may effectively correct dyslipidemia in patients with diabetes mellitus without significantly compromising glycemic control. Fibric acid derivatives and estrogen raise plasma HDL-C levels by different mechanisms of action, and these agents may be used with nicotinic acid. Combination therapy (especially HMG-CoA reductase inhibitor and nicotinic acid) should be considered in patients with atherosclerotic cardiovascular disease and low plasma HDL-C levels.