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

Merck Research Laboratories, Rahway, NJ, USA.
The American Journal of Cardiology (Impact Factor: 3.28). 04/2008; 101(5):625-30. DOI: 10.1016/j.amjcard.2007.10.023
Source: PubMed


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.

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    • "ER niacin is associated with a lower frequency, intensity, and duration of flushing than immediate release niacin [96–98]. Laropiprant is an antagonist of the DP1 receptor, inhibits cutaneous flushing and significantly improves the tolerability of niacin by over 50% [96, 97]. "
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    ABSTRACT: The key role of dyslipidaemia in determining cardiovascular disease (CVD) has been proved beyond reasonable doubt, and therefore several dietary and pharmacological approaches have been developed. The discovery of statins has provided a very effective approach in reducing cardiovascular risk as documented by the results obtained in clinical trials and in clinical practice. The current efficacy of statins or other drugs, however, comes short of providing the benefit that could derive from a further reduction of LDL cholesterol (LDL-C) in high-risk and very high risk patients. Furthermore, experimental data clearly suggest that other lipoprotein classes beyond LDL play important roles in determining cardiovascular risk. For these reasons a number of new potential drugs are under development in this area. Aim of this review is to discuss the available and the future pharmacological strategies for the management of dyslipidemia.
    Full-text · Article · Sep 2012
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    • "These figures are similar to those observed with niacin alone, indicating that laropiprant does not attenuate the lipid benefits. Paolini and colleagues4,100 also looked at the impact of ERN/laropiprant on lipid levels and blood pressure although this was a short term study more concerned with safety and tolerability. A drop in LDL-C of 15% was observed, as was an increase in HDL-C of 20%. "
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    ABSTRACT: 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.
    Preview · Article · Sep 2011 · Clinical Medicine Insights: Cardiology
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    • "In studies evaluating the combination of niacin with laropiprant on flushing it was shown that the rate of flushing was significantly decreased compared to patients on niacin without laropiprant.46–49,51 In the group using additional laropiprant the rate of flushing was decreased to placebo level after approximately 3 months while it remained elevated in patients using niacin without laropiprant. "
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    ABSTRACT: Although statins reduce cardiovascular morbidity and mortality further risk reduction is needed. In this respect low HDL-cholesterol concentrations and/or elevated triglyceride concentrations may be potential treatment targets. Niacin (nicotinic acid) is an effective drug which increases the plasma concentration of high-density lipoprotein (HDL)-cholesterol and decreases the concentration of low-density lipoprotein (LDL)-cholesterol, triglycerides and lipoprotein(a). Clinical studies indicate that niacin can significantly reduce the risk for cardiovascular events. However, niacin is not very commonly used because of significant side effects (especially flushing). Laropiprant is a potent selective antagonist of PGD2-receptor subtype-1 and can thus reduce niacin-induced flushing. Although the addition of laropiprant will reduce the frequency of flushing, it will not completely eliminate this side effect. Laropiprant does not change the effect of niacin on lipids or other side effects of niacin (ie, gastro-intestinal problems, glucose elevation). The combination of niacin with laropiprant may therefore enable use of niacin at higher doses and therefore exploit the full potential of the drug. Endpoint studies that will be published over the next few years will show whether this treatment modality also translates into clinical effect in patients treated with statins. Until publication of these studies niacin/laropiprant should be used only in high-risk patients not achieving lipid goals on statins.
    Preview · Article · Nov 2009 · Vascular Health and Risk Management
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