R e v i e w P a p e r

Mechanisms of Flushing Due to Niacinand Abolition of These Effects

Aditya Sood, BS; Rohit Arora, MD

There are many factors that increase the risk ofcardiovascular disease, and a prominent factoramong these is dyslipidemia. The following litera-ture review focuses on the use of niacin therapyin order to treat dyslipidemia and how to controlthe associated ‘‘niacin flush.’’ The associatedstudies gathered are reviews and randomized con-trol trials. They were obtained by using electronicsearches. Certain keywords took precedence, andarticles focusing on niacin therapy were chosen.Recent research has found promising insight intomore effective prevention of the niacin-mediatedflush through a selective antagonist for the pros-taglandin D2 receptor, laropiprant. Aspirin (orNSAIDs) also provide some prevention for flush-ing, although recent studies have shown that it isnot as effective as laropiprant. There is a needfor further research in order to come to a clearconclusion regarding combined therapies ofaspirin and laropiprant pretreatment, as well asexact dosage requirements. J Clin Hypertens(Greenwich). 2009;11:685–689. ª2009 Wiley

Periodicals, Inc.

Niacin, also known as nicotinic acid and vita-min B3, is a colorless, water-soluble solid

that has been known to have many pharmaco-logic uses. When niacin is taken in large doses, itblocks the breakdown of fats in adipose tissue,therefore altering the lipid levels of blood. Niacinmay be used in treating hyperlipidemia because itlowers very-low-density lipoprotein cholesterol(VLDL-C), which is a precursor of low-densitylipoprotein cholesterol (LDL-C), or ‘‘bad’’ choles-terol. Due to its inhibitory effects on breakdownof fats, niacin causes a decrease in free fatty acidsin the blood, therefore decreasing secretion ofVLDL-C and cholesterol by the liver.

Also, by lowering VLDL-C levels in the blood,niacin increases the level of high-density lipoproteincholesterol (HDL-C), or ‘‘good’’ cholesterol. There-fore, niacin serves a purpose in helping patients withlow HDL-C levels who are at high risk for myocar-dial infarction. Niacin was the first lipid drug shownto prevent cardiovascular disease and death in alarge-scale placebo-controlled trial.1 It has mainlybeen the HDL-C–elevating effects of nicotinic acidthat recently led to a renewed interest in this drug.2–4

There are a variety of extended-release formulationsof niacin in the market. Statins are the most potentcholesterol-reducing agents available, reducing LDL-C, or ‘‘bad’’ cholesterol by almost 30% to 50%.However, they have less of an effect than niacin andfibrates in reducing triglyceride levels and raisinglevels of HDL-C, or ‘‘good’’ cholesterol. Whenniacin therapy was used in combination with sim-vastatin (belonging to the class of statins), it reducedclinical cardiovascular events by as much as 80%.5

PROBLEMSOne of the inherent problems with niacin therapy toprevent severe cardiovascular issues due to highcholesterol are the side effects that occur with the

From the Chicago Medical School ⁄ North ChicagoVeterans Affairs, North Chicago, ILAddress for correspondence:Aditya Sood, BS, Chicago Medical School ⁄ NorthChicago Veterans Affairs, 3001 Green Bay Road,North Chicago, IL, 60064E-mail: aditya.sood@my.rfums.orgManuscript received June 17, 2008; revised September 3,2008; accepted November 4, 2008

doi: 10.1111/j.1559-4572.2008.00050.x

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pharmacologic doses of niacin administered. Facialflushing is the most common reported side effect inpatients. This effect is essentially mediated by prosta-glandin D2 and its effects on dilation of small bloodvessels. The ‘‘niacin flush’’ consists of skin reddening,itching, and ⁄or burning starting 10 to 20 minutesafter oral ingestion of the drugs and lasting about 60to 90 minutes.6 This cutaneous vasodilation occurs in70% to 100% of patients in clinical trials and cases,and many patients are forced to discontinue the medi-cation due to the severe flushing of the face and upperbody.7,8 It is important that these effects are con-trolled in order to allow treatment of such conditionsas dyslipidemia.

There has been much advancement in the pre-ventative methods of flushing with niacin intake.This research study will discuss how some of thesemechanisms may be used to best control, eliminate,and ⁄or prevent flushing. It is critical to recognizethat flushing is a frequent event with niacin admin-istration that can be managed with adequate physi-cian and patient education.

EFFECT ON RATE OF NIACINADMINISTRATION AND ITS METABOLISMIn an experiment conducted in 12 healthy males, adose-escalation study was performed with 2000 mgniacin administered at 3 different dosing rates:slow, intermediate, and fast.9 Plasma and urinewere subsequently analyzed to determine the phar-macokinetics of niacin and its metabolites. It wasfound that the maximum plasma concentration andout-of-sample predictive ability for niacin and nico-tinuric acid (NUA) increased with the dosing rate,suggesting that the amount of niacin absorbedincreased, or that clearance of niacin decreased, asthe dosing rate increased.9 Niacin is used both inthe immediate- and extended-release formulationsfor treatment of dyslipidemia. The rate of niacinadministration is believed to affect the adverseevent profile, most likely by influencing its meta-bolic profile.9 It can be interpreted that an increasein the niacin dosing rate (reflecting a more immedi-ate release) may lead to an increase in total expo-sure to niacin and NUA, although total doseadministered was the same.9 Immediate-release nia-cin has been associated with cutaneous flushing,whereas sustained-release formulations have beenassociated with hepatotoxicity.8,10,11

In studies pertaining to niacin extended-releasetablets, dated 1998, there was one reference to‘‘prolonged-release’’ nicotinic acid reducing the inci-dence of flushing within the first 2 weeks of treat-ment by more than 50%, compared with

immediate-release nicotinic acid.12 Also, the inci-dence of flushing was shown to decrease furtherwith continued therapy. In a 96-week study usingnicotinic acid, 1.9 episodes ⁄patient ⁄month duringthe first 4 weeks of treatment had decreased to0.19 episodes ⁄patient ⁄month by the end of thestudy.7 Niacin is involved in extensive metabolismvia 2 major pathways.13–18 The first pathway is viaglycine conjugation with niacin to form NUA,which is responsible for the flushing effect ofniacin. The second pathway involves formation ofnicotinamide adenine dinucleotide, which is respon-sible for the majority of hepatotoxicity. The mecha-nism behind nicotinic acid action is as follows:Nicotinic acid binds to high-affinity G-protein–cou-pled receptors expressed in adipose tissue.19–21 TheG inhibitory–coupled receptor decreases cAMPlevels and therefore inhibits lipolysis. When thishappens, there is a reduced circulating level of non-esterified fatty acids, which are precursorsfor hepatic triacylglycerol synthesis and, thus,VLDL-C.22,23

MEDIATION OF NICOTINIC ACID–INDUCED FLUSHINGAs mentioned previously, nicotinic acid–inducedcutaneous vasodilation, or flushing, is one of themajor problems with the therapeutic use of thisdrug, as it develops in virtually every patient takingnicotinic acid. In a few studies, it was determinedthat nicotinic acid–induced flushing is mediated bythe GPR109 NA receptor and involves the forma-tion of vasodilatory prostanoids, which mediate notonly the short-term metabolic effects but also theflushing response.24,25 Studies have also pointed toepidermal langerhans cells as essential for the cuta-neous flushing response by nicotinic acid; theyrespond to an increase in intracellular calcium con-centration due to nicotinic acid, and they expressprostanoid synthases required for the formation ofvasodilatory prostanoids, including prostaglandinE2 (PGE2) and prostaglandin D2 (PGD2).2 Thecalcium increase is the major trigger for activationof phospholipase A2 and the subsequent formationof arachidonic acid, which is further metabolizedby cyclooxygenase-1 and PGE2 and PGD2 synthas-es to create the vasodilatory prostanoids. It hasbeen shown in experiments that depletion of theseepidermal langerhans cells but not of macrophagesof dendritic cells ablates nicotinic acid–inducedflushing.2 Therefore, from the study mentioned, itwould seem as though epidermal langerhans cells,besides their immunologic role, are essential media-tors of nicotinic acid–induced flushing or local

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regulation of blood flow. This is an important find-ing that shows potential for a generation of newstrategies to suppress unwanted effects.

It has also been hypothesized that macrophagesare the source of nicotinic acid–induced PGD2secretions. The epidermal langerhans cells men-tioned above are similar in morphology and func-tion to macrophages and are also similarly derivedfrom monocytes. Nicotinic acid (0.1–0.3 mmol ⁄L)induced PGD2 secretion in cultured human macro-phages but not in monocytes or endothelial cells.26

Preincubation of the cells with aspirin (100mmol ⁄L) entirely prevented the PGD2 side effects(see below for effects of acetylsalicylic acid [ASA]).This study provides some evidence that macro-phages play a significant role in mediating theniacin flush and may also lead to better strategiesto eliminate this limiting side effect.26

Another study, conducted in 2006, screened alarge set of human tissue and cells for the expres-sion of GPR109A and characterized them by usingimmunocytochemistry with antibodies and specificcell markers, then assayed them for PGD2 releasefollowing nicotinic acid stimulation.27 The resultsmaintained that langerhans cells specifically respondto nicotinic acid by releasing PGD2, which thenactivates vascular cells and causes cutaneous vaso-dilation. The GPR109A mRNA distribution in pri-mary tissues was primarily expressed in a variety ofimmune cell types and epidermis, but it was notdetected in endothelial cells, smooth muscle cells,dermal fibroblasts, or dermis.27

In a more recent study, it was asked whether per-oxisome proliferator-activated receptor a (PPARa)activation modulates epidermal langerhans cellfunction.28 The results showed that PPARa isexpressed in immature langerhans cells and isdown-regulated in mature langerhans cells, suggest-ing that an early decrease in PPARa expression inthe cells may allow them to mature. It was alsoconcluded that PPARa activation by endogenousligands may provide a molecular signal that allowslangerhans cells to remain in an immature statewithin the epidermis for extended periods of timedespite minor environmental stimuli.28 SincePPARa activity can also be modulated by exoge-nous compounds, it is also a promising drug targetin inflammatory skin diseases.

The most recent data on niacin’s mechanism ofaction indicate that it directly inhibits hepaticdiacylglycerol acyltransferase 2, resulting in aninhibition of triglyceride synthesis and decreasedapolipoprotein B–containing lipoproteins.29 Byinhibiting the surface expression of hepatic ATP

synthase b chain, niacin decreases hepatic holopar-ticle high-density lipoprotein catabolism and raisesHDL-C levels. Niacin also increases redox potentialin arterial endothelial cells, resulting in the inhibi-tion of redox-sensitive genes. These recent findingsmay help to better explain the multiple actions ofniacin.29

EVIDENCE FOR USE OF ASA (ASPIRIN)It was determined decades ago that the flushingresponse of nicotinic acid can be inhibited by pre-treatment with cyclooxygenase inhibitors.15,29–31 Itis known that flushing due to nicotinic acid is med-iated by prostaglandins, and because ASA (aspirin)is an effective inhibitor of prostaglandin synthesis,it has been used and has been successful in prevent-ing or reducing the severity of niacin-induced flush-ing, even currently. Although the recommendationto use ASA is supported by both pharmacologicevidence and experience from clinical studies, it isdifficult to determine the relationship betweenASA dose and efficacy in reducing the intensity ⁄frequency of flushing.32

Some studies suggest that a low dose (80 mg) ofASA would be ineffective,33 although most studiesuse a 325-mg dose and presume full effective-ness. According to Niaspan (Abbott Laboratories,Abbott Park, IL) prescribing information, adminis-tration guidelines for extended-release niacin indi-cate that flushing can be minimized by careful doseescalation, administration of extended-release niacinat bedtime with administration of ASA 30 minutesprior, and avoiding taking the drug on an emptystomach. The manufacturers of Niaspan have alsostated that <6% of their patients discontinue usebecause of flushing.34 Daily use of ASA and ⁄orother NSAIDs in doses of at least 325 mg 30 min-utes before niacin administration is required, anddue to this there may be a potential limit to long-term use.35–38 An example of a limiting effectwould be the onset of gastrointestinal bleeding orgeneralized prolonged bleeding time.

SUPPRESSION OF FLUSHING WITH ANANTAGONIST TO PGD2 RECEPTORSUBTYPE 1Laropiprant is a selective antagonist of the PGD2receptor subtype 1 (DP1) that may be involved inthe mediation of niacin-induced flushing. It hasbeen shown that the coadministration of laro-piprant at doses of 30, 100, or 300 mg withextended-release niacin significantly lowered flush-ing symptom scores (by approximately �50%) andalso significantly decreased malar skin blood flow

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as measured by laser Doppler perfusion imaging.39

These experiments concluded that the DP1 receptorantagonist laropiprant was effective in suppressingboth subjective and objective manifestations of nia-cin-induced vasodilation.39 The results also showedthat laropiprant 300 mg and extended-release nia-cin 1500 mg resulted in less flushing and warmthcompared with pretreatment with ASA 325 mgbefore administration of extended-release niacin1500 mg. The laropiprant decreased by 75% thepeak increase in skin blood flow that was inducedby extended-release niacin alone. The fact thatpretreatment with ASA (at 325 mg 30 minutesbefore niacin administration) was less effective thancoadministration with laropiprant (100 or 300 mg)provides great insight into where the future ofniacin treatment may be headed.39

The evaluation of safety, tolerability, pharmaco-kinetics, and pharmacodynamics of single and mul-tiple oral doses of laropiprant in healthy malevolunteers was conducted in another study.40 Itwas found that single doses up to 900 mg andmultiple doses up to 450 mg were generally welltolerated. The results exhibited dose-proportionalpharmacokinetics and also were not affected byfood. The oral absorption is rapid (2–8 hours), andthe terminal half-life is approximately 12 to 18hours.40 There were also no serious adverse effectsassociated with usage and no discontinuations dueto adverse effects.40

A more recent phase 2 dose-ranging study wasdesigned to assess whether laropiprant wouldreduce extended-release niacin–induced flushing indyslipidemic patients and support an acceleratedextended-release niacin dosing paradigm: initiatingextended-release niacin at 1 g and advancing rap-idly to 2 g.41 In part A of the study, 154 dyslipi-demic patients were randomized to laropiprant 150mg ⁄d or placebo in a 9-week 2-period crossoverstudy. Patients who completed part A (n=122)entered part B (with a 2-week washout), togetherwith additional patients who entered part B directly(n=290). Part B patients were randomized to pla-cebo, extended-release niacin 1 g (no previous titra-tion), or extended-release niacin 1 g coadministeredwith laropiprant 18.75, 37.5, 75, or 150 mg for 4weeks, with doubling of the respective doses for theremaining 4 weeks. Patients treated with laropip-rant and extended-release niacin experienced signifi-cantly less extended-release niacin–induced flushingthan those treated with extended-release niacinalone during the initiation of treatment (extended-release niacin 1 g, week 1) and the maintenancetreatment (extended-release niacin 1–2 g, weeks

2–8).41 It can be concluded that all doses of laro-piprant were maximally effective in inhibitingniacin-induced flushing without altering the benefi-cial lipid effects of the extended-release niacin.Overall, the significant reduction in extended-release niacin–induced flushing provided by laro-piprant plus extended-release niacin supports anaccelerated extended-release niacin dose advance-ment paradigm to achieve rapidly a 2-g dose indyslipidemic patients.41 A possible advantage ofusing laropiprant over ASA is that NSAIDs affectplatelet aggregation and cause an increase in bleed-ing time compared with placebo, while laropiprantdoes not (following single doses up to 400 mg ormultiple doses up to 450 mg).40

CONCLUSIONSNiacin lowers triglyceride and LDL-C levels andraises HDL-C levels. Current treatment for dyslipi-demia via niacin therapy is restricted in a sensebecause the flushing response seen in most patientsleads to discontinued use after a short period oftime. While ASA pretreatment has allowed for thecontinuation of niacin treatment in many cases,there are potential long-term complications thatmay arise if used for long periods of time, includinggastrointestinal bleeding and prolonged bleedingtime. The selective antagonist of the PGD2 receptorsubtype 1 (DP1), laropiprant, holds much promisein enhancing the tolerability of and compliancewith niacin treatment for patients with cardiovascu-lar disease or dyslipidemia. While substantial strideshave been made in niacin therapy and its associa-tions with dyslipidemia, there is a need for furtherresearch, especially in terms of event-based trials.

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