Review Paper

Mechanisms of Flushing Due to and Abolition of These Effects

Aditya Sood, BS; Rohit Arora, MD

There are many factors that increase the risk of that has been known to have many pharmaco- cardiovascular disease, and a prominent factor logic uses. When niacin is taken in large doses, it among these is dyslipidemia. The following litera- blocks the breakdown of fats in adipose tissue, ture review focuses on the use of niacin therapy therefore altering the lipid levels of blood. Niacin in order to treat dyslipidemia and how to control may be used in treating hyperlipidemia because it the associated ‘‘niacin flush.’’ The associated lowers very-low-density lipoprotein cholesterol studies gathered are reviews and randomized con- (VLDL-C), which is a precursor of low-density trol trials. They were obtained by using electronic lipoprotein cholesterol (LDL-C), or ‘‘bad’’ choles- searches. Certain keywords took precedence, and terol. Due to its inhibitory effects on breakdown articles focusing on niacin therapy were chosen. of fats, niacin causes a decrease in free fatty acids Recent research has found promising insight into in the blood, therefore decreasing secretion of more effective prevention of the niacin-mediated VLDL-C and cholesterol by the . flush through a selective antagonist for the pros- Also, by lowering VLDL-C levels in the blood, taglandin D2 , laropiprant. (or niacin increases the level of high-density lipoprotein NSAIDs) also provide some prevention for flush- cholesterol (HDL-C), or ‘‘good’’ cholesterol. There- ing, although recent studies have shown that it is fore, niacin serves a purpose in helping patients with not as effective as laropiprant. There is a need low HDL-C levels who are at high risk for myocar- for further research in order to come to a clear dial infarction. Niacin was the first lipid drug shown conclusion regarding combined therapies of to prevent cardiovascular disease and death in a aspirin and laropiprant pretreatment, as well as large-scale placebo-controlled trial.1 It has mainly exact dosage requirements. J Clin Hypertens been the HDL-C–elevating effects of nicotinic acid 2–4 (Greenwich). 2009;11:685–689. ª2009 Wiley thatrecentlyledtoarenewedinterestinthisdrug. Periodicals, Inc. There are a variety of extended-release formulations of niacin in the market. are the most potent cholesterol-reducing agents available, reducing LDL- iacin, also known as nicotinic acid and vita- C, or ‘‘bad’’ cholesterol by almost 30% to 50%. min B , is a colorless, water-soluble solid N 3 However, they have less of an effect than niacin and fibrates in reducing triglyceride levels and raising From the Chicago Medical School ⁄ North Chicago levels of HDL-C, or ‘‘good’’ cholesterol. When Veterans Affairs, North Chicago, IL niacin therapy was used in combination with sim- Address for correspondence: vastatin (belonging to the class of statins), it reduced Aditya Sood, BS, Chicago Medical School ⁄ North 5 Chicago Veterans Affairs, 3001 Green Bay Road, clinical cardiovascular events by as much as 80%. North Chicago, IL, 60064 E-mail: [email protected] PROBLEMS Manuscript received June 17, 2008; revised September 3, One of the inherent problems with niacin therapy to 2008; accepted November 4, 2008 prevent severe cardiovascular issues due to high doi: 10.1111/j.1559-4572.2008.00050.x cholesterol are the side effects that occur with the

VOL. 11 NO. 11 NOVEMBER 2009 THE JOURNAL OF CLINICAL HYPERTENSION 685 pharmacologic doses of niacin administered. Facial immediate-release nicotinic acid.12 Also, the inci- flushing is the most common reported side effect in dence of flushing was shown to decrease further patients. This effect is essentially mediated by prosta- with continued therapy. In a 96-week study using glandin D2 and its effects on dilation of small blood nicotinic acid, 1.9 episodes ⁄patient ⁄month during vessels. The ‘‘niacin flush’’ consists of skin reddening, thefirst4weeksoftreatmenthaddecreasedto itching, and ⁄or burning starting 10 to 20 minutes 0.19 episodes ⁄patient ⁄month by the end of the after oral ingestion of the drugs and lasting about 60 study.7 Niacin is involved in extensive metabolism to 90 minutes.6 This cutaneous occurs in via 2 major pathways.13–18 The first pathway is via 70% to 100% of patients in clinical trials and cases, glycine conjugation with niacin to form NUA, and many patients are forced to discontinue the medi- which is responsible for the flushing effect of cation due to the severe flushing of the face and upper niacin. The second pathway involves formation of body.7,8 It is important that these effects are con- nicotinamide adenine dinucleotide, which is respon- trolled in order to allow treatment of such conditions sible for the majority of hepatotoxicity. The mecha- as dyslipidemia. nism behind nicotinic acid action is as follows: There has been much advancement in the pre- Nicotinic acid binds to high-affinity G-protein–cou- ventative methods of flushing with niacin intake. pled receptors expressed in adipose tissue.19–21 The This research study will discuss how some of these G inhibitory–coupled receptor decreases cAMP mechanisms may be used to best control, eliminate, levels and therefore inhibits lipolysis. When this and ⁄or prevent flushing. It is critical to recognize happens, there is a reduced circulating level of non- that flushing is a frequent event with niacin admin- esterified fatty acids, which are precursors istration that can be managed with adequate physi- for hepatic triacylglycerol synthesis and, thus, cian and patient education. VLDL-C.22,23

EFFECT ON RATE OF NIACIN MEDIATION OF NICOTINIC ACID– ADMINISTRATION AND ITS METABOLISM INDUCED FLUSHING In an experiment conducted in 12 healthy males, a As mentioned previously, nicotinic acid–induced dose-escalation study was performed with 2000 mg cutaneous vasodilation, or flushing, is one of the niacin administered at 3 different dosing rates: major problems with the therapeutic use of this slow, intermediate, and fast.9 Plasma and urine drug, as it develops in virtually every patient taking were subsequently analyzed to determine the phar- nicotinic acid. In a few studies, it was determined macokinetics of niacin and its metabolites. It was that nicotinic acid–induced flushing is mediated by found that the maximum plasma concentration and the GPR109 NA receptor and involves the forma- out-of-sample predictive ability for niacin and nico- tion of vasodilatory , which mediate not tinuric acid (NUA) increased with the dosing rate, only the short-term metabolic effects but also the suggesting that the amount of niacin absorbed flushing response.24,25 Studies have also pointed to increased, or that clearance of niacin decreased, as epidermal langerhans cells as essential for the cuta- the dosing rate increased.9 Niacin is used both in neous flushing response by nicotinic acid; they the immediate- and extended-release formulations respond to an increase in intracellular calcium con- for treatment of dyslipidemia. The rate of niacin centration due to nicotinic acid, and they express administration is believed to affect the adverse synthases required for the formation of event profile, most likely by influencing its meta- vasodilatory prostanoids, including bolic profile.9 It can be interpreted that an increase E2 (PGE2) and (PGD2).2 The in the niacin dosing rate (reflecting a more immedi- calcium increase is the majortriggerforactivation ate release) may lead to an increase in total expo- of phospholipase A2 and the subsequent formation sure to niacin and NUA, although total dose of , which is further metabolized administered was the same.9 Immediate-release nia- by -1 and PGE2 and PGD2 synthas- cin has been associated with cutaneous flushing, es to create the vasodilatory prostanoids. It has whereas sustained-release formulations have been been shown in experiments that depletion of these associated with hepatotoxicity.8,10,11 epidermal langerhans cells but not of macrophages In studies pertaining to niacin extended-release of dendritic cells ablates nicotinic acid–induced tablets, dated 1998, there was one reference to flushing.2 Therefore, from the study mentioned, it ‘‘prolonged-release’’ nicotinic acid reducing the inci- would seem as though epidermal langerhans cells, dence of flushing within the first 2 weeks of treat- besides their immunologic role, are essential media- ment by more than 50%, compared with tors of nicotinic acid–induced flushing or local

686 THE JOURNAL OF CLINICAL HYPERTENSION VOL. 11 NO. 11 NOVEMBER 2009 regulation of blood flow. This is an important find- synthase b chain, niacin decreases hepatic holopar- ing that shows potential for a generation of new ticle high-density lipoprotein catabolism and raises strategies to suppress unwanted effects. HDL-C levels. Niacin also increases redox potential It has also been hypothesized that macrophages in arterial endothelial cells, resulting in the inhibi- are the source of nicotinic acid–induced PGD2 tion of redox-sensitive genes. These recent findings secretions. The epidermal langerhans cells men- may help to better explain the multiple actions of tioned above are similar in morphology and func- niacin.29 tion to macrophages and are also similarly derived from monocytes. Nicotinic acid (0.1–0.3 mmol ⁄L) EVIDENCE FOR USE OF ASA (ASPIRIN) inducedPGD2secretioninculturedhumanmacro- It was determined decades ago that the flushing phages but not in monocytes or endothelial cells.26 response of nicotinic acid can be inhibited by pre- Preincubation of the cells with aspirin (100 treatment with cyclooxygenase inhibitors.15,29–31 It mmol ⁄L) entirely prevented the PGD2 side effects is known that flushing due to nicotinic acid is med- (see below for effects of acetylsalicylic acid [ASA]). iated by , and because ASA (aspirin) This study provides some evidence that macro- is an effective inhibitor of prostaglandin synthesis, phages play a significant role in mediating the it has been used and has been successful in prevent- niacin flush and may also lead to better strategies ing or reducing the severity of niacin-induced flush- to eliminate this limiting side effect.26 ing, even currently. Although the recommendation Another study, conducted in 2006, screened a to use ASA is supported by both pharmacologic large set of human tissue and cells for the expres- evidence and experience from clinical studies, it is sion of GPR109A and characterized them by using difficult to determine the relationship between immunocytochemistry with antibodies and specific ASA dose and efficacy in reducing the intensity ⁄ cell markers, then assayed them for PGD2 release frequency of flushing.32 following nicotinic acid stimulation.27 The results Some studies suggest that a low dose (80 mg) of maintained that langerhans cells specifically respond ASA would be ineffective,33 although most studies to nicotinic acid by releasing PGD2, which then use a 325-mg dose and presume full effective- activates vascular cells and causes cutaneous vaso- ness. According to Niaspan (Abbott Laboratories, dilation. The GPR109A mRNA distribution in pri- Abbott Park, IL) prescribing information, adminis- mary tissues was primarily expressedinavarietyof tration guidelines for extended-release niacin indi- immune cell types and epidermis, but it was not cate that flushing can be minimized by careful dose detected in endothelial cells, smooth muscle cells, escalation, administration of extended-release niacin dermal fibroblasts, or dermis.27 at bedtime with administration of ASA 30 minutes In a more recent study, it was asked whether per- prior, and avoiding taking the drug on an empty oxisome proliferator-activated receptor a (PPARa) stomach. The manufacturers of Niaspan have also activation modulates epidermal langerhans cell stated that <6% of their patients discontinue use function.28 The results showed that PPARa is because of flushing.34 Daily use of ASA and ⁄or expressed in immature langerhans cells and is other NSAIDs in doses of at least 325 mg 30 min- down-regulated in mature langerhans cells, suggest- utes before niacin administration is required, and ing that an early decrease in PPARa expression in due to this there may be a potential limit to long- the cells may allow them to mature. It was also term use.35–38 An example of a limiting effect concluded that PPARa activation by endogenous would be the onset of gastrointestinal bleeding or ligands may provide a molecular signal that allows generalized prolonged bleeding time. langerhans cells to remain in an immature state within the epidermis for extended periods of time SUPPRESSION OF FLUSHING WITH AN despite minor environmental stimuli.28 Since ANTAGONIST TO PGD2 RECEPTOR PPARa activity can also be modulated by exoge- SUBTYPE 1 nous compounds, it is also a promising drug target Laropiprant is a selective antagonist of the PGD2 in inflammatory skin diseases. receptor subtype 1 (DP1) that may be involved in The most recent data on niacin’s mechanism of the mediation of niacin-induced flushing. It has action indicate that it directly inhibits hepatic been shown that the coadministration of laro- diacylglycerol acyltransferase 2, resulting in an piprant at doses of 30, 100, or 300 mg with inhibition of triglyceride synthesis and decreased extended-release niacin significantly lowered flush- apolipoprotein B–containing lipoproteins.29 By ing symptom scores (by approximately 50%) and inhibiting the surface expression of hepatic ATP also significantly decreased malar skin blood flow

VOL. 11 NO. 11 NOVEMBER 2009 THE JOURNAL OF CLINICAL HYPERTENSION 687 as measured by laser Doppler perfusion imaging.39 2–8).41 It can be concluded that all doses of laro- These experiments concluded that the DP1 receptor piprant were maximally effective in inhibiting antagonist laropiprant was effective in suppressing niacin-induced flushing without altering the benefi- both subjective and objective manifestations of nia- cial lipid effects of the extended-release niacin. cin-induced vasodilation.39 The results also showed Overall, the significant reduction in extended- that laropiprant 300 mg and extended-release nia- release niacin–induced flushing provided by laro- cin 1500 mg resulted in less flushing and warmth piprant plus extended-release niacin supports an compared with pretreatment with ASA 325 mg accelerated extended-releaseniacindoseadvance- before administration of extended-release niacin ment paradigm to achieve rapidly a 2-g dose in 1500 mg. The laropiprant decreased by 75% the dyslipidemic patients.41 A possible advantage of peak increase in skin blood flow that was induced using laropiprant over ASA is that NSAIDs affect by extended-release niacin alone. The fact that platelet aggregation and cause an increase in bleed- pretreatment with ASA (at 325 mg 30 minutes ing time compared with placebo, while laropiprant before niacin administration) was less effective than does not (following single doses up to 400 mg or coadministration with laropiprant (100 or 300 mg) multiple doses up to 450 mg).40 provides great insight into where the future of niacin treatment may be headed.39 CONCLUSIONS The evaluation of safety, tolerability, pharmaco- Niacin lowers triglyceride and LDL-C levels and kinetics, and pharmacodynamics of single and mul- raises HDL-C levels. Current treatment for dyslipi- tiple oral doses of laropiprant in healthy male demia via niacin therapy is restricted in a sense volunteers was conducted in another study.40 It because the flushing response seen in most patients was found that single doses up to 900 mg and leads to discontinued use after a short period of multiple doses up to 450 mg were generally well time. While ASA pretreatment has allowed for the tolerated. The results exhibited dose-proportional continuation of niacin treatment in many cases, pharmacokinetics and also were not affected by there are potential long-term complications that food. The oral absorption is rapid (2–8 hours), and may arise if used for long periods of time, including the terminal half-life is approximately 12 to 18 gastrointestinal bleeding and prolonged bleeding hours.40 There were also no serious adverse effects time. The selective antagonist of the PGD2 receptor associated with usage and no discontinuations due subtype 1 (DP1), laropiprant, holds much promise to adverse effects.40 in enhancing the tolerability of and compliance A more recent phase 2 dose-ranging study was with niacin treatment for patients with cardiovascu- designed to assess whether laropiprant would lar disease or dyslipidemia. While substantial strides reduce extended-release niacin–induced flushing in have been made in niacin therapy and its associa- dyslipidemic patients and support an accelerated tions with dyslipidemia, there is a need for further extended-release niacin dosing paradigm: initiating research, especially in terms of event-based trials. extended-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 150 REFERENCES mg ⁄d or placebo in a 9-week 2-period crossover 1 Canner PL, Berge KG, Wenger NK, et al. 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