Editing Niacin (section)

==As lipid-modifying medication==
In the United States, prescription niacin, in immediate-release and slow-release forms, is used to treat primary [[hyperlipidemia]] and [[hypertriglyceridemia]].<ref name=DailyMed /><ref name=Niaspan /> It is used either as a monotherapy or in combination with other lipid-modifying drugs. Dosages start at 500&nbsp;mg/day and are often gradually increased to as high as 3000&nbsp;mg/day for immediate release or 2000&nbsp;mg/day for slow release (also referred to as sustained release) to achieve the targeted lipid changes (lower LDL-C and triglycerides, and higher HDL-C).<ref name=DailyMed>{{cite web |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ce739d68-d89c-437c-90fb-3c0c45140f22 |title=NIACOR-niacin tablet |date=March 2020 |website=DAILYMED, US National Library of Medicine |access-date=9 May 2020 |archive-date=9 August 2020 |archive-url=https://web.archive.org/web/20200809105743/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ce739d68-d89c-437c-90fb-3c0c45140f22 |url-status=live }}</ref><ref name=Niaspan>{{cite web |url=http://www.rxabbott.com/pdf/niaspan.pdf |archive-url=https://ghostarchive.org/archive/20221009/http://www.rxabbott.com/pdf/niaspan.pdf |archive-date=2022-10-09 |url-status=live |title=Niaspan Patient Package and Product Information (PPPI) |date= December 2018 |access-date=9 May 2020}}</ref> Prescriptions in the US peaked in 2009, at 9.4{{nbsp}}million{{citation needed|date=November 2022}} and had declined to 800{{nbsp}}thousand by 2020.<ref name="ClinCalc Niacin" />

Systematic reviews found no effect of prescription niacin on all-cause mortality, cardiovascular mortality, myocardial infarctions, nor fatal or non-fatal strokes despite raising [[high-density lipoprotein|HDL]] cholesterol in patients already taking statins.<ref name=Kee2014>{{cite journal | vauthors = Keene D, Price C, Shun-Shin MJ, Francis DP | title = Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients | journal = BMJ | volume = 349 | pages = g4379 | date = July 2014 | pmid = 25038074 | pmc = 4103514 | doi = 10.1136/bmj.g4379 }}</ref><ref name=Mani2015>{{cite journal |vauthors=Mani P, Rohatgi A |title=Niacin Therapy, HDL Cholesterol, and Cardiovascular Disease: Is the HDL Hypothesis Defunct? |journal=Curr Atheroscler Rep |volume=17 |issue=8 |pages=43 |date=August 2015 |pmid=26048725 |pmc=4829575 |doi=10.1007/s11883-015-0521-x }}</ref> Reported side effects include an increased risk of new-onset type 2 diabetes.<ref name=Schand2017>{{cite journal | vauthors = Schandelmaier S, Briel M, Saccilotto R, Olu KK, Arpagaus A, Hemkens LG, Nordmann AJ | title = Niacin for primary and secondary prevention of cardiovascular events | journal = The Cochrane Database of Systematic Reviews | volume = 2017 | pages = CD009744 | date = June 2017 | issue = 6 | pmid = 28616955 | doi = 10.1002/14651858.CD009744.pub2 | pmc = 6481694 }}</ref><ref name=Ong2014 /><ref name=Goldie2016 /><ref>{{cite journal | vauthors = Garg A, Sharma A, Krishnamoorthy P, Garg J, Virmani D, Sharma T, Stefanini G, Kostis JB, Mukherjee D, Sikorskaya E | title = Role of Niacin in Current Clinical Practice: A Systematic Review | journal = The American Journal of Medicine | volume = 130 | issue = 2 | pages = 173–187 | date = February 2017 | pmid = 27793642 | doi = 10.1016/j.amjmed.2016.07.038 | doi-access = free }}</ref>

===Mechanisms===
Niacin reduces synthesis of low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), [[lipoprotein(a)]] and [[triglycerides]], and increases [[high-density lipoprotein]] cholesterol (HDL-C).<ref name="Villines, T. C. 2012 p 14">{{cite journal | vauthors = Villines TC, Kim AS, Gore RS, Taylor AJ | s2cid = 27925461 | title = Niacin: the evidence, clinical use, and future directions | journal = Current Atherosclerosis Reports | volume = 14 | issue = 1 | pages = 49–59 | date = February 2012 | pmid = 22037771 | doi = 10.1007/s11883-011-0212-1 }}</ref> The lipid-therapeutic effects of niacin are partly mediated through the activation of [[G protein-coupled receptor]]s, including [[hydroxycarboxylic acid receptor 2]] (HCA<sub>2</sub>)and [[hydroxycarboxylic acid receptor 3]] (HCA<sub>3</sub>), which are highly expressed in [[adipose tissue|body fat]].<ref>{{cite journal | vauthors = Soga T, Kamohara M, Takasaki J, Matsumoto S, Saito T, Ohishi T, Hiyama H, Matsuo A, Matsushime H, Furuichi K |title = Molecular identification of nicotinic acid receptor | journal = Biochemical and Biophysical Research Communications | volume = 303 | issue = 1 | pages = 364–9 | date = March 2003 | pmid = 12646212 | doi = 10.1016/S0006-291X(03)00342-5 }}</ref><ref>{{cite journal | vauthors = Wise A, Foord SM, Fraser NJ, Barnes AA, Elshourbagy N, Eilert M, Ignar DM, Murdock PR, Steplewski K, Green A, Brown AJ, Dowell SJ, Szekeres PG, Hassall DG, Marshall FH, Wilson S, Pike NB | title = Molecular identification of high and low affinity receptors for nicotinic acid | journal = The Journal of Biological Chemistry | volume = 278 | issue = 11 | pages = 9869–74 | date = March 2003 | pmid = 12522134 | doi = 10.1074/jbc.M210695200 | doi-access = free }}</ref> HCA<sub>2</sub> and HCA<sub>3</sub> inhibit [[cyclic adenosine monophosphate]] (cAMP) production and thus suppress the release of free [[fatty acids]] (FFAs) from body fat, reducing their availability to the liver to synthesize the blood-circulating lipids in question.<ref name="Gille, A. 2008">{{cite journal | vauthors = Gille A, Bodor ET, Ahmed K, Offermanns S | title = Nicotinic acid: pharmacological effects and mechanisms of action | journal = Annual Review of Pharmacology and Toxicology | volume = 48 | issue = 1 | pages = 79–106 | year = 2008 | pmid = 17705685 | doi = 10.1146/annurev.pharmtox.48.113006.094746 }}</ref><ref>{{cite journal | vauthors = Wanders D, Judd RL | title = Future of GPR109A agonists in the treatment of dyslipidaemia | journal = Diabetes, Obesity & Metabolism | volume = 13 | issue = 8 | pages = 685–91 | date = August 2011 | pmid = 21418500 | doi = 10.1111/j.1463-1326.2011.01400.x | s2cid = 205536280 }}</ref><ref name=Costet2010>{{cite journal |vauthors=Costet P |title=Molecular pathways and agents for lowering LDL-cholesterol in addition to statins |journal=Pharmacol Ther |volume=126 |issue=3 |pages=263–78 |date=June 2010 |pmid=20227438 |doi=10.1016/j.pharmthera.2010.02.006 }}</ref> A decrease in free fatty acids also suppresses liver expression of [[apolipoprotein C3]] and [[PPARGC1B|PPARg coactivator-1b]], thus increasing VLDL-C turnover and reducing its production.<ref>{{cite journal | vauthors = Hernandez C, Molusky M, Li Y, Li S, Lin JD | title = Regulation of hepatic ApoC3 expression by PGC-1β mediates hypolipidemic effect of nicotinic acid | journal = Cell Metabolism | volume = 12 | issue = 4 | pages = 411–9 | date = October 2010 | pmid = 20889132 | pmc = 2950832 | doi = 10.1016/j.cmet.2010.09.001 }}</ref> Niacin also directly inhibits the action of [[diacylglycerol O-acyltransferase 2]] (DGAT2) a key enzyme for triglyceride synthesis.<ref name=Costet2010/>

The mechanism behind niacin increasing HDL-C is not totally understood, but seems to occur in various ways. Niacin increases [[apolipoprotein A1]] levels by inhibiting the breakdown of this protein, which is a component of HDL-C.<ref>{{cite journal |vauthors=Malik S, Kashyap ML |s2cid=27918392 |title=Niacin, lipids, and heart disease |journal=Curr Cardiol Rep |volume=5 |issue=6 |pages=470–6 |date=November 2003 |pmid=14558989 |doi=10.1007/s11886-003-0109-x }}</ref><ref>{{cite journal | vauthors = Creider JC, Hegele RA, Joy TR | s2cid = 22526314 | title = Niacin: another look at an underutilized lipid-lowering medication | journal = Nature Reviews. Endocrinology | volume = 8 | issue = 9 | pages = 517–28 | date = September 2012 | pmid = 22349076 | doi = 10.1038/nrendo.2012.22 }}</ref> It also inhibits HDL-C hepatic uptake by suppressing production of the [[cholesterol ester transfer protein]] (CETP) gene.<ref name="Villines, T. C. 2012 p 14"/> It stimulates the [[ABCA1|ABCA1 transporter]] in monocytes and macrophages and [[Downregulation and upregulation|upregulates]] [[peroxisome proliferator-activated receptor gamma]], resulting in reverse cholesterol transport.<ref>{{cite journal | vauthors = Rubic T, Trottmann M, Lorenz RL | title = Stimulation of CD36 and the key effector of reverse cholesterol transport ATP-binding cassette A1 in monocytoid cells by niacin | journal = Biochemical Pharmacology | volume = 67 | issue = 3 | pages = 411–9 | date = February 2004 | pmid = 15037193 | doi = 10.1016/j.bcp.2003.09.014 }}</ref>

===Combined with statins===
Extended release niacin was combined with [[lovastatin]] (Advicor), and with [[simvastatin]] (Simcor), as prescription drug combinations. The combination niacin/lovastatin was approved by the U.S. [[Food and Drug Administration]] (FDA) in 2001.<ref name=Advicor>{{cite web |url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/21-249_Advicor.cfm |title=Drug Approval Package: Advicor (Niacin Extended-Release & Lovastatin) NDA #21-249 |date=13 September 2002 |website=U.S. [[Food and Drug Administration]] (FDA) |access-date=17 May 2020 |archive-date=4 August 2020 |archive-url=https://web.archive.org/web/20200804174117/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/21-249_Advicor.cfm |url-status=live }}</ref> The combination niacin/simvastatin was approved by the FDA in 2008.<ref>{{cite web | title=Drug Approval Package: Simcor (Niacin/Simvastatin) NDA #022078 | website=U.S. [[Food and Drug Administration]] (FDA) | date=31 July 2008 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022078s000TOC.cfm | access-date=14 November 2022 | archive-date=14 November 2022 | archive-url=https://web.archive.org/web/20221114011457/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022078s000TOC.cfm | url-status=live }}</ref><ref name=Simcor>{{Cite press release |url=https://www.drugs.com/newdrugs/abbott-receives-fda-approval-simcor-niaspan-simvastatin-novel-combination-medicine-comprehensive-846.html | work = Drugs.com | title = Abbott Receives FDA Approval for Simcor (Niaspan / simvastatin), a Novel Combination Medicine for Comprehensive Cholesterol Management |access-date=2008-03-15 |archive-date=5 August 2020 |archive-url=https://web.archive.org/web/20200805074725/https://www.drugs.com/newdrugs/abbott-receives-fda-approval-simcor-niaspan-simvastatin-novel-combination-medicine-comprehensive-846.html |url-status=live }}</ref> Subsequently, large outcome trials using these niacin and statin therapies were unable to demonstrate incremental benefit of niacin beyond statin therapy alone.<ref>{{cite journal |vauthors=Toth PP, Murthy AM, Sidhu MS, Boden WE |title=Is HPS2-THRIVE the death knell for niacin? |journal=J Clin Lipidol |volume=9 |issue=3 |pages=343–50 |date=2015 |pmid=26073392 |doi=10.1016/j.jacl.2015.01.008 }}</ref> The FDA withdrew approval of both drugs in 2016. The reason given: "Based on the collective evidence from several large cardiovascular outcome trials, the Agency has concluded that the totality of the scientific evidence no longer supports the conclusion that a drug-induced reduction in triglyceride levels and/or increase in HDL-cholesterol levels in statin-treated patients results in a reduction in the risk of cardiovascular events." The drug company discontinued the drugs.<ref name=FDAWithdrawal>{{cite web |url=https://www.federalregister.gov/documents/2016/04/18/2016-08894/abbvie-inc-withdrawal-of-approval-of-new-drug-applications-for-advicor-and-simcor |title=AbbVie Inc.; Withdrawal of Approval of New Drug Applications for Advicor and Simcor |date=18 April 2016 |website=U.S. Federal Register |access-date=17 May 2020 |archive-date=5 August 2020 |archive-url=https://web.archive.org/web/20200805003411/https://www.federalregister.gov/documents/2016/04/18/2016-08894/abbvie-inc-withdrawal-of-approval-of-new-drug-applications-for-advicor-and-simcor |url-status=live }}</ref>

===Contraindications===
Prescription immediate release (Niacor) and extended release (Niaspan) niacin are [[contraindicated]] for people with either active or a history of [[liver disease]] because both, but especially Niaspan, have been associated with instances of serious, on occasion fatal, liver failure.<ref name=Niaspan /><ref name="ReferenceB"/> Both products are contraindicated for people with existing [[peptic ulcer disease]], or other bleeding problems because niacin lowers platelet count and interferes with blood clotting.<ref name=DailyMed /><ref name=Niaspan /><ref name="ReferenceB"/> Both products are also contraindicated for women who are pregnant or expecting to become pregnant because safety during pregnancy has not been evaluated in human trials. These products are contraindicated for women who are lactating because it is known that niacin is excreted into human milk, but the amount and potential for adverse effects in the nursing infant are not known. Women are advised to either not nurse their child or discontinue the drug. High-dose niacin has not been tested or approved for use in children under 16 years.<ref name=DailyMed /><ref name=Niaspan /><ref name="ReferenceB">{{cite web | title=Niaspan- niacin tablet, film coated, extended release | website=DailyMed | date=20 August 2013 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0dd18020-c211-423d-b3d8-a926ae626e14 | access-date=14 November 2022 | archive-date=14 November 2022 | archive-url=https://web.archive.org/web/20221114011459/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0dd18020-c211-423d-b3d8-a926ae626e14 | url-status=live }}</ref>

===Adverse effects===
The most common adverse effects of medicinal niacin ({{nowrap|500–3000&nbsp;mg}}) are flushing (e.g., warmth, redness, itching or tingling) of the face, neck and chest, headache, abdominal pain, diarrhea, [[dyspepsia]], nausea, vomiting, [[rhinitis]], [[pruritus]] and rash.<ref name=lpi/><ref name="NIH Fact Sheet" /><ref name="ReferenceB"/> These can be minimized by initiating therapy at low dosages, increasing dosage gradually, and avoiding administration on an empty stomach.<ref name="ReferenceB"/>

The acute adverse effects of high-dose niacin therapy ({{nowrap|1–3&nbsp;grams per day}}) &ndash; which is commonly used in the treatment of [[hyperlipidemia]]s &ndash; can further include [[hypotension]], fatigue, [[glucose intolerance]] and [[insulin resistance]], heartburn, blurred or impaired vision, and [[macular edema]].<ref name=lpi/><ref name="NIH Fact Sheet" /> With long-term use, the adverse effects of high-dose niacin therapy (750&nbsp;mg per day) also include [[liver failure]] (associated with fatigue, nausea, and [[loss of appetite]]), [[hepatitis]], and [[acute liver failure]];<ref name=lpi/><ref name="NIH Fact Sheet" /> these hepatotoxic effects of niacin occur more often when extended-release [[dosage form]]s are used.<ref name=lpi/><ref name="NIH Fact Sheet" /> The long-term use of niacin at greater than or equal to 2&nbsp;grams per day also significantly increases the [[risk ratio|risk]] of [[cerebral hemorrhage]], [[ischemic stroke]], [[gastrointestinal ulcer]]ation and [[gastrointestinal bleeding|bleeding]], [[diabetes]], [[dyspepsia]], and diarrhea.<ref name="NIH Fact Sheet"/>

====Flushing====
[[Flushing (physiology)|Flushing]] &ndash; a short-term [[vasodilation|dilatation]] of skin [[arteriole]]s, causing reddish skin color &ndash; usually lasts for about 15 to 30 minutes, although sometimes can persist for weeks. Typically, the face is affected, but the reaction can extend to neck and upper chest. The cause is blood vessel dilation<ref name=lpi/><ref name="NIH Fact Sheet" /> due to elevation in prostaglandin GD<sub>2</sub> ([[PGD2]]) and [[serotonin]].<ref name="ReferenceA"/><ref>{{cite journal | vauthors = Benyó Z, Gille A, Kero J, Csiky M, Suchánková MC, Nüsing RM, Moers A, Pfeffer K, Offermanns S | title = GPR109A (PUMA-G/HM74A) mediates nicotinic acid-induced flushing | journal = The Journal of Clinical Investigation | volume = 115 | issue = 12 | pages = 3634–40 | date = December 2005 | pmid = 16322797 | pmc = 1297235 | doi = 10.1172/JCI23626 }}</ref><ref>{{cite journal | vauthors = Benyó Z, Gille A, Bennett CL, Clausen BE, Offermanns S | s2cid = 30199951 | title = Nicotinic acid-induced flushing is mediated by activation of epidermal langerhans cells | journal = Molecular Pharmacology | volume = 70 | issue = 6 | pages = 1844–9 | date = December 2006 | pmid = 17008386 | doi = 10.1124/mol.106.030833 }}</ref><ref>{{cite journal | vauthors = Maciejewski-Lenoir D, Richman JG, Hakak Y, Gaidarov I, Behan DP, Connolly DT | title = Langerhans cells release prostaglandin D2 in response to nicotinic acid | journal = The Journal of Investigative Dermatology | volume = 126 | issue = 12 | pages = 2637–46 | date = December 2006 | pmid = 17008871 | doi = 10.1038/sj.jid.5700586 | doi-access = free }}</ref> Flushing was often thought to involve histamine, but histamine has been shown not to be involved in the reaction.<ref name="ReferenceA">{{cite journal | vauthors = Papaliodis D, Boucher W, Kempuraj D, Michaelian M, Wolfberg A, House M, Theoharides TC | s2cid = 5609632 | title = Niacin-induced "flush" involves release of prostaglandin D2 from mast cells and serotonin from platelets: evidence from human cells in vitro and an animal model | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 327 | issue = 3 | pages = 665–72 | date = December 2008 | pmid = 18784348 | doi = 10.1124/jpet.108.141333 }}</ref> Flushing is sometimes accompanied by a prickly or [[itching]] sensation, in particular, in areas covered by clothing.<ref name="NIH Fact Sheet" />

Prevention of flushing requires altering or blocking the prostaglandin-mediated pathway.<ref name="NIH Fact Sheet" /><ref name="kamanna">{{cite journal | vauthors = Kamanna VS, Kashyap ML | title = Mechanism of action of niacin | journal = The American Journal of Cardiology | volume = 101 | issue = 8A | pages = 20B–26B | date = April 2008 | pmid = 18375237 | doi = 10.1016/j.amjcard.2008.02.029 }}</ref> [[Aspirin]] taken half an hour before the niacin prevents flushing, as does [[ibuprofen]]. Taking niacin with meals also helps reduce this side effect.<ref name="NIH Fact Sheet" /> Acquired tolerance will also help reduce flushing; after several weeks of a consistent dose, most people no longer experience flushing.<ref name="NIH Fact Sheet" /> Slow- or "sustained"-release forms of niacin have been developed to lessen these side effects.<ref name=autogenerated1>{{cite book |author=Katzung, Bertram G. |title=Basic and clinical pharmacology |publisher=McGraw-Hill Medical Publishing Division |location=New York |year=2006 |isbn=978-0-07-145153-6 }}</ref><ref>{{cite journal | title = Options for therapeutic intervention: How effective are the different agents? | journal = European Heart Journal Supplements | volume = 8 | pages = F47–F53 | doi = 10.1093/eurheartj/sul041 | vauthors = Barter P | date = October 2006 | issue = F| doi-access = free }}</ref>

====Liver damage====
Niacin in medicinal doses can cause modest elevations in serum [[transaminase]] and unconjugated [[bilirubin]], both biomarkers of liver injury. The increases usually resolve even when drug intake is continued.<ref name=LiverTox2014>{{cite book |title = IN: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury (Internet) |chapter = Niacin |publisher=National Institute of Diabetes and Digestive and Kidney Diseases |pmid=31643504 |date=February 2014 |location = Bethesda, MD }}</ref><ref name="bil1" /><ref name="bil2" /> However, less commonly, the sustained release form of the drug can lead to serious [[hepatotoxicity]], with onset in days to weeks. Early symptoms of serious liver damage include nausea, vomiting and abdominal pain, followed by [[jaundice]] and [[Itch|pruritus]]. The mechanism is thought to be a direct toxicity of elevated serum niacin. Lowering dose or switching to the immediate release form can resolve symptoms. In rare instances the injury is severe, and progresses to liver failure.<ref name=LiverTox2014 />

====Diabetes====
The high doses of niacin used to treat [[hyperlipidemia]] have been shown to elevate [[blood sugar|fasting blood glucose]] in people with type 2 [[diabetes mellitus|diabetes]].<ref name=Ong2014>{{cite journal |vauthors=Ong KL, Barter PJ, Waters DD |title=Cardiovascular drugs that increase the risk of new-onset diabetes |journal=Am. Heart J. |volume=167 |issue=4 |pages=421–8 |date=April 2014 |pmid=24655688 |doi=10.1016/j.ahj.2013.12.025 |s2cid=205306912 |url=http://www.escholarship.org/uc/item/6gd606b1 |access-date=27 June 2020 |archive-date=28 June 2020 |archive-url=https://web.archive.org/web/20200628180527/https://escholarship.org/uc/item/6gd606b1 |url-status=live |hdl=1959.4/unsworks_43825 |hdl-access=free }}</ref> Long-term niacin therapy was also associated with an increase in the risk of new-onset type 2 diabetes.<ref name=Ong2014 /><ref name=Goldie2016>{{cite journal | vauthors = Goldie C, Taylor AJ, Nguyen P, McCoy C, Zhao XQ, Preiss D | title = Niacin therapy and the risk of new-onset diabetes: a meta-analysis of randomised controlled trials | journal = Heart | volume = 102 | issue = 3 | pages = 198–203 | date = February 2016 | pmid = 26370223 | pmc = 4752613 | doi = 10.1136/heartjnl-2015-308055 }}</ref>

====Other adverse effects====
High doses of niacin can also cause niacin [[maculopathy]], a thickening of the [[macula]] and [[retina]], which leads to blurred vision and blindness. This maculopathy is reversible after niacin intake ceases.<ref>{{cite journal |vauthors=Domanico D, Verboschi F, Altimari S, Zompatori L, Vingolo EM |title=Ocular Effects of Niacin: A Review of the Literature |journal=Med Hypothesis Discov Innov Ophthalmol |volume=4 |issue=2 |pages=64–71 |date=2015 |pmid=26060832 |pmc=4458328 }}</ref> Niaspan, the slow-release product, has been associated with a reduction in platelet content and a modest increase in prothrombin time.<ref name=Niaspan />