stay updated with our newsletter

Subscribe
Facebook Twitter Linkedin

Is Niacin Still an Effective Option for Lipid Management?

The lipid management landscape has evolved considerably over time. Beginning in the mid-1950s, niacin emerged as one of the first pharmacologic therapies for dyslipidemia. It remained an important component of lipid management for decades before statins became the mainstay of therapy. Meanwhile, within integrative medicine, botanicals such as red yeast rice and bergamot have gained widespread use.

Given the robust evidence supporting niacin, it remains an important consideration for cardiometabolic health. In this discussion, we’ll explore the science behind niacin and the evidence that may help reestablish its role as an effective, multifaceted lipid management strategy.

Niacin’s Many Names: Clearing Up Confusion

Niacin and related compounds are used for a range of therapeutic and wellness applications, including dermatology, metabolic health, and aging-related research. Although these compounds share related biochemical pathways, they are not necessarily interchangeable and can have distinct mechanisms of action and clinical applications.

Nicotinic acid is a form of vitamin B3 commonly referred to as niacin. At therapeutic doses, nicotinic acid/niacin has historically been used for lipid management. Nicotinamide, also known as niacinamide, is another form of vitamin B3 and is widely used both topically and orally, particularly for dermatologic applications.1 These terms are often mistakenly used interchangeably, and it’s important to prescribe the correct form therapeutically.

Nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) are distinct compounds that serve as intermediates in the biosynthesis of nicotinamide adenine dinucleotide (NAD⁺). NAD⁺ is an essential cellular coenzyme involved in energy metabolism, redox reactions, cellular signaling, and other fundamental biological processes. NMN and NR have attracted significant interest in the aging and longevity field because they can increase NAD⁺-related metabolites in humans.2,3 Niacin is also capable of increasing NAD⁺ at therapeutic doses.4,5

Why Has Niacin Been Forgotten for Lipid Management?

When you think of niacin, what’s the first thing that comes to mind? Many might automatically associate it with the flushing side effect. Prostaglandin-mediated flushing is not harmful or dangerous and is a temporary effect; however, it’s the primary reason patients discontinue therapy.6

To reduce flushing, sustained-release (SR) niacin (also referred to as long-acting niacin) was developed in the 1960s; however, its use was limited by hepatotoxicity. Many SR formulations are still sold as over-the-counter supplements. Extended-release (ER) formulations were developed in the 1990s as an intermediate between immediate-release and SR niacin. Unlike SR formulations, ER niacin is not associated with similarly severe hepatotoxicity.7-9 However, familiarity with the hepatotoxicity associated with older SR formulations may lead clinicians to incorrectly attribute the same risk to newer ER formulations.

Related: Study Shows Wax-Matrix Niacin Safely Improves Several Lipid Measures

 

Unlike statins and natural alternatives such as red yeast rice, niacin does not impair mitochondrial function; instead, it enhances it as an NAD+ precursor, which has been shown to improve muscle strength and performance.

The Two Niacin Trials That Made Headlines

Two trials, the 2011 AIM-HIGH (Atherothrombosis Intervention in Metabolic syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) and 2014 HPS2-THRIVE (Heart Protection Study 2 Treatment on HDL to Reduce the Incidence of Vascular Events) trials, led to niacin’s decline despite limitations in how those studies were designed and interpreted. While the addition of niacin to other lipid-lowering therapies increased HDL and decreased triglyceride levels, the trials didn’t observe clinical cardiovascular (CV) benefit, and HPS2-THRIVE observed more serious adverse events.10,11 News headlines concluded niacin was useless and harmful.

These trials have received criticism for methodological flaws.12-15 The AIM-HIGH trial only studied the population for 3 years, which arguably is not enough time to observe long-term clinical benefits. The HPS2-THRIVE trial included lapropriant, a prostaglandin D2 (PGD2) antagonist to inhibit niacin-induced flushing. Lapropriant may have diminished the positive impact of niacin and promoted adverse risks. Adverse effects were significantly higher in Chinese participants, indicating the need for caution in prescribing for this patient population.12,13 The findings do not indicate that niacin alone was responsible for the adverse clinical or metabolic measures.

Niacin is most effective for cardiovascular disease (CVD) reduction when the baseline HDL is less than 32 mg/dL, and triglycerides are greater than 200 mg/dL.14,15 Patients with higher baseline cholesterol experience the greatest benefit from niacin therapy.16 Because niacin was given after aggressive lipid modification with other agents, it may have been destined to fail from the start.

These studies ultimately led to the FDA’s 2016 withdrawal of approval for niacin coadministration with statins and fenofibric acid.17 Since then, niacin has largely fallen out of favor in mainstream medicine, and its potential benefits as an individual therapy have been overshadowed or forgotten. But we shouldn’t throw the baby out with the bathwater. These findings should be interpreted in the context of combination therapy and should not necessarily be extrapolated to niacin as an individual therapy.

Statins and Related Nutraceuticals are Not Without Risk

While statins have become the standard of care, side effects can limit their use. Statins (and red yeast rice) inhibit HMG-CoAR (β-hydroxyβ-methylglutaryl coenzyme A reductase), the enzyme catalyzing the rate-limiting step of cholesterol biosynthesis.18 They both have similar adverse effect profiles that include musculoskeletal disorders, elevated liver enzymes, digestive upset, and kidney injury.18,19 Statin-associated muscle symptoms (SAMS) are a major reason patients discontinue therapy, with patient surveys suggesting this happens in up to 30-62% of patients.20

In addition to reducing endogenous cholesterol synthesis, HMG-CoA reductase inhibition results in reduced Coenzyme Q10 (CoQ10) production. These biochemical alterations can lead to decreased mitochondrial function, which may manifest as myopathy and fatigue. Prescribing CoQ10 along with statins should be considered, although clinical trials are mixed on its benefit.21,22

Unlike statins and natural alternatives such as red yeast rice, niacin does not impair mitochondrial function; instead, it enhances it as an NAD+ precursor, which has been shown to improve muscle strength and performance.4

Even though statins achieve substantial reductions in LDL-C, there remains significant CV risk.15,22 Statin monotherapy may not always be the optimal therapeutic approach as it minimally impacts other lipid and inflammatory parameters.

Diabetes increases the risk of atherosclerotic CVD, and statins have shown benefit in this population. However, statins also have the known side effect of increasing blood glucose and increasing the risk of new-onset diabetes.23 Niacin can also increase blood glucose but does not increase diabetes risk.24

Why Niacin Shouldn’t Be Overlooked

Niacin is distinct from other cardiometabolic medications and merits consideration as a first-line therapy because of its multifactorial effects across the lipid profile. In liver cells, niacin inhibits the enzyme diacylglycerol O-acyltransferase 2 (DGAT2), which supports normal triglyceride production and cholesterol metabolism.25,26 In fat cells, niacin binds hydroxycarboxylic acid receptor 2 (HCA2), which inhibits the release of free fatty acids into the bloodstream.27

Unlike therapies that primarily target a single lipid parameter, niacin favorably influences multiple atherogenic and protective lipoproteins, including:15

  • LDL cholesterol (lowers 5% to 25%)
  • HDL cholesterol (increases 15% to 35%)
  • Small, dense LDL28
  • Oxidized LDL
  • Lipoprotein(a) (lowers 24% to 38%
  • Triglycerides (lowers 20% to 50%)
  • Apo A128
  • Apo B29

A notable landmark study includes the earlier Coronary Drug Project, a placebo-controlled multicenter trial of lipid-lowering medications in the secondary prevention of coronary heart disease. Immediate-release (IR) niacin treatment was associated with significant reductions in CV events and long-term mortality.12,16 Effects are comparable to those reported in trials of statin monotherapy.12

Because of flushing issues, extended-release forms were created, and trials have shown equal efficacy and improved compliance compared with immediate-release niacin.7,8,30,31

Although the AIM-HIGH and HPS2-THRIVE trials did not demonstrate favorable clinical outcomes, numerous studies have reported benefits of niacin across various measures of coronary and vascular atherosclerosis. A comprehensive review of these studies is provided in Table 1 of the 2013 article by Boden et. al. and will not be revisited here.12 Larger reviews and clinical studies evaluating niacin have become increasingly scarce over the past decade, resulting in continued reliance on earlier studies to characterize the potential efficacy of niacin.

Niacin is one of the most effective therapies for raising HDL-C levels. There is an independent, inverse relationship between low levels of HDL-C and CV risk, even without elevated LDL-C. The National Cholesterol Education Program (NCEP) recommends lowering LDL-C and raising HDL-C when it is <40 mg/dL, with no guidance on target levels of HDL-C.12 Niacin increases HDL-C by 20-40%.26

Not only does niacin increase HDL levels, but it also improves HDL functionality.32 HDL from healthy individuals has been shown to enhance endothelial nitric oxide production, reduce endothelial oxidative stress, improve endothelium-dependent vasodilation, and promote endothelial repair. In contrast, HDL function is impaired in patients with cardiometabolic disease. Notably, a study of 33 patients with diabetes found that treatment with ER niacin restored these endothelial-protective functions of HDL.33 Studies are mixed, with one study showing a shift towards possible proinflammatory activity.34

Niacin also has many nonlipid actions that influence CV health.13,15 Niacin has anti-inflammatory effects in monocytes/macrophages, adipocytes, and the vascular endothelium.15 Adding ER niacin to statins reduces high-sensitivity C-reactive protein (hsCRP) by 15% and lipoprotein-associated phospholipase A2 by 20% in patients with CHD.35 As previously discussed, niacin also raises cellular NAD⁺.

Niacin is the leading evidence-based non-prescription lipid therapy and may be appropriate for select patients, including those who:

  • Decline statins
  • Cannot tolerate statins
  • Prefer nutritional approaches
  • Have elevated Lipoprotein(a), ApoB, and/or triglycerides
  • Have metabolic syndrome
  • Require broader lipid optimization

Although mainstream medicine has rejected its use, many integrative practitioners still find niacin beneficial.13 A 2016 analysis concluded:
“This meta-analysis demonstrates that niacin reduces CVE, despite the negative results of AIM-HIGH and HPS2-THRIVE. Niacin benefits seem to be mediated by the reduction in atherogenic particles and are independent of changes in HDL-C. Our results suggest that niacin remains an effective treatment as an add-on therapy in patients with insufficient response to statins.”

Clinical Pearls for Prescribing Niacin

Tolerance to niacin can develop, with a decrease in flushing over time. Several strategies can help reduce flushing for patients.6,26

  • Use extended-release (ER) niacin: ER niacin is shown to reduce flushing compared to immediate-release (IR). ER niacin in a wax matrix allows for a more gradual nutrient release and smoother blood concentrations.31,36 Depending on the product, it’s delivered over 6 to 12 hours, compared to IR niacin, which is delivered over 1 to 2 hours.8,37 The slower exposure reduces flushing while maintaining therapeutic dosing.
  • Gradual titration: Whether using IR or ER forms, titration over several weeks can help offset flushing. Some companies offer titration kits to help onboard patients onto niacin.
  • Divided doses: Dosing ER niacin 12 hours apart helps reduce flushing potential.
  • Take with meals: Niacin is absorbed more quickly on an empty stomach, which is more likely to cause flushing.
  • Avoid triggers: Alcohol, hot beverages, spicy foods, and hot showers close to or after dosing can intensify flushing.

The Evolution of Cardiometabolic Care

Today’s cardiometabolic care is moving beyond a singular focus on LDL cholesterol toward a more comprehensive therapeutic strategy. Properly formulated and prescribed, niacin merits renewed consideration as an evidence-based nutritional intervention that favorably impacts multiple lipid parameters associated with atherosclerotic CVD.

References:

  1. Huber R, Wong A. Nicotinamide: An Update and Review of Safety & Differences from Niacin. Skin Therapy Letter. Nov 2020;25(5):7–11.
  2. Yoshino J, Baur JA, Imai SI. NAD(+) Intermediates: The Biology and Therapeutic Potential of NMN and NR. Cell Metabolism. Mar 6 2018;27(3):513–528. doi:10.1016/j.cmet.2017.11.002
  3. Damgaard MV, Treebak JT. What is really known about the effects of nicotinamide riboside supplementation in humans. Sci Adv. Jul 21 2023;9(29):eadi4862. doi:10.1126/sciadv.adi4862
  4. Pirinen E, Auranen M, Khan NA, et al. Niacin Cures Systemic NAD(+) Deficiency and Improves Muscle Performance in Adult-Onset Mitochondrial Myopathy. Cell Metabolism. Jun 2 2020;31(6):1078–1090.e5. doi:10.1016/j.cmet.2020.04.008
  5. Romani M, Hofer DC, Katsyuba E, Auwerx J. Niacin: an old lipid drug in a new NAD(+) dress. Journal of Lipid Research. Apr 2019;60(4):741–746. doi:10.1194/jlr.S092007
  6. Davidson MH. Niacin use and cutaneous flushing: mechanisms and strategies for prevention. The American journal of Cardiology. Apr 17 2008;101(8a):14b–19b. doi:10.1016/j.amjcard.2008.02.028
  7. Guyton JR. Extended-release niacin for modifying the lipoprotein profile. Expert Opin Pharmacother. Jun 2004;5(6):1385–98. doi:10.1517/14656566.5.6.1385
  8. Pieper JA. Understanding niacin formulations. The American journal of managed care. Sep 2002;8(12 Suppl):S308–14.
  9. Bhardwaj SS, Chalasani N. Lipid-lowering agents that cause drug-induced hepatotoxicity. Clin Liver Dis. Aug 2007;11(3):597–613, vii. doi:10.1016/j.cld.2007.06.010
  10. Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. The New England Journal of Medicine. Dec 15 2011;365(24):2255–67. doi:10.1056/NEJMoa1107579
  11. Landray MJ, Haynes R, Hopewell JC, et al. Effects of extended-release niacin with laropiprant in high-risk patients. The New England Journal of Medicine. Jul 17 2014;371(3):203–12. doi:10.1056/NEJMoa1300955
  12. Boden WE, Sidhu MS, Toth PP. The therapeutic role of niacin in dyslipidemia management. J Cardiovasc Pharmacol Ther. Mar 2014;19(2):141–58. doi:10.1177/1074248413514481
  13. Houston M, Pizzorno J. “Niacin Doesn’t Work and Is Harmful!” Proclaim the Headlines. Yet Another Highly Publicized Questionable Study to Discredit Integrative Medicine. Integrative Medicine (Encinitas, Calif). Oct 2014;13(5):8–11.
  14. Siniawski D, Santos-Gallego CG, Badimon JJ, Masson WM. Niacin is still beneficial. Implications from an updated meta-regression analysis. Acta Cardiol. Aug 2016;71(4):463–72. doi:10.2143/ac.71.4.3159701
  15. Digby JE, Ruparelia N, Choudhury RP. Niacin in cardiovascular disease: recent preclinical and clinical developments. Arteriosclerosis, Thrombosis, and Vascular Biology. Mar 2012;32(3):582–8. doi:10.1161/atvbaha.111.236315
  16. Berge KG, Canner PL. Coronary drug project: experience with niacin. Coronary Drug Project Research Group. European Journal of Clinical Pharmacology. 1991;40 Suppl 1:S49–51.
  17. FDA. AbbVie Inc. et al; Withdrawal of Approval of Indications Related to the Coadministration With Statins in Applications for Niacin Extended-Release Tablets and Fenofibric Acid Delayed-Release Capsules. Accessed Aug 21 2026, https://www.federalregister.gov/documents/2016/04/18/2016-08887/abbvie-inc-et-al-withdrawal-of-approval-of-indications-related-to-the-coadministration-with-statins
  18. Cicero AFG, Fogacci F, Stoian AP, Toth PP. Red Yeast Rice for the Improvement of Lipid Profiles in Mild-to-Moderate Hypercholesterolemia: A Narrative Review. Nutrients. May 12 2023;15(10)doi:10.3390/nu15102288
  19. Newman CB, Preiss D, Tobert JA, et al. Statin Safety and Associated Adverse Events: A Scientific Statement From the American Heart Association. Arteriosclerosis, Thrombosis, and Vascular Biology. Feb 2019;39(2):e38–e81. doi:10.1161/atv.0000000000000073
  20. Zaleski AL, Taylor BA, Thompson PD. Coenzyme Q10 as Treatment for Statin-Associated Muscle Symptoms-A Good Idea, but…. Advances in Nutrition (Bethesda, Md). Jul 1 2018;9(4):519s–523s. doi:10.1093/advances/nmy010
  21. Tippairote T, Bjørklund G, Gasmi A, et al. Combined Supplementation of Coenzyme Q(10) and Other Nutrients in Specific Medical Conditions. Nutrients. Oct 19 2022;14(20)doi:10.3390/nu14204383
  22. Hoffmann TK, Tucker MA, Parker DL. Emerging risk factors and risk markers for cardiovascular disease: looking beyond NCEP ATP III. Formulary. 2009;44(8):237.
  23. Effects of statin therapy on diagnoses of new-onset diabetes and worsening glycaemia in large-scale randomised blinded statin trials: an individual participant data meta-analysis. Lancet Diabetes Endocrinol. May 2024;12(5):306–319. doi:10.1016/s2213-8587(24)00040-8
  24. Phan BA, Muñoz L, Shadzi P, et al. Effects of niacin on glucose levels, coronary stenosis progression, and clinical events in subjects with normal baseline glucose levels (<100 mg/dl): a combined analysis of the Familial Atherosclerosis Treatment Study (FATS), HDL-Atherosclerosis Treatment Study (HATS), Armed Forces Regression Study (AFREGS), and Carotid Plaque Composition by MRI during lipid-lowering (CPC) study. The American Journal of Cardiology. Feb 1 2013;111(3):352–5. doi:10.1016/j.amjcard.2012.09.034
  25. Ganji SH, Tavintharan S, Zhu D, Xing Y, Kamanna VS, Kashyap ML. Niacin noncompetitively inhibits DGAT2 but not DGAT1 activity in HepG2 cells. Journal of Lipid Research. Oct 2004;45(10):1835–45. doi:10.1194/jlr.M300403-JLR200
  26. Kamanna VS, Ganji SH, Kashyap ML. The mechanism and mitigation of niacin-induced flushing. International Journal of Clinical Practice. Sep 2009;63(9):1369–77. doi:10.1111/j.1742-1241.2009.02099.x
  27. Lukasova M, Hanson J, Tunaru S, Offermanns S. Nicotinic acid (niacin): new lipid-independent mechanisms of action and therapeutic potentials. Trends in Pharmacological Sciences. Dec 2011;32(12):700–7. doi:10.1016/j.tips.2011.08.002
  28. Superko HR, McGovern ME, Raul E, Garrett B. Differential effect of two nicotinic acid preparations on low-density lipoprotein subclass distribution in patients classified as low-density lipoprotein pattern A, B, or I. The American Journal of Cardiology. Sep 1 2004;94(5):588–94. doi:10.1016/j.amjcard.2004.05.021
  29. Saboori S, Yousefi Rad E, Tammam J, Thondre PS, Coe S. Effects of niacin on apo A1 and B levels: a systematic review and meta-analysis of randomised controlled trials. The British Journal of Nutrition. Apr 14 2024;131(7):1225–1235. doi:10.1017/s000711452300288x
  30. Capuzzi DM, Guyton JR, Morgan JM, et al. Efficacy and safety of an extended-release niacin (Niaspan): a long-term study. The American Journal of Cardiology. Dec 17 1998;82(12a):74U–81U; discussion 85U–86U. doi:10.1016/s0002-9149(98)00731-0
  31. Dunatchik AP, Ito MK, Dujovne CA. A systematic review on evidence of the effectiveness and safety of a wax-matrix niacin formulation. Journal of Clinical Lipidology. Mar–Apr 2012;6(2):121–31. doi:10.1016/j.jacl.2011.07.003
  32. Green PS, Vaisar T, Pennathur S, et al. Combined statin and niacin therapy remodels the high-density lipoprotein proteome. Circulation. Sep 16 2008;118(12):1259–67. doi:10.1161/circulationaha.108.770669
  33. Sorrentino SA, Besler C, Rohrer L, et al. Endothelial-vasoprotective effects of high-density lipoprotein are impaired in patients with type 2 diabetes mellitus but are improved after extended-release niacin therapy. Circulation. Jan 5 2010;121(1):110–22. doi:10.1161/circulationaha.108.836346
  34. Gordon SM, Amar MJ, Jeiran K, et al. Effect of niacin monotherapy on high density lipoprotein composition and function. Lipids in Health and Disease. Aug 21 2020;19(1):190. doi:10.1186/s12944-020-01350-3
  35. Kuvin JT, Dave DM, Sliney KA, et al. Effects of extended-release niacin on lipoprotein particle size, distribution, and inflammatory markers in patients with coronary artery disease. The American Journal of Cardiology. Sep 15 2006;98(6):743–5. doi:10.1016/j.amjcard.2006.04.011
  36. Keenan JM, Fontaine PL, Wenz JB, Myers S, Huang ZQ, Ripsin CM. Niacin revisited. A randomized, controlled trial of wax-matrix sustained-release niacin in hypercholesterolemia. Archives of Internal Medicine. Jul 1991;151(7):1424–32. doi:10.1001/archinte.151.7.1424
  37. Keenan JM. Wax-matrix extended-release niacin vs inositol hexanicotinate: a comparison of wax-matrix, extended-release niacin to inositol hexanicotinate “no-flush” niacin in persons with mild to moderate dyslipidemia. Journal of Clinical Lipidology. Jan–Feb 2013;7(1):14–23. doi:10.1016/j.jacl.2012.10.004

 

Related Articles