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Niacin to Lower "Cholesterol" - 9A

Other Cholesterol Lowering Drugs

Many statin drugs are now “off-patent.” That means these drugs can be manufactured by generic drug companies and offered at a lower cost than when they were protected under patent laws. Subsequently, the pharmaceutical industry developed a whole new set of drugs to lower cholesterol that are "on patent" to garner higher profits.

Scientific American weighed in on the value of new versus old drugs in an article titled "When Older Drugs are Better Drugs."[i]

"The trend toward using newer medications often develops during doctor residency training. Pharmaceutical firms market their products to young doctors in all specialties. Whether with free meals, medical tools, or travel scholarships, pharmaceutical companies find ways to influence doctors’ prescribing practices. Because most physicians continue recommending the medications they learned in residency, these companies strategically expose residents to newer medications that are still under patent and thus far more profitable for the manufacturers."

Importantly, both new and old cholesterol-lowering drugs provide strong evidence that lowering LDL is not beneficial to your heart. According to the CDC, the following drugs lower LDL or cholesterol.

  • Statins. These drugs lower LDL cholesterol by slowing down the liver’s production of cholesterol. They also increase the liver’s ability to remove LDL cholesterol that is already in the blood.

  • Bile acid sequestrants. Bile acid sequestrants help remove cholesterol from the bloodstream by removing bile acids. The body needs bile acids and makes them by breaking down LDL cholesterol.

  • Niacin, or nicotinic acid. Niacin is a B vitamin that can "improve" (should say "change") all lipoprotein levels. Nicotinic acid raises high-density lipoprotein (HDL) cholesterol levels while lowering total cholesterol, LDL cholesterol, and triglyceride levels.

  • Fibrates. They mainly lower triglycerides.

  • Injectable medicine. A newer type of drug called PCSK9 inhibitors lowers cholesterol (wrong, they lower LDL exclusively). These medicines are primarily used in people who have familial hypercholesterolemia, a genetic condition that causes very high levels of LDL cholesterol. (Note, that was not their original intent).


Niacin has a fantastic therapeutic profile as opposed to a fantastic therapeutic effect.

That is, all the lipid levels change for the presumed better on high-dose niacin. Surely heart disease must go down under these circumstances. However, such is not the case. The NEJM published a paper with an interesting title.

"Niacin at 56 Years of Age - Time for an Early Retirement?"[i]

This is another paper the medical community is fearful to acknowledge because it goes against the cholesterol-lowering doctrine. Published in 2011, it has been cited just 36 times, whereas articles touting the benefits of statins often are quoted thousands of times. The "Early Retirement" paper is written by Robert P Giugliano, MD, Associate Professor of Cardiovascular Medicine at Harvard Medical School. He is a man with a sense of humor. He wrote,

"Despite the achievement of the expected favorable changes in the levels of HDL (an increase of 25 percent), LDL (a decrease of 12 percent), and triglycerides (a decrease of 29 percent) with niacin, the clinical results were chillingly null; niacin did not reduce the incidence of the primary composite endpoint (reducing heart disease), nor did it show any clinical benefit overall or in a major subgroup. The trial was stopped early by the independent data and safety monitoring board because the boundary for futility had been crossed, and

an unexpectedly higher number of ischemic strokes was observed in patients assigned to niacin."

The moral of this story is do not mess with your lipids, even with a seemingly natural substance. The dose makes the poison.

[i] Giugliano, Robert P. "Niacin at 56 years of age–time for an early retirement." N Engl J Med 365.24 (2011): 2318-20.


Here is the full paper...

A reduction in serum cholesterol with niacin therapy in humans was first described in 1955, when Altschul and colleagues reported, in a letter to the editor, the findings in 11 healthy medical students and 57 patients.1 Subsequent clinical studies showed multiple favorable effects of niacin therapy on lipid particles, including decreases in levels of low-density lipoprotein (LDL) cholesterol, triglycerides, small dense LDL cholesterol, very-low-density lipoprotein, lipoprotein(a), and apolipoprotein Β and increases in levels of high-density lipoprotein (HDL) cholesterol and selective lipoprotein A-1 particles.2 The mechanism of action of niacin is complex, involves several biochemical pathways, and is still not well defined.3

The current indications for niacin — reducing the risk of reinfarction, favorably altering lipid levels, and slowing the progression of atherosclerosis — are derived from three lines of evidence: the Coronary Drug Project (CDP),4 studies of combination therapy consisting of niacin and a second lipid-lowering agent, and evaluation of surrogate markers.

From 1966 through 1969, the CDP enrolled 8341 men, 40 to 64 years of age, with a prior myocardial infarction to one of five lipid-modifying therapies. There was no significant difference between the men who were treated with niacin (1119 subjects) and those who received a placebo (2789 subjects) in the primary endpoint of the rate of death from any cause (24.4% and 25.4%, respectively) over a minimum follow-up period of 5 years. However, the rates of myocardial infarction and cerebrovascular events were significantly reduced with niacin — by 26% and 24%, respectively.

It is worth noting, however, that 40 or more years ago, many therapies that have since been proven to reduce mortality or morbidity after myocardial infarction either were not routinely administered (e.g., aspirin and beta-blockers) or were not yet available (e.g., statins, inhibitors of the renin–angiotensin–aldosterone system, P2Y12 inhibitors, and implantable defibrillators).

The second line of evidence, derived from studies of combined therapy consisting of niacin and a second lipid-lowering drug, does not inform us about the benefit of adding niacin alone to background therapy; for example, in the HDL-Atherosclerosis Treatment Study ( number, NCT00000553), was it simvastatin, simvastatin plus niacin, or niacin alone that was responsible for the observed clinical benefit? 5 Finally, studies using surrogate markers (e.g., carotid intima–media thickness) remain controversial,6 since they have shown inconsistent results, even when proven lipid-modifying therapies that clearly reduce clinical endpoints have been evaluated by these means.7,8

Thus, a critical appraisal of the prior studies of niacin reveals three shaky pillars supporting its clinical efficacy and identifies a need for large, modern trials of clinical endpoints. The first of these is reported in this issue of the Journal. 9 The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes trial (AIMHIGH, NCT00120289)9 was designed with 85% power to show a 25% reduction in the primary endpoint (a composite of the first event of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization), with the addition of 1500 to 2000 mg of niacin per day in patients 45 years of age or older with established cardiovascular disease and atherogenic dyslipidemia.

The trial was cast as a test of the HDL-raising effects of niacin, but as shown in the causal diagram10 in Figure 1, any clinical benefit observed with niacin would be difficult to attribute solely to the effect on HDL. The strengths of the trial design include the efforts made to maintain the double-blinding (blinding of lipid values other than LDL and administration of very low doses of niacin in the placebo group), the well-controlled LDL cholesterol level achieved (a median of <70 mg per deciliter [1.81 mmol per liter]), the event-driven design, and the low rates of loss to follow-up (0.7%) and withdrawal of consent (0.8%).

Despite the achievement of the expected favorable changes in the levels of HDL cholesterol (an increase of 25%), LDL cholesterol (a decrease of 12%), and triglycerides (a decrease of 29%) with niacin, the clinical results were chillingly null; niacin did not reduce the incidence of the primary composite endpoint, nor did it show any clinical benefit overall or in a major subgroup. The trial was stopped early by the independent data and safety monitoring board because the boundary for futility had been crossed, and an unexpectedly higher number of ischemic strokes was observed in patients assigned to niacin.

What are the potential explanations for these findings? It is important to understand that although the event rate was lower than initially projected, it would be incorrect to conclude that the study was designed with insufficient power since, by definition, an event-driven trial is adequately powered for the number of events and the treatment effect specified. Rather, the assumption of a 25% treatment effect appears to have been too generous given the modest absolute difference between the treatment groups in the HDL cholesterol levels achieved (a difference of 4 to 5 mg per deciliter [0.10 to 0.13 mmol per liter]), the low LDL cholesterol levels achieved owing to potent background lipid therapy (with approximately 75% of the patients in the placebo group receiving simvastatin at doses ≥40 mg, and approximately 20% receiving combination therapy consisting of ezetimibe plus simvastatin), and a 25% rate of premature discontinuation in the niacin group.

Although the numeric excess in ischemic strokes (which, after inclusion of three upgraded events identified during a post hoc re-review of investigator-reported transient ischemic attacks, yielded a borderline significant result) is of concern, there are several reasons, internal and external to the study, that raise doubts regarding a causal relationship. No prior study or meta-analysis with niacin had observed a similar imbalance in ischemic stroke (in fact, the rate of total stroke was reduced by approximately 20% in the CDP), and no plausible biologic mechanism has been advanced.

[I'll give you one - inadequate supply of lipids to repair damaged vessels. These vessels slowly become inflamed, and their structure is compromised, leading to an "ischemic (bursting) event. Harvard, you know better!]

Furthermore, eight patients (all in the niacin group) had a stroke 2 months or more after discontinuation of the drug. Finally, the specter of a spurious association between a therapy and a low-frequency unexpected event in a moderate-sized trial, when multiple endpoints are evaluated without statistical adjustment for multiplicity of testing, is not new to the lipid field.11 Nonetheless, the disappointing results of AIMHIGH do not provide support for the use of niacin as an add-on therapy to statins in patients with preexisting stable cardiovascular disease who have well-controlled LDL cholesterol levels.

Given the lack of efficacy shown in this trial, the frequent occurrence of flushing with niacin therapy that some patients find intolerable, and the unresolved question of an increased risk of ischemic stroke, one can hardly justify the continued expenditure of nearly $800 million per year in the United States for branded extended-release niacin.12 However, before holding a final retirement party for niacin, it would appear to be more prudent to assign it to occasional part-time work, such as in statin-intolerant patients (see the Perspective article by Maningat and Breslow13), while we await the results from the much larger Heart Protection Study 2: Treatment of HDL to Reduce the Incidence of Vascular Events trial (HPS2- THRIVE, NCT00461630),14 which is targeted to be completed in 2013.

Regardless of whether niacin is ultimately retired or not, one should not abandon the HDL-raising hypothesis altogether. Several ongoing studies15,16 with other promising drugs that raise HDL cholesterol levels substantially (by as much as 150%) by means of different mechanisms and that, in some cases, can lower LDL cholesterol levels by as much as 40% are well underway.

Disclosure forms provided by the author are available with the full text of this article at From the Cardiovascular Medicine Division, Brigham and Women’s Hospital, Harvard Medical School, Boston.

This article (10.1056/NEJMe1112346) was published on November 15, 2011, at


1. Altschul R, Hoffer A, Stephen JD. Influence of nicotinic acid on serum cholesterol in man. Arch Biochem Biophys 1955;54: 558-9. 2. Kamanna VS, Kashyap ML. Mechanism of action of niacin on lipoprotein metabolism. Curr Atheroscler Rep 2000;2:36-46. 3. Hochholzer W, Berg DD, Giugliano RP. The facts behind niacin. Ther Adv Cardiovasc Dis 2011;5:227-40. 4. Clofibrate and niacin in coronary heart disease. JAMA 1975;231:360-81. 5. Brown BG, Zhao X-Q, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345:1583-92. 6. Polak JF, Pencina MJ, Pencina KM, O’Donnell CJ, Wolf PA, D’Agostino RB. Carotid-wall intima–media thickness and cardiovascular events. N Engl J Med 2011;365:213-21. 7. Carotid Atorvastatin Study in Hyperlipidemic Post-Menopausal Women. a Randomised Evaluation of Atorvastatin versus Placebo (CASHMERE) (NCT#00163163). Pfizer PhRMA Web synopsis protocol A2581051. Final report. October 29, 2007 (http:// .pdf). 8. Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet 2001;357:577-81. 9. The AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255-67. 10. Greenland S, Pearl J, Robins JM. Causal diagrams for epidemiologic research. Epidemiology 1999;10:37-48. 11. Peto R, Emberson J, Landray M, et al. Analyses of cancer data from three ezetimibe trials. N Engl J Med 2008;359:1357- 66. 12. DrugPatentWatch. Niaspan patent expiration dates, annual sales, and drug therapeutic class (http://www.drugpatentwatch .com). 13. Maningat P, Breslow JL. Needed: pragmatic clinical trials for statin-intolerant patients. N Engl J Med 2011;365:2250-1. 14. Heart Protection Study 2: treatment of HDL to reduce the incidence of vascular events. (NCT #00461630). HPS2 THRIVE home page ( 15. Cannon CP, Shah S, Dansky HM, et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med 2010;363:2406-15. 16. Schwartz GG, Olsson AG, Ballantyne CM, et al. Rationale and design of the dal-OUTCOMES trial: efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome. Am Heart J 2009;158(6):896.e3-901.e3.

Copyright © 2011 Massachusetts Medical Society


Index & Upcoming (short) blogs on cholesterol and statins

Number 1: Cholesterol fun (true) facts - completed

Number 2: Is the actual cholesterol molecule important? c - completed

Number 3: What is an optimal TC value? Remember, no one knows their actual cholesterol molecule value. - completed

Number 4: Surprising fact about cholesterol as an antibiotic - completed

Number 5: TC simple math - dumb doctors - completed

Number 6: What is LDL really? - completed

Number 7: Statins - do they lower the cholesterol molecule? - completed

Number 8: What did we learn from the new "biologics" to lower "cholesterol" - completed

Number 9: Niacin and other "cholesterol" management treatments

Number 10: What did Natasha Campbell-McBride say about cholesterol/lipids?

Number 11: What is a QALY, and how does it relate to "cholesterol"?

Number 12: Idiot doctor from Johns Hopkins, Roger Blumenthal

Number 13: Who says statins do NOT extend life?


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1 Comment

Ramon Chávez
Ramon Chávez
Dec 05, 2023

Niacin not just help with lipid levels but is a precursor of NAD which is essential for metabolic homeostasis.☺️

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