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Niacin (nicotinic acid), also known as vitamin B3, is one of eight known B vitamins. It has been used for decades to lower cholesterol and reduce cardiovascular risk. However, today its use is somewhat debated.
Meat and fish are the richest sources of nicotinic acid followed by fortified enriched grain, vegetables, and yeast. Tuna, salmon, chicken, turkey, lamb, beef, pork, mushrooms, legumes, tomatoes, oatmeal, cottage cheese, and leafy greens are all good sources.
Nicotinic acid can be produced by the body from tryptophan, an amino acid found in protein-rich food. Therefore, niacin does not qualify as a vitamin provided that an adequate dietary supply of tryptophan is available.
Nicotinic acid is essential for normal function of the nervous system and the maintenance of healthy skin and mucous membranes. Without it, the body cannot convert food into glucose to produce energy.
In 1937, niacin was found to prevent and cure pellagra, a condition characterized by sensitivity to sunlight, diarrhea, skin lesions, dementia, mental confusion, and inflammation of the mouth and tongue.
Deficiency of nicotinic acid is very rare today. In the U.S. alcoholism is the primary cause of niacin deficiency giving rise to the term alcoholism-related pellagra (1).
In 1955 it was shown that niacin lowers cholesterol in humans (2). Today, it is mostly used to improve blood lipids and reduce the risk of atherosclerotic cardiovascular disease (ASCVD).
The term niacin refers to nicotinic acid and nicotinamide (also called niacinamide). It is important to make a distinction between those two because nicotinamide has not been shown to have any effect on cholesterol and lipoproteins. Hence, in this article and general medical practice, niacin refers to nicotinic acid and not nicotinamide.
The Effects on Lipid Metabolism
Niacin was the first drug discovered to treat high blood levels of cholesterol (hypercholesterolemia). It inhibits the production of very-low-density lipoprotein (VLDL) in the liver and consequently its metabolite, low-density lipoprotein (LDL)(3).
VLDL transports both triglycerides and cholesterol. Once in the circulation, VLDL is broken down in capillary beds, releasing triglycerides for energy utilization by cells or storage in adipose tissue. After triglycerides are released from VLDL, its composition changes, and it becomes intermediate-density lipoprotein (IDL). Later, when the amount of cholesterol increases, IDL becomes low-density lipoprotein (LDL)(4).
Niacin raises high-density lipoprotein cholesterol (HDL-C) by as much as 30-35 percent. This effect is caused by a reduction of cholesterol transfer from HDL to VLDL and delayed clearance of HDL (5). The drug also lowers total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides, and lipoprotein(a).
Hence, there is no doubt that niacin is a very effective lipid-lowering agent. But, to what extent does the lipid-lowering ability translate into less ASCVD?
The Effects on Atherosclerosis
Atherosclerosis is the hallmark of cardiovascular disease. It is caused by a complex interplay between lipoproteins, white blood cells, the immune system and the natural elements of the arterial wall. Atherosclerosis leads to the formation of lesions or plaques that protrude into the lumen of the artery causing arterial narrowing, which can disturb blood flow. A rupture of an atherosclerotic plaque may lead to blood clotting (thrombosis) causing a sudden disruption of blood flow in an artery.
Several clinical studies have addressed the effect of niacin on atherosclerotic plaques by using imaging techniques.
Cholesterol Lowering Atherosclerosis Study (CLAS)
CLAS used coronary angiography to compare niacin plus colestipol with placebo in 103 patients with previous coronary bypass surgery (6). After 4 years significantly more drug-treated subjects demonstrated non-progression (52% drug- vs 15% placebo-treated) and regression (18% drug- vs 6% placebo-treated) in native coronary artery plaques. Significantly fewer drug-treated subjects developed new lesions in native coronary arteries (14% drug- vs. 40% placebo-treated) and bypass grafts (16% drug- vs. 38% placebo-treated).
HDL Atherosclerosis Treatment Study (HATS)
HATS studied simvastatin plus niacin and antioxidant-vitamin therapy, alone and together, compared with placebo, in patients with coronary disease and low HDL-C (7). The anti-oxidant therapy was composed of vitamin E, 1000 mg of vitamin C, 25 mg of natural beta-carotene, and 100 μg of selenium. Simvastatin plus niacin provided marked clinical and angiographically measurable benefits on coronary artery blockages compared with antioxidant vitamin therapy and placebo.
The ARBITER Trials
The Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) trials 2 and 3 were the first studies to suggest a benefit of adding niacin to statin treatment (8,9). Measurements of carotid intima-media thickness (CIMT) were used to assess the efficacy of treatment.
The Oxford Niaspan Study
In 2009, investigators at Oxford University published the results of a 52-week trial examining carotid wall area quantified by magnetic resonance imaging in 71 statin-treated patients with low HDL-C (11). The study found that high-dose modified-release niacin, compared with placebo, significantly reduces carotid atherosclerosis within 12 months.
Summary of the Niacin Imaging Trials
In summary, the results of the niacin atherosclerosis imaging trials are quite impressive. They clearly suggest that the lipid-lowering effects of the drug are accompanied by a regression of atherosclerosis.
But, to what extent does the niacin-induced regression of atherosclerotic plaque burden translate into better prognosis for the patient?
The Clinical Outcome Trials
Four large randomized trials have addressed the effects of niacin on clinical end-points.
Coronary Drug Project (CDP)
The CDP a large randomized placebo-controlled trial conducted during 1966-1974, tested five lipid-lowering agents in 8.341 men with a previous history of heart attack (myocardial infarction)(12). Of those, only niacin remains a viable treatment option today.
Although niacin did not reduce all-cause mortality in the CDP, the rates of recurrent myocardial infarction and stroke were significantly lowered on the drug compared with placebo. The relative reduction was 28% for recurrent myocardial infarction ( 10.7% vs 14.8%) and 21% for stroke (8.8% vs. 11.1%). After a mean follow-up period of 15 years, mortality in the niacin group was 11% lower than in the placebo group (52.0 versus 58.2%; p = 0.0004).
Despite the positive long-term results of the CDP, there were several caveats. Firstly, niacin showed no significant benefit at five-year follow-up for either all-cause or coronary mortality which was the initial target of the study. Secondly, excess incidence of arrhythmias, gastrointestinal side effects, and higher blood glucose levels occurred in the niacin group. Thirdly, as expected, flushing, itching, urticaria, and other types of rash were common side effects of the drug.
The Stockholm Ischaemic Heart Disease Secondary Prevention Study
The study randomized 555 patients following myocardial infarction to niacin plus clofibrate or a control group receiving no lipid-lowering drug therapy (13). All-cause mortality and coronary heart disease mortality were reduced in the drug-treated group by 26 and 36 percent respectively; both are statistically significant. The positive treatment effect was confined to those with triglyceride levels above 143 mg/dL (1.5 mmol/L).
The authors of the paper highlighted that caution should be exercised in the interpretation of the results as the trial was not blind.
Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH)
High levels of triglycerides and low HDL-C is typical for patients with the metabolic syndrome. These patients are at increased risk of cardiovascular events. A 2005 meta-analysis found that the presence of the metabolic syndrome was associated with a 12-17 percent increased risk of cardiovascular mortality, and 6-7 percent increased risk of overall mortality (14).
In patients with established ASCVD, residual cardiovascular risk persists despite the achievement of target LDL-C levels with statin therapy. This is particularly true for patients with low HDL-C and high triglyceride levels (15).
AIM-HIGH was a randomized, double-blind, clinical outcome trial of extended-release (ER) niacin versus placebo in 3.414 patients with established ASCVD, low HDL-C, moderately elevated triglycerides, and treated with a statin (16).
AIM-HIGH was terminated early in May 2011 for futility and because of concern about increased numbers of ischemic strokes in patients treated with niacin, which was not significantly different from placebo after final adjudication. The mean follow-up period was three years. The study found no additional benefit to treatment with niacin.
Several arguments have been put forward to explain the lack of effect of niacin when added to statin treatment in this study. Stabilization of plaque may already have been achieved by statin treatment before randomization to study drug. Secondly, the provision of 100-150 mg of niacin daily in the placebo tablets may have reduced the ability of the trial to detect a benefit of niacin.
Heart Protection Study 2 – Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE)
HPS2-THRIVE randomly assigned 25,673 adults ages 50 to 80 with vascular disease to receive ER niacin 2 grams daily plus laropiprant (to reduce flushing from niacin) or placebo (17). All patients received simvastatin 40 mg daily, and if LDL-C reduction was inadequate with simvastatin, ezetimibe 10 mg daily was added. The study results were published 2014.
There was a relatively long run-in phase to demonstrate that the patients could tolerate simvastatin and then the addition of niacin/laropiprant.
After a median follow-up of 3.9 years, there was no reduction with niacin/laropiprant in the primary endpoint of a first major vascular event (13.2 versus 13.7 percent). There was no benefit either in the subgroup of patients with low HDL-C and elevated triglycerides.
There was a statistically nonsignificant increase in mortality (6.2 versus 5.7 percent). Despite the run-in period, there was an increase in serious adverse events including muscular disorders (myopathy), gastrointestinal side effects, and rash. Niacin/laropiprant worsened glucose control with both an increase in new cases of diabetes and severe disturbance in diabetes control. Additionally, there were unanticipated increases in serious infections.
Because niacin was administered together with laropiprant in HPS2-THRIVE, it is not possible to sort out the effects that might have been due to laropiprant, particularly.
Summary of the Clinical Outcome Trials
Early studies on the clinical efficacy of niacin were promising. The CDP and the Stockholm study indicated that the lipid-lowering effects of the drug might be translated into clinical efficacy and improved survival. This was further supported by data from imaging trials suggesting that treatment might reduce atherosclerotic burden thus favorably affecting the underlying cause of cardiovascular disease.
There is no denying that the results of AIM-HIGH and HPS2-THRIVE were a huge disappointment. Before these trial data were available, niacin was one of the most promising drugs available for modifying the course of ASCVD.
After two years in AIM-High, niacin therapy had significantly increased the median HDL-cholesterol level from 35 mg/dL (0.91 mmol/L) to 42 mg/dL (1.08 mmol/L), lowered the triglyceride level from 164 mg/dL(1.85 mmol/L) to 122 mg/dL (1.38 mmol/L), and lowered the LDL cholesterol level from 74 mg/dL (1.91 mmol/L) to 62 mg/dL (1.60 mmol/L). Surprisingly, these effects were not translated into improved clinical outcome.
Given the adverse effects of adding niacin/laropiprant to statin treatment in HPS2-THRIVE, adding niacin to statin treatment should be avoided. Although there may be some exceptions to this rule, such as patients at extremely high risk, such combination therapy should be used with extreme caution.
Flushing is a very common side effect of niacin. At standard doses (1.5 to 4.5 g/day), flushing occurs in 80 percent of patients and itching, paresthesias, and nausea each occur in about 20 percent (18). These adverse effects often diminish over time. Flushing may be less frequent with controlled release Niaspan (19).
Gastrointestinal side effects are common but may be less frequent if niacin is taken with food.
With the immediate release (IR) preparation of niacin, taking aspirin (325 to 650 mg) 30 minutes prior to dosing or ibuprofen (200 mg) 60 minutes before dosing can reduce flushing.
Elevation of liver enzymes is relatively common on and may progress to liver damage. Therefore, regular monitoring of liver tests is mandatory.
Niacin may cause insulin resistance and raise fasting glucose levels (13).
Niacin may increase plasma levels of uric acid and precipitate acute gouty arthritis. The drug should be avoided in patients with a history of gout.
Nicotinic acid is available in several formulations that include immediate-release (crystalline) and sustained release formulations such as Niacor and Niaspan.
Over the counter preparations that are marketed as causing “no flush” may have no free nicotinic acid and are therefore ineffective for treating lipid abnormalities.
Immediate-release niacin preparations are inexpensive, contain a full amount of free nicotinic acid, and are safer than most sustained-release preparations (20).
The immediate-release preparations are often available over the counter. A doctor’s prescription is usually needed for sustained released formulations of niacin such as Niacor and Niaspan.
The Take-Home Message
Niacin (nicotinic acid), also known as vitamin B3, is one of eight known B vitamins.
Deficiency of niacin is very rare today, hence supplements are seldom needed.
Niacin, or nicotinic acid, was the first pharmaceutical agent discovered to treat hypercholesterolemia.
It is a potent lipid lowering drug and reduces total cholesterol, LDL-cholesterol, triglycerides, and lipoprotein(a) and raises HDL-cholesterol.
Several imaging studies suggest that it reduces atherosclerotic plaque burden.
In 2011 and 2014, the clinical rationale for the use of the niacin encountered a roadblock when two large randomized trials (AIM-HIGH and HPS2-THRIVE) showed that the addition of the drug to intensive statin treatment of patients with cardiovascular disease did not improve clinical outcome.
Hence, in the modern era of intensive statin use, the use of niacin as a lipid-lowering agent may be of limited value.Thus, its use should be limited to high-risk individuals and those who are intolerant to statins.
The use of niacin is associated with several adverse effects among which flushing, itching, skin rash, and indigestion are most common. More severe side effects such as elevation of liver enzymes and raised blood glucose are also fairly common.