- What is nicotinic acid
- Nicotinic acid vs niacin
- Nicotinic acid benefits
- Nicotinic acid mechanism of action
- Nicotinic acid uses
- Nicotinic acid contraindications
- Nicotinic acid food sources
- Nicotinic acid dosage
What is nicotinic acid
Nicotinic acid is also known as Niacin (a combination of nicotinamide and nicotinic acid) or vitamin B3 1). Nicotinic acid (niacin or vitamin B3) is one of the water-soluble B vitamins. Niacin is naturally present in many foods, added to some food products, and available as a dietary supplement.
Niacin is a B vitamin that’s made and used by your body to turn food into energy. Niacin helps keep your nervous system, digestive system and skin healthy.
Niacin (vitamin B3) is often part of a daily multivitamin, but most people get enough niacin from the food they eat. Foods rich in niacin include yeast, milk, meat, tortillas and cereal grains.
Niacin is a B vitamin that’s made and used by your body to turn food into energy. Niacin helps keep your nervous system, digestive system and skin healthy.
Niacin (vitamin B3) is often part of a daily multivitamin, but most people get enough niacin from the food they eat. Foods rich in niacin include yeast, milk, meat, tortillas and cereal grains.
Most people in the United States consume more than the Recommended Dietary Allowance (RDA) for niacin. An analysis of data from the 2015–2016 National Health and Nutrition Examination Survey (NHANES) found that the average daily niacin intake from foods and beverages was 21.4 mg for ages 2–19 2). In adults, the average daily niacin intake from foods and beverages was 31.4 mg in men and 21.3 mg in women. An analysis of data from the 2009-2012 NHANES found that only 1% of adults had intakes of niacin from foods and beverages below the Estimated Average Requirement (EAR, the average daily level of intake estimated to meet the requirements of 50% of healthy individuals; usually used to assess the nutrient intakes of groups of people and to plan nutritionally adequate diets for them; can also be used to assess the nutrient intakes of individuals) 3). Among all racial and ethnic groups, Hispanics had the greatest prevalence, 1.3%, of niacin intakes below the EAR 4).
According to self-reported data from the 2013-2014 NHANES, 21% of all individuals aged 2 and older took a dietary supplement containing niacin 5). The proportion of users increased with age from 8% of those aged 12-19 years to 39% of men and 40% of women aged 60 and older. Supplement use doubled or tripled total niacin intakes compared with intakes from diet alone. According to data from the 2003-2006 NHANES, 10% of all individuals aged 2 and older who took dietary supplements had total niacin intakes that reached or exceeded the Tolerable Upper Intake Level (UL or the Maximum daily intake unlikely to cause adverse health effects) 6).
Niacin has seen extensive use, alone or in combination, with statin medications (hydroxymethyl glutaryl coenzyme A reductase or HMG-CoA inhibitors) in the reduction of total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, very-low-density lipoprotein (VLDL), and lipoprotein levels. People use prescription niacin (Niacor, Niaspan) to help control their cholesterol. Moreover, niacin is the most potent agent used to increase plasma high-density lipoprotein (HDL) cholesterol 7). In patients with diabetes mellitus or mixed dyslipidemia, niacin has demonstrated in clinical trials that it can counterbalance cardiovascular risk in this patient population, hence decreasing cardiovascular morbidity and mortality, especially when used in combination with statin drugs 8).
The recommended daily amount of niacin for adult males is 16 milligrams (mg) a day and for adult women who aren’t pregnant, 14 mg a day.
All tissues in the body convert absorbed niacin into its main metabolically active form, the coenzyme nicotinamide adenine dinucleotide (NAD). More than 400 enzymes require NAD to catalyze reactions in the body, which is more than for any other vitamin-derived coenzyme 9). Nicotinamide adenine dinucleotide (NAD) is also converted into another active form, the coenzyme nicotinamide adenine dinucleotide phosphate (NADP), in all tissues except skeletal muscle 10).
NAD and NADP are required in most metabolic redox processes in cells where substrates are oxidized or reduced. NAD is primarily involved in catabolic reactions that transfer the potential energy in carbohydrates, fats, and proteins to adenosine triphosphate (ATP), the cell’s primary energy currency 11). NAD is also required for enzymes involved in critical cellular functions, such as the maintenance of genome integrity, control of gene expression, and cellular communication 12). NADP, in contrast, enables anabolic reactions, such as the synthesis of cholesterol and fatty acids, and plays a citical role in maintaining cellular antioxidant function.
Most dietary niacin is in the form of nicotinic acid and nicotinamide, but some foods contain small amounts of NAD and NADP. The body also converts some tryptophan, an amino acid in protein, to NAD, so tryptophan is considered a dietary source of niacin.
When NAD and NADP are consumed in foods, they are converted to nicotinamide in the gut and then absorbed 13). Ingested niacin is absorbed primarily in the small intestine, but some is absorbed in the stomach 14).
Even when taken in very high doses of 3–4 g, niacin is almost completely absorbed. Once absorbed, physiologic amounts of niacin are metabolized to NAD. Some excess niacin is taken up by red blood cells to form a circulating reserve pool. The liver methylates any remaining excess to N1-methyl-nicotinamide, N1-methyl-2-pyridone-5-carboxamide, and other pyridone oxidation products, which are then excreted in the urine. Unmetabolized nicotinic acid and nicotinamide might be present in the urine as well when niacin intakes are very high.
Levels of niacin in the blood are not reliable indicators of niacin status. The most sensitive and reliable measure of niacin status is the urinary excretion of its two major methylated metabolites, N1-methyl-nicotinamide and N1-methyl-2-pyridone-5-carboxamide 15). Excretion rates in adults of more than 17.5 micromol/day of these two metabolites reflect adequate niacin status, while excretion rates between 5.8 and 17.5 micromol/day reflect low niacin status. An adult has deficient niacin status when urinary-excretion rates are less than 5.8 micromol/day. Indicators of inadequacy such as this and other biochemical signs (e.g., a 2-pyridone oxidation product of N1-methyl-nicotinamide below detection limits in plasma or low erythrocyte NAD concentrations) occur well before overt clinical signs of deficiency 16). Another measure of niacin status takes into account the fact that NAD levels decline as niacin status deteriorates, whereas NADP levels remain relatively constant 17). A “niacin number” (NAD/[NAD + NADP] concentrations in whole blood x 100) below 130 suggests niacin deficiency 18). A “niacin index” (the ratio of erythrocyte NAD to NADP concentrations) below 1 suggests that an individual is at risk of developing niacin deficiency 19). No functional biochemical tests that reflect total body stores of niacin are available 20).
When taken orally in appropriate amounts, niacin appears to be safe.
High doses of niacin available via prescription can cause:
- Severe skin flushing combined with dizziness
- Rapid heartbeat
- Nausea and vomiting
- Abdominal pain
- Liver damage
Serious side effects are most likely if you take between 2,000 to 6,000 mg of niacin a day. If you think you might have overdosed on niacin, seek medical attention immediately.
If you have liver disease, peptic ulcer disease or severe low blood pressure (hypotension), don’t take large amounts of niacin. The supplement has been linked with liver damage, can cause hypotension and might activate a peptic ulcer.
Taking niacin also might worsen allergies, gallbladder disease and symptoms of certain thyroid disorders. If you have diabetes, niacin can interfere with blood glucose control. Use niacin with caution if you have the complex form of arthritis gout. Niacin can cause an excess of uric acid in the blood (hyperuricemia), putting you at risk of gout.
If you’re pregnant, don’t take prescription niacin for high cholesterol. However, if needed to prevent or treat niacin deficiency, niacin is likely safe to take during pregnancy and in breast-feeding women when used in recommended amounts.
Figure 1. Niacin (Nicotinamide + Nicotinic acid)
Nicotinic acid deficiency
Severe niacin deficiency leads to pellagra, a disease characterized by a pigmented rash or brown discoloration on skin exposed to sunlight; the skin also develops a roughened, sunburned-like appearance 21). In addition, pellagra can cause a bright red tongue and changes in the digestive tract that lead to vomiting, constipation, or diarrhea. The neurological symptoms of pellagra can include depression; apathy; headache; fatigue; loss of memory that can progress to aggressive, paranoid, and suicidal behaviors; and auditory and visual hallucinations 22). As pellagra progresses, anorexia develops, and the affected individual eventually dies 23).
The symptoms of pellagra include:
- Digestive problems
- Inflamed skin
- Mental impairment
Pellagra is uncommon in industrialized populations and is mostly limited to people living in poverty, such as refugees and displaced people who eat very limited diets low in niacin and protein 24). Pellagra was not uncommon in the early 20th century among individuals living in poverty in the southern United States and parts of Europe whose limited diets consisted mainly of corn 25). The World Health Organization (WHO) recommends treating pellagra with 300 mg/day nicotinamide in divided doses for 3-4 weeks along with a B-complex or yeast product to treat likely deficiencies in other B vitamins 26).
Although frank niacin deficiencies leading to pellagra are very rare in the United States, some individuals have marginal or low niacin status 27).
Groups at risk of Niacin Inadequacy
Niacin inadequacy usually arises from insufficient intakes of foods containing niacin and tryptophan. It can also be caused by factors that reduce the conversion of tryptophan to niacin, such as low intakes of other nutrients 28). The following groups are among those most likely to have inadequate niacin status.
- People with undernutrition: People who are undernourished because they live in poverty or have anorexia, alcohol use disorder, AIDS, inflammatory bowel disease, or liver cirrhosis often have inadequate intakes of niacin and other nutrients 29).
- People with inadequate riboflavin, pyridoxine, and/or iron intakes: People who do not consume enough riboflavin (vitamin B2), pyridoxine (vitamin B6), or iron convert less tryptophan to niacin because enzymes in the metabolic pathway for this conversion depend on these nutrients to function 30).
- People with Hartnup disease: Hartnup disease is a rare genetic disorder involving the renal, intestinal, and cellular transport processes for several amino acids, including tryptophan. Hartnup disease interferes with the absorption of tryptophan in the small intestine and increases its loss in the urine via the kidneys 31). As a result, the body has less available tryptophan to convert to niacin.
- People with carcinoid syndrome: Carcinoid syndrome is caused by slow-growing tumors in the gastrointestinal tract that release serotonin and other substances. It is characterized by facial flushing, diarrhea, and other symptoms. In those with carcinoid syndrome, tryptophan is preferentially oxidized to serotonin and not metabolized to niacin 32). As a result, the body has less available tryptophan to convert to niacin.
Niacin can interact with certain medications, and several types of medications might adversely affect niacin levels. A few examples are provided below. Individuals taking these and other medications on a regular basis should discuss their niacin status with their healthcare providers.
Possible interactions include:
- Alcohol. Taking niacin with alcohol might increase the risk of liver damage and worsen niacin side effects, such as flushing and itching.
- Allopurinol (Zyloprim). If you’re taking niacin and have gout, you might need to take more of this gout medicine to control your gout.
- Anticoagulant and anti-platelet drugs, herbs and supplements. These types of drugs, herbs and supplements reduce blood clotting. Taking niacin with them might increase your risk of bleeding.
- Blood pressure drugs, herbs and supplements. Niacin might have an additive effect when you take blood pressure drugs, herbs or supplements. This could increase your risk of low blood pressure (hypotension).
- Chromium. Taking niacin with chromium might lower your blood sugar. If you have diabetes and take niacin and chromium, closely monitor your blood sugar levels.
- Diabetes drugs. If you have diabetes, niacin can interfere with blood glucose control. You might need to adjust the dose of your diabetes drugs. Large doses of nicotinic acid can raise blood glucose levels by causing or aggravating insulin resistance and increasing hepatic production of glucose. Some studies have found that nicotinic acid doses of 1.5 g/day or more are most likely to increase blood glucose levels in individuals with or without diabetes 33). People who take any antidiabetes medications should have their blood glucose levels monitored if they take high-dose nicotinic acid supplements concomitantly because they might require dose adjustments.
- Hepatotoxic drugs, herbs and supplements. These drugs, herbs and supplements, like niacin, cause liver damage.
- Statins. Research indicates that taking niacin with these cholesterol medications offers little additional benefit when compared with statins alone, and might increase the risk of side effects.
- Zinc. Taking zinc with niacin might worsen niacin side effects, such as flushing and itching.
- Isoniazid and pyrazinamide (together in Rifater®), used to treat tuberculosis, are structural analogs of niacin and interrupt the production of niacin from tryptophan by competing with a vitamin B6-dependent enzyme required for this process 34). In addition, isoniazid can interfere with niacin’s conversion to NAD. Although pellagra can occur in patients with tuberculosis treated with isoniazid, it can be prevented with increased intakes of niacin.
Nicotinic acid vs niacin
Niacin is a combination of nicotinamide and nicotinic acid. Nicotinamide (Figure 1) is the amide form of vitamin B3 (niacin) and is obtained through synthesis in the body or as a dietary source and supplement 35). Nicotinic acid is the other form of the water soluble vitamin B3 (Figure 1). Although also present from animal sources, the principal form of niacin in dietary plant sources is nicotinic acid that is rapidly absorbed through the gastrointestinal epithelium 36). Nicotinamide is subsequently generated through the conversion of nicotinic acid in the liver or through the hydrolysis of NAD+. Once nicotinamide is obtained in the body, it functions as the precursor for the coenzyme ß-nicotinamide adenine dinucleotide (NAD+) 37) and also is essential for the synthesis of nicotinamide adenine dinucleotide phosphate (NADP+) 38). Initially, nicotinamide is changed to its mononucleotide form (NMN) with the enzyme nicotinic acid/nicotinamide adenylyltransferase yielding the dinucleotides NAAD+ and NAD+. NAAD+ also yields NAD+ through NAD+ synthase 39) or NAD+ can be synthesized through nicotinamide riboside kinase that phosphorylates nicotinamide riboside to NMN 40). These cellular pathways are essential for energy
metabolism and may directly impact normal physiology, as well as disease progression 41).
Nicotinic acid benefits
Very high doses of nicotinic acid—more than 100 times the Recommended Dietary Allowance (RDA)—taken for months or years are effective treatments for dyslipidemias. Nicotinamide does not have this effect because, unlike nicotinic acid, it does not bind to the receptors that mediate nicotinic acid’s effects on lipid profiles 42). Studies conducted since the late 1950s show that these doses can increase high-density lipoprotein (HDL; “good”) cholesterol levels by 10-30% and reduce low-density lipoprotein (LDL; “bad”) cholesterol levels by 10-25%, triglyceride levels by 20-50%, and lipoprotein(a) levels by 10-30% 43). Together, these changes in lipid parameters might be expected to reduce the risk of first-time or subsequent cardiac events, such as heart attacks and strokes, in adults with atherosclerotic cardiovascular disease. However, despite dozens of published clinical trials, experts do not agree on the value of nicotinic acid to treat cardiovascular disease, especially given its side effects, safety concerns, and poor patient compliance 44).
In one large clinical trial from the 1970s 45), 8,341 participants aged 30 to 64 years who had had one or more heart attacks were randomized to take one of five lipid-lowering medications, including 3,000 mg/day nicotinic acid, or a placebo for an average of 6.2 years. Those taking nicotinic acid lowered their serum cholesterol levels by an average of 9.9% and triglyceride levels by 26.1% over 5 years of treatment. During 5 to 8.5 years of treatment, these participants had significantly fewer nonfatal myocardial infarctions but more cardiac arrhythmias than those in the placebo group. Their overall rates of mortality and cause-specific mortality, including from coronary heart disease, did not decline. But 9 years after the study ended, participants who had taken the nicotinic acid experienced significantly fewer (11%) deaths from all causes than those who had taken the placebo 46).
Statin medications have become the treatment of choice for hyperlipidemia and lowering the risks of atherosclerotic cardiovascular disease. For this reason, clinical trials of nicotinic acid in the past several decades have examined whether it provides any additional cardiovascular protection to people taking statins 47).
In the largest international, multicenter, clinical trial of nicotinic acid to date, 25,673 adults aged 50-80 years (83% men) with cardiovascular disease who were taking a statin were randomized to take 2 g/day extended-release nicotinic acid with a medication to reduce nicotinic acid’s flushing effect and therefore improve treatment compliance or a matching placebo for a median of 4 years 48). The nicotinic acid group had a mean reduction in LDL cholesterol (of 10 mg/dl) and triglycerides (of 33 mg/dl) and an increase in HDL cholesterol (of 6 mg/dl), but this group had no significant reduction in rates of major vascular events compared with the placebo (statin-only) group. Furthermore, the nicotinic acid group had a significantly greater risk of diabetes, gastrointestinal dyspepsia, diarrhea, ulceration, bleeding events in the gut and brain, and skin rashes and ulcerations. An earlier randomized clinical trial of 3,414 patients with established cardiovascular disease was stopped after 3 years when the researchers found that patients taking niacin (1,500-2,000 mg/day extended release) in addition to their cholesterol-reduction medications did not have fewer cardiovascular events than those taking medication alone, even though the niacin reduced triglyceride and LDL-cholesterol levels further and raised HDL cholesterol levels further 49). The results also showed that patients taking niacin had an increased risk of ischemic stroke.
The authors of two 2017 systematic reviews examining the clinical trial data concluded that nicotinic acid therapy provides little if any protection from atherosclerotic heart disease, even though the therapy raises HDL cholesterol levels and lowers total cholesterol, LDL cholesterol, and triglyceride levels. One of these reviews examined 23 randomized controlled trials of moderate to high quality in 39,195 participants aged 33-71 years (average 65 years; majority were male). Some had experienced a heart attack, and most were taking a statin. The doses used and treatment duration in these studies varied widely; the median dose of nicotinic acid was 2 g/day (range 0.5 to 4 g/day) for a median of 11.5 months (range 6 months to 6 years) 50). Overall, use of nicotinic acid did not reduce overall mortality or cardiovascular mortality rates or the number of fatal or nonfatal myocardial infarctions or strokes. Eighteen percent of participants taking nicotinic acid discontinued treatment because of side effects. The second review examined 13 randomized controlled trials with 35,206 participants with, or at risk of, atherosclerotic cardiovascular disease 51). Overall, the addition of nicotinic acid supplementation (dose range not specified) to statin therapy taken for a mean of 33 months (with a broad range of 6 to 60 months) did not lead to significant reductions in rates of all-cause or cardiovascular mortality, myocardial infarction, or stroke. Nicotinic acid treatment was associated with a significantly higher risk of gastrointestinal and musculoskeletal adverse events. In addition, four of the studies that examined diabetes as an outcome found that the patients taking niacin had a significantly higher risk of developing the disease.
A 2018 review of three randomized controlled trials with 29,195 patients found that all-cause mortality increased by 10% more in those who took 1 to 3 g/day extended release nicotinic acid in addition to a statin medication than patients taking the statin alone 52).
In their guidelines for lowering blood cholesterol levels, the American College of Cardiology and the American Heart Association advise that nonstatin therapies, compared with or in addition to statin therapy, do not provide atherosclerotic cardiovascular disease risk-reduction benefits that outweigh the potential harms of their adverse effects 53). When discussing the use of nicotinic acid supplements to reduce the risk of hyperlipidemia (for example, in patients unable to tolerate statin medications), the two professional societies recommend that patients take 500 mg/day extended-release nicotinic acid supplements and increase the dose to a maximum of 2,000 mg/day over 4 to 8 weeks or take 100 mg immediate-release nicotinic acid three times a day and increase the dose to 3,000 mg/day divided into two or three doses. Their joint statement about monitoring supplement users who take niacin to reduce hyperlipidemia risk for adverse effects is described in the health risks from excessive niacin section below. In their 2018 report, these two professional societies stated what although niacin may be useful in some cases of severe hypertriglyceridemia, it has only mild LDL-lowering effects. The societies therefore do not recommend using it as an add-on drug to statin therapy 54).
Overall, the evidence indicates that nicotinic acid supplementation improves blood lipid profiles but has no significant effects on risk of cardiovascular events. Although nicotinic acid is a nutrient, if very high doses (thousands of mg) are taken to treat hyperlipidemias, the supplement is being used as a drug. Such doses should only be taken with medical approval and supervision.
Nicotinic acid mechanism of action
Niacin, after undergoing biochemical reactions in the mitochondria with nicotinamide, and tryptophan forms nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP). NAD and NADP are the active forms of niacin which, when reduced to NAD(H) and NADP(H) respectively, participates in catabolic redox reactions and are cofactors in anabolic redox reactions.
Although niacin has been in use for many years, its beneficial pleiotropic effects make it a challenge to grasp its mechanism of action fully. However, a targeted mechanism of action based on certain effects niacin has in the human body are:
Niacin Antihyperlipidemic Activity
Lipid-lowering ability of niacin is very diverse and still under investigation. The exact mechanism of action by which niacin lowers cholesterol is not fully understood, it may act by inhibiting the synthesis of very low density lipoprotein (VLDL), inhibiting the release of free fatty acids from adipose tissue, increasing lipoprotein lipase activity, and reducing the hepatic synthesis of very low density lipoprotein cholesterol (VLDL-C) and low density lipoprotein cholesterol (LDL-C) 55).
One proposed mechanism is the action of niacin’s antilipolytic effect, thought to be mediated via nicotinic acid receptors. An alternate mechanism recently uncovered is the ability of niacin to speed up the intracellular degradation of Apolipoprotein B (ApoB) containing lipoproteins, such as VLDL and LDL by inhibiting triglyceride synthesis. Also, niacin inhibits diacylglycerol acyltransferase 2 (DGAT2), thereby decreasing hepatic triglyceride synthesis. A suggested mechanism for the increase of HDL-cholesterol levels is the fact that niacin decreases the degradation of ApoA-I-containing lipoproteins, increases peroxisome proliferator-activated receptor γ (PPARγ) expression and enhances PPARγ transcriptional activity in macrophages 56). Levels of free fatty acids become lowered via niacin’s downregulating action of cyclic adenosine monophosphate. By doing so, it decreases the most important intracellular mediator of pro-lipolytic stimuli 57).
When Niacin is given in high doses alone or in combination with other medicines, it’s effective in lowering low density lipoprotein (LDL) cholesterol and triglyceride and raising high density lipoprotein (HDL) cholesterol, which makes this agent of unique value in the therapy of dyslipidemia. This may help prevent the development of pancreatitis (inflammation of the pancreas) and other problems caused by high levels of cholesterol and triglycerides in the blood. Niacin is also used to help lower risk of heart attack in patients with a history of heart attack and hyperlipidemia 58), 59).
Increased fasting glycemia
This is thought to be through the roles of niacin-responsive G protein-coupled receptor (GPR109a) and plasma free fatty acids (FFAs). Though details of the mechanism are yet to be fully uncovered, research has observed a direct relationship has between insulin resistance in muscles and high FFA (in the form of lipid overload) concentrations in non-adipose tissues. Also, intestinal cells in vivo are showed to increase their local glucose uptake when GPR109a gets stimulated by niacin, an effect that may contribute to loss of glycemic control 60).
Though still yet to be fully uncovered, the mechanism of action through current research may be the inverse relation between nicotinamide adenine dinucleotide (NAD) concentrations and dietary niacin intake. Researchers have demonstrated that reduced intracellular NAD concentrations lead to loss of a cell’s power to undergo division and growth, leading to cell aging and death 61). NAD-dependent enzymes such as sirtuin proteins and poly(ADP-ribose) polymerase (PARP) not only provide continuous protection of the genome but are also necessary for the repair of damaged DNA. Researchers observed increased cancer incidence and reactive oxygen species with decreased PARP. Also, lifespan-extending effects of caloric restriction, which are mediated by sirtuins, have been associated with premature aging and disorders like Huntington and other age-associated neurological disorders, in cells with defective sirtuins 62).
Niacin may inhibit glioma cell invasion both in vivo and in vitro. Epithelial-mesenchymal transition (EMT) is involved in the process of cell migration, adhesion, and polarity; it also has involvement in the downregulation of E-cadherin, an epithelial marker and upregulation of Snail1, a mesenchymal marker, both processes which are important to the normal developmental of mesoderm and neural crest migration. Research has found tumor cells to have EMT-like processes, which not only gives them the ability to recur but to cause immunosuppression and cell invasion. The degradation of Snail1, an EMT-promoting transcription factor that leads to invasion of U251 glioblastoma multiforme cells, was found to be facilitated in cells with niacin treatment, thus leading to a decrease in tumor invasion 63).
Nicotinic acid uses
Research on the use of oral niacin to treat specific conditions shows:
- High cholesterol. Prescription niacin is used to increase high-density lipoprotein (HDL) cholesterol — the “good” cholesterol that helps remove low-density lipoprotein (LDL), the “bad” cholesterol, from your bloodstream. Despite niacin’s ability to raise HDL, research suggests that niacin therapy isn’t linked to lower rates of death, heart attack or stroke.
- Niacin deficiency (pellagra). Niacin and a related nutrient called niacinamide are used to treat or prevent niacin deficiency. This condition isn’t common in the United States.
- Niacin deficiency has been linked to birth defects. A study in mice suggested that niacin supplementation during gestation prevented birth defects. Research is needed to prove a similar benefit in humans.
Dyslipidemia, defined as elevated total or low-density lipoprotein (LDL) cholesterol levels, or low levels of high-density lipoprotein (HDL) cholesterol, is an important risk factor for coronary heart disease (CHD) and stroke.
Niacin as a prescription medicine can be used in a number of situations including the following:
- Niaspan® and generic niacin ER, available as a prescription medicine, provides 500-1,000 mg extended-release nicotinic acid. It is used to treat high blood cholesterol levels.
- Alone or in combination with other medications, such as HMG-CoA inhibitors (statins) or bile acid-binding resins;
- to decrease the risk of another heart attack in patients with high cholesterol who have had a heart attack;
- to prevent worsening of atherosclerosis (buildup of cholesterol and fats along the walls of the blood vessels) in patients with high cholesterol and coronary artery disease;
- to reduce the amount of triglycerides (other fatty substances) in the blood in patients with very high triglycerides who are at risk of pancreatic disease (conditions affecting the pancreas, a gland that produces fluid to break down food and hormones to control blood sugar).
- Niacin is also used to prevent and treat pellagra (niacin deficiency), a disease caused by inadequate diet and other medical problems.
Results of a clinical study in people with heart disease and well-controlled cholesterol levels that compared people who took niacin and simvastatin with people who took simvastatin alone and found similar results for the two groups in the rate of heart attacks or strokes. Taking niacin along with simvastatin or lovastatin also has not been shown to reduce the risk of heart disease or death compared with the use of niacin, simvastatin, or lovastatin alone 64). Talk to your doctor if you have questions about the risks and benefits of treating increased amounts of cholesterol in your blood with niacin and other medications.
- Niacin and niacinamide are indicated for prevention and treatment of vitamin B3 deficiency states.
- Vitamin B3 (Niacin) when given in high doses, is effective in lowering low density lipoprotein (LDL) cholesterol, triglycerides, and raising high density lipoprotein (HDL) cholesterol, which makes this agent of unique value in the therapy of dyslipidemia. The magnitude of individual lipid and lipoprotein responses may be influenced by the severity and type of underlying lipid abnormality. The increase in total high density lipoprotein (HDL) “good” cholesterol is associated with a shift in the distribution of HDL subfractions with an increase in the HDL2:HDL3 ratio and an increase in apolipoprotein A-I content. Vitamin B3 (Niacin) treatment also decreases the serum levels of apolipoprotein B-100 (apo B), the major protein component of the VLDL (very low-density lipoprotein) and LDL fractions, and of lipoprotein-a, a variant form of low density lipoproteins cholesterol (LDL) independently associated with coronary risk 65), 66).
- When given at these doses (1000 mg – 6000 mg daily), niacin has been shown to increase HDL and lower LDL cholesterol levels and to decrease rates of cardiovascular events in high risk individuals 67). The mechanism of action of niacin in hyperlipidemia is not well understood, but is believed to be related to inhibition of cAMP signaling pathways in adipocytes, which results in decreased release of lipids from fat cells. Niacin was officially approved for use in the United States in 1957 and is still widely used, although its role in management of hyperlipidemia in patients taking statins and other cholesterol lowering agents remains uncertain and controversial 68), 69).
- Niacin comes as a tablet and an extended-release (long-acting) tablet to take by mouth. The regular tablet usually is taken two to three times a day with meals, and the extended-release tablet is taken once a day, at bedtime, after a low-fat snack. Follow the directions on your prescription label or package label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Swallow the extended-release tablets whole; do not split, chew, or crush them. Take niacin exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor. For many years, doses of 1 to 3 grams of nicotinic acid per day has been a treatment option for low HDL cholesterol and high LDL cholesterol and triglyceride levels.
- Regular niacin is available in multiple generic forms, under several brand names (including Niacor), in many concentrations as either tablets or capsules from 50 to 1,000 mg each. When used to treat hyperlipidemia, regular niacin is generally referred to as intermediate release [IR] niacin. IR-niacin must be taken several times daily and is associated with a high rate of cutaneous flushing. The recommended dosage for hyperlipidemia is 1 to 6 grams daily, starting at low doses (100 mg three times daily) and increasing at weekly intervals based upon tolerance and effect.
- Sustained release [SR] formulations of niacins have been developed which are available over-the-counter. SR niacin can be taken once daily and is less likely to cause flushing, but is not approved for use in hyperlipidemia and has been associated with a high rates of hepatotoxicity in some studies.
- Extended release (ER) capsules and tablets of niacin are available in concentrations ranging from 125 to 1,000 mg, which are approved for use in hyperlipidemia and have not been associated with a higher rate of hepatotoxicity compared to regular niacin. Niacin ER is available by prescription and over-the-counter in generic forms and under several brand names such as Niaspan and Niobid. The recommended daily dosage of niacin ER ranges from 500 to 2,000 mg generally given once daily at bedtime. Niacin is also available in combination with other lipid lowering drugs such as lovastatin (Advicor). Common side effects of niacin include nausea, fatigue, pruritus and flushing; flushing being a major dose-limiting side effect.
- Niacin and niacinamide are also used to prevent niacin deficiency and to treat pellagra. Some clinicians prefer niacinamide for the treatment of pellagra because it lacks vasodilating effects. Pellagra may result from dietary deficiency, isoniazid therapy, or from decreased conversion of tryptophan to niacin in Hartnup disease or carcinoid tumors.
Some other studied uses of niacin other than the ones stated above are 70):
- Decreases the incidence of cardiovascular events, premature aging, age-associated neurological disorders such as:
- Alzheimer disease
- Huntington disease
- Amyotrophic lateral sclerosis (ALS)
- Muscular atrophy
- Parkinson disease
- Squamous cell carcinoma
- It also has therapeutic use in the treatment of diabetic encephalopathy, schizophrenia, malignant glioma, neurodegenerative diseases, hyperphosphatemia in chronic kidney disease and arthritis 71)
- Circadian rhythm and metabolism regulation through sirtuins
- Intracellular calcium regulation
Although niacin and niacinamide have not been shown by well-controlled trials to have therapeutic value, the drugs have been used for the management of schizophrenic disorder, drug-induced hallucinations, chronic brain syndrome, hyperkinesis, unipolar depression, motion sickness, alcohol dependence, livedoid vasculitis, acne, and leprosy 72).
Nicotinic acid contraindications
Contraindications to niacin include the following conditions:
- Patients with active peptic ulcer disease
- Patients who have active liver disease or present with unexplained and persistent elevations in hepatic transaminases
- Patients with hypersensitivity to niacin or any component of this medication
- Patients with arterial bleeding
Nicotinic acid food sources
Niacin is present in a wide variety of foods. Many animal-based foods—including poultry, beef, and fish—provide about 5-10 mg niacin per serving, primarily in the highly bioavailable forms of NAD and NADP 73). Plant-based foods, such as nuts, legumes, and grains, provide about 2-5 mg niacin per serving, mainly as nicotinic acid. In some grain products, however, naturally present niacin is largely bound to polysaccharides and glycopeptides that make it only about 30% bioavailable 74). Many breads, cereals, and infant formulas in the United States and many other countries contain added niacin. Niacin that is added to enriched and fortified foods is in its free form and therefore highly bioavailable 75).
Tryptophan is another food source of niacin because this amino acid—when present in amounts beyond that required for protein synthesis—can be converted to NAD, mainly in the liver 76). The most commonly used estimate of efficiency for tryptophan conversion to NAD is 1:60 (i.e., 1 mg niacin [NAD] from 60 mg tryptophan). Turkey is an example of a food high in tryptophan; a 3-oz portion of turkey breast meat provides about 180 mg tryptophan, which could be equivalent to 3 mg niacin 77). However, the efficiency of the conversion of tryptophan to NAD varies considerably in different people 78). Table 1 lists several food sources of niacin.
Niacin is found in (https://www.nal.usda.gov/sites/www.nal.usda.gov/files/niacin.pdf):
- Enriched breads and cereals
- Lean meats
Table 1. Selected Food Sources of Niacin
|Beef liver, pan fried, 3 ounces||14.9||93|
|Chicken breast, meat only, grilled, 3 ounces||10.3||64|
|Marinara (spaghetti) sauce, ready to serve, 1 cup||10.3||64|
|Turkey breast, meat only, roasted, 3 ounces||10.0||63|
|Salmon, sockeye, cooked, 3 ounces||8.6||54|
|Tuna, light, canned in water, drained, 3 ounces||8.6||54|
|Pork, tenderloin, roasted, 3 ounces||6.3||39|
|Beef, ground, 90% lean, pan-browned, 3 ounces||5.8||36|
|Rice, brown, cooked, 1 cup||5.2||33|
|Breakfast cereals fortified with 25% DV niacin||5.0||31|
|Peanuts, dry roasted, 1 ounce||4.2||26|
|Rice, white, enriched, cooked, 1 cup||2.3||14|
|Potato (russet), baked, 1 medium||2.3||14|
|Sunflower seeds, dry roasted, 1 ounce||2.0||13|
|Bread, whole wheat, 1 slice||1.4||9|
|Pumpkin seeds, dry roasted, 1 ounce||1.3||8|
|Soymilk, unfortified, 1 cup||1.3||8|
|Bread, white, enriched, 1 slice||1.3||8|
|Lentils, boiled and drained, ½ cup||1.0||6|
|Bulgur, cooked, 1 cup||0.9||6|
|Banana, 1 medium||0.8||5|
|Edamame, frozen, prepared, ½ cup||0.7||4|
|Raisins, ½ cup||0.6||4|
|Tomatoes, cherry, ½ cup||0.5||3|
|Broccoli, boiled, drained, chopped, ½ cup||0.4||3|
|Cashews, dry roasted, 1 ounce||0.4||3|
|Yogurt, plain, low fat, 1 cup||0.3||2|
|Apple, 1 medium||0.2||1|
|Chickpeas, canned, drained, 1 cup||0.2||1|
|Milk, 1% milkfat, 1 cup||0.2||1|
|Spinach, frozen, chopped, boiled, ½ cup||0.2||1|
|Tofu, raw, firm, ½ cup||0.2||1|
|Onions, chopped, ½ cup||0.1||1|
* These values are for the niacin content of foods only. They do not include the contribution of tryptophan, some of which is converted to NAD in the body.
** DV = Daily Value. The U.S. Food and Drug Administration (FDA) developed DVs to help consumers compare the nutrient contents of foods and dietary supplements within the context of a total diet. The DV for niacin on the new Nutrition Facts and Supplement Facts labels and used for the values in Table 1 is 16 mg for adults and children aged 4 years and older. FDA required manufacturers to use these new labels starting in January 2020, but companies with annual sales of less than $10 million may continue to use the old labels that list a niacin DV of 20 mg until January 2021 79). The FDA does not require food labels to list niacin content unless niacin has been added to the food. Foods providing 20% of more of the DV are considered to be high sources of a nutrient.
Dietary Reference Intakes for Niacin
The best way to get the daily requirement of essential vitamins is to eat a balanced diet that contains a variety of foods.
- 0 to 6 months: 2* milligrams per day (mg/day)
- 7 to 12 months: 4* mg/day*Adequate Intake (AI)
- 1 to 3 years: 6 mg/day
- 4 to 8 years: 8 mg/day
- 9 to 13 years: 12 mg/day
Adolescents and Adults (RDA)
- Males age 14 and older: 16 mg/day
- Females age 14 and older: 14 mg/day, 18 mg/day during pregnancy, 17 mg/day during lactation
Specific recommendations depend on age, gender, and other factors (such as pregnancy). Women who are pregnant or breast-feeding need higher amounts. Ask your health care provider which amount is best for you.
Table 2. Recommended Dietary Allowances (RDAs) for Niacin
|Birth to 6 months*||2 mg||2 mg|
|7–12 months*||4 mg NE||4 mg NE|
|1–3 years||6 mg NE||6 mg NE|
|4–8 years||8 mg NE||8 mg NE|
|9–13 years||12 mg NE||12 mg NE|
|14–18 years||16 mg NE||14 mg NE||18 mg NE||17 mg NE|
|19+ years||16 mg NE||14 mg NE||18 mg NE||17 mg NE|
Footnote: * Adequate Intake
Niacin equivalents = NE. The Food and Nutrition Board defines 1 niacin equivalents (NE) as 1 mg niacin or 60 mg of the amino acid tryptophan (which the body can convert to niacin). Niacin Recommended Dietary Allowance (RDA) for adults are based on niacin metabolite excretion data. For children and adolescents, niacin RDAs are extrapolated from adult values on the basis of body weight. The Adequate Intake (AI) for infants from birth to 6 months is for niacin alone, as young infants use almost all the protein they consume for growth and development; it is equivalent to the mean intake of niacin in healthy, breastfed infants. For infants aged 7-12 months, the Adequate Intake (AI) for niacin is in mg niacin equivalents (NE) and is based on amounts consumed from breast milk and solid foods.
Recommended Dietary Allowance (RDA): Average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals; often used to plan nutritionally adequate diets for individuals.
Adequate Intake (AI): Intake at this level is assumed to ensure nutritional adequacy; established when evidence is insufficient to develop an RDA.
Nicotinic acid supplement
Niacin is a component of most multivitamin and vitamin B preparations in concentrations close to the minimum daily requirement, which are not effective in lowering lipid levels. Niacin is also found in many herbal mixtures and energy drinks, but generally in low or modest doses. Nicotinic acid and nicotinamide are the two most common forms of niacin in supplements. Some niacin-only supplements contain 500 mg or more per serving, which is much higher than the recommended dietary allowance (RDA) for this nutrient.
The recommended dietary allowance (RDA) of this vitamin is 14 to 16 mg daily in adults, and slightly more for pregnant women (18 mg) and less for children (2 to 12 mg). Niacin given at or around these doses is not associated with significant side effects or liver injury 80).
Nicotinic acid in supplemental amounts beyond nutritional needs can cause skin flushing, so some formulations are manufactured and labeled as prolonged, sustained, extended, or timed release to minimize this unpleasant side effect. Nicotinamide does not produce skin flushing because of its slightly different chemical structure 81). Niacin supplements are also available in the form of inositol hexanicotinate, and these supplements are frequently labeled as being “flush free” because they do not cause flushing. The absorption of niacin from inositol hexanicotinate varies widely but on average is 30% lower than from nicotinic acid or nicotinamide, which are almost completely absorbed 82). A niacin-like compound, nicotinamide riboside, is also available as a dietary supplement, but it is not marketed or labelled as a source of niacin.
Nicotinic acid dosage
Niacin is available in two chemical forms. As nicotinic acid only, used for hyperlipoproteinemia or peripheral vascular disease. Another form is both nicotinic acid and nicotinamide (niacinamide), used for nutritional supplementation or pellagra. Oral extended-release tablets come in 250 mg, 500 mg, 750mg, 1000 mg, 3000 mg. Dosing of 1 to 3 grams/day was found to reduce serum LDL cholesterol and increase serum HDL cholesterol 83).
Research showed that a formulation of modified release niacin and with crystalline immediate-release niacin offered similar results 84).
Immediate-release tablets come dosages ranging from 50mg to 500mg. Initial dosing should be as low as possible to decrease adverse effect reactions and slowly titrated, preferably no more than 500 mg over four weeks to the patient’s response and tolerance.
Reverses in insulin resistance induced by lipid overload and rapid reduction of plasma free fatty acid (FFA) were observed with acute administration of niacin 85).
At the time of niacin administration, patients should avoid alcohol as it may increase the risk of pruritus and flushing. Niacin therapy is not a recommended pharmaceutical therapy in patients who are chronic alcohol abusers due to an increased risk of hepatotoxicity.
Oral dosage (nicotinic acid or nicotinamide/niacinamide)
- Up to 500 mg/day orally, depending on the severity of niacin deficiency.
Intravenous or Intramuscular dosage
- 50 to 100 mg intramuscular five times daily, or 25 to 100 mg given by slow intravenous infusion twice daily, depending on the severity of niacin deficiency. Maximum: 500 mg/daily.
- Dosing is up to 300 mg/day given by slow intravenous infusion, depending on the severity of niacin deficiency.
Hypercholesterolemia, mixed dyslipidemia or hypertriglyceridemia, type 4 or 5
Dosing is 1500 to 3000 mg/day orally, divided either as two or three times daily.
- Starting dose: 250 mg orally at bedtime, with a gradual increase of 250 mg/day every 4 to 7 days up to 2000 mg/day.
- After two months, the dosage may be increased to 250 to 500 mg/day every 2 to 4weeks, with a maximum of 6000 mg/day.
- 325 mg aspirin 30 minutes before a dose may reduce flushing;
- Medication should be given without food.
- Niacin is FDA Pregnancy Category C. When used at high doses to treat conditions such as dyslipidemia, niacin may cause harm to an unborn fetus.
- Niacin has no black box warning.
Nicotinic acid side effects
Side effects only occur for prescription medication to treat hyperlipidemia are far higher than the recommended dietary allowance (RDA) and are generally in the range of 1 to 6 grams (1000 mg – 6000 mg daily) daily.
Depending on the strength of the medicine and also the number of doses you take each day, the time allowed between doses, common side effects are:
Flushing: Even normal doses (example 1000 to 3000 mg/day) can be associated with feeling warmth, redness, itching or tingling of the face, neck, arms or upper chest and lasts 20 to 30 minutes. This is called “flushing”. In most cases, this problem will get better after taking niacin on a regular basis for a while 86). Flushing reaction associated with its crystalline nicotinic acid component (not nicotinamide) is the most common and studied the toxicity of niacin, which is both person-to-person and dose-dependent. To prevent flushing, do not drink hot beverages or alcohol at the same time you take niacin. Pretreatment of 30 minutes with aspirin (up to 325 mg) can be useful to counter this side effect. Laropiprant, a potent, selective antagonist of prostaglandin D2( PGD2)-receptor subtype-1 not only helps reduce this side effect of niacin but allows for optimal pharmacological dosing if needed 87). New forms of nicotinic acid reduce this side effect. Nicotinamide does not cause these side effects. Some clinicians prefer niacinamide for the treatment of pellagra because it lacks vasodilating effects 88).
One reaction to consider is niacin’s effects (whether used alone or in combination with statin medications) on glycemic control in patients with dyslipidemia, regardless of their diabetes mellitus status who are undergoing niacin therapy.
In non-diabetic patients with dyslipidemia, on average, five years of niacin therapy, whether used alone or in laropiprant combination therapy, was associated with a 34% increased risk of developing diabetes 89).
Also, niacin has demonstrated to increase fasting glycemic levels in patients with diabetes. Avoiding niacin therapy has been recommended in patients with metabolic syndrome or diabetes 90).
Other side effects include hyperuricemia, gastrointestinal disorders, rash, increase in homocysteine levels, hypotension, dyspepsia, elevations in AST and ALT, nausea, vomiting, and paresthesias 91).
Serious adverse reactions: Peptic ulcer disease, arrhythmias, anaphylaxis, hepatotoxicity, hepatic necrosis, fulminant, macular edema 92).
Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor immediately if any of the following side effects occur:
- Darkening of urine
- light gray-colored stools
- loss of appetite
- severe abdominal or stomach pain
- yellow eyes or skin
- feeling of warmth
- flushing or redness of the skin, especially on the face and neck
- nausea or vomiting
- rash or itching
- runny nose
- stuffy nose
Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.
Health risks from excessive niacin
No adverse effects have been reported from the consumption of naturally occurring niacin in foods 93). However, high intakes of both nicotinic acid and nicotinamide taken as a dietary supplement or medication can cause adverse effects, although their toxicity profiles are not the same.
Thirty to 50 mg nicotinic acid or more typically causes flushing; the skin on the patient’s face, arms, and chest turns a reddish color because of vasodilation of small subcutaneous blood vessels. The flushing is accompanied by burning, tingling, and itching sensations 94). These signs and symptoms are typically transient and can occur within 30 minutes of intake or over days or weeks with repeated dosing; they are considered an unpleasant, rather than a toxic, side effect. However, the flushing can be accompanied by more serious signs and symptoms, such as headache, rash, dizziness, and/or a decrease in blood pressure. Supplement users can reduce the flushing effects by taking nicotinic acid supplements with food, slowly increasing the dose over time, or simply waiting for the body to develop a natural tolerance.
When taken in pharmacologic doses of 1,000 to 3,000 mg/day, nicotinic acid can also cause more serious adverse effects 95). Many of these effects have occurred in patients taking high-dose nicotinic acid supplements to treat hyperlipidemias. These adverse effects can include hypotension severe enough to increase the risk of falls; fatigue; impaired glucose tolerance and insulin resistance; gastrointestinal effects, such as nausea, heartburn, and abdominal pain; and ocular effects, such as blurred or impaired vision and macular edema (a buildup of fluid at the center of the retina). High doses of nicotinic acid taken over months or years can also be hepatotoxic; effects can include increased levels of liver enzymes; hepatic dysfunction resulting in fatigue, nausea, and anorexia; hepatitis; and acute liver failure 96). Hepatotoxicity is more likely to occur with the use of extended-release forms of nicotinic acid 97).
To minimize the risk of adverse effects from nicotinic acid supplementation or to identify them before they become serious, the American College of Cardiology and the American Heart Association recommend measuring hepatic transaminase, fasting blood glucose or hemoglobin A1C, and uric acid levels in all supplement users before they start therapy, while the dose is being increased to a maintenance level, and every 6 months thereafter 98). The societies also recommend that patients not use nicotinic acid supplements or stop using them if their hepatic transaminase levels are more than two or three times the upper limits of normal; if they develop persistent hyperglycemia, acute gout, unexplained abdominal pain, gastrointestinal symptoms, new-onset atrial fibrillation, or weight loss; or if they have persistent and severe skin reactions, such as flushing or rashes.
Nicotinamide does not cause skin flushing and has fewer adverse effects than nicotinic acid, and these effects typically begin with much higher doses 99). Nausea, vomiting, and signs of liver toxicity can occur with nicotinamide intakes of 3,000 mg/day 100). In several small studies of participants undergoing hemodialysis, the most common adverse effects from 500-1,500 mg/day nicotinamide supplementation for several months were diarrhea and thrombocytopenia (low platelet count) 101).
The Food Nutrition Board has established Tolerable Upper Intake Level (UL or maximum daily intake unlikely to cause adverse health effects) for niacin that apply only to supplemental niacin for healthy infants, children, and adults 102). These Tolerable Upper Intake Levels (ULs) are based on the levels associated with skin flushing. The FNB acknowledges that although excess nicotinamide does not cause flushing, a UL for nicotinic acid based on flushing can prevent the potential adverse effects of nicotinamide 103). The Tolerable Upper Intake Level (UL), therefore, applies to both forms of supplemental niacin. However, the UL does not apply to individuals who are receiving supplemental niacin under medical supervision 104).
Table 3. Tolerable Upper Intake Levels (ULs) for Niacin
|Birth to 6 months||None established*||None established*|
|7–12 months||None established*||None established*|
|1–3 years||10 mg||10 mg|
|4–8 years||15 mg||15 mg|
|9–13 years||20 mg||20 mg|
|14–18 years||30 mg||30 mg||30 mg||30 mg|
|19+ years||35 mg||35 mg||35 mg||35 mg|
Footnote: * Breast milk, formula, and food should be the only sources of niacin for infants.
Large doses of nicotinic acid can cause
For high cholesterol and triglycerides:
- For oral dosage forms (extended-release capsules, oral solution, or regular tablets):
Adults—500 to 2000 milligrams (mg) one to three times a day.
- For oral dosage form (extended-release tablets):
Adults and children older than 16 years of age—At first, 500 milligrams (mg) per day, taken at bedtime. After 4 weeks, your doctor will increase your dose to 1000 mg per day, taken at bedtime. However, the dose is usually not more than 2000 mg per day.
- Increased blood sugar (glucose) level
- Liver damage
- Peptic ulcers
- Skin rashes
- Rhabdomyolysis (serious muscle problem when used with statin medicine)
This medicine may make you dizzy. Do not drive or do anything else that could be dangerous until you know how this medicine affects you. Stand or sit up slowly.
If you need to stop taking extended-release niacin, even for a short time, talk to your doctor before you start taking it again. You may need to start back on a lower dose.
Tell any doctor or dentist who treats you that you are using this medicine. This medicine may affect certain medical test results.
Your doctor will do lab tests at regular visits to check on the effects of this medicine.
Nicotinic acid and Hepatotoxicity
Niacin in doses above 500 mg daily causes transient, asymptomatic elevations in serum aminotransferase levels in up to 20% of people. The elevations are rarely greater than 3 times the upper limit of the normal range and usually resolve spontaneously even with continuation of the drug. The effect is partially dose related and is more common with doses above 3 g/day. In some patients, there is an overall decrease in serum proteins synthesized by the liver and, in some instances, coagulopathy with an increase in prothrombin time and decline in serum albumin, coagulation factors and apolipoproteins. These changes resolve rapidly upon stopping therapy and may not recur with lower doses.
Niacin can also cause serious hepatotoxicity, but this is uncommon. Significant hepatotoxicity is particularly common with high doses of sustained release niacin. In many cases, the injury becomes apparent after a dose increase or after switching from the regular crystalline to a sustained release form. The pattern is primarily hepatocellular, although cases with a cholestatic pattern have been described. The patients present with jaundice, itching, nausea, vomiting and fatigue. When the injury is the result of switching from the crystalline to the sustained release form, the injury may present acutely within days or a few weeks with a prodromal period of nausea, vomiting and abdominal pain, that is followed by jaundice and pruritus. Early during the injury serum aminotransferase levels are very high and then usually fall rapidly with discontinuation or dose lowering. The clinical phenotype resembles acute hepatic necrosis, suggesting a direct toxic effect. Imaging studies of the liver may reveal areas of hypodensity (“starry sky liver”) interpreted as focal fatty infiltration that resolves after stopping the drug. Liver biopsy typically shows varying degrees of centrolobular necrosis with only mild inflammation.
Mechanism of Injury
The mechanism of hepatotoxicity is assumed to be an intrinsic toxic reaction related to high serum levels of niacin that overwhelm the high affinity, low concentration nicotinic acid receptors (that are responsible for the flushing response). The finding that niacin can be restarted at lower doses after an episode of clinically apparent injury indicates that the hepatic damage is unlikely to be idiosyncratic or due to hypersensitivity.
Outcome and Management
Niacin hepatotoxicity appears to be dose dependent and more common with the sustained release form of the drug. Hepatotoxicity is less common with regular, crystalline niacin or extended release niacin. Most cases are mild and resolve rapidly upon stopping the medication, although in some instances, the injury is acute and severe and progresses to liver failure that is fatal or requires emergency liver transplantation. Complete resolution of the clinical symptoms is expected within days of stopping niacin, whereas serum enzyme elevations may require several weeks or months to resolve. Rechallenge with the same form leads to rapid recurrence and should be avoided. If the injury occurred after switching to a SR formulation, the crystalline form of niacin may be restarted at a lower dose and with caution.
Laboratory monitoring is recommended in patients on niacin therapy due to its diverse side effects.
In pre-diabetes or diabetic patients, frequent monitoring of blood glucose is necessary as niacin can increase fasting blood glucose.
In patients on diabetic medications, such as acarbose, albiglutide, alogliptin, glipizide, or insulin, should also have blood glucose monitors as niacin has an antagonistic effect on blood glucose.
Niacin can cause an increase in uric acid, thus exerting an antagonist effect on medications for gout, such as pegloticase and allopurinol.
Niacin exerts an additive reaction with blood pressure medications (amlodipine clozapine, bisoprolol, diltiazem) opioids (morphine, oxycodone, tramadol, methadone) antipsychotics (quetiapine, risperidone) phosphodiesterase type 5 inhibitor (tadalafil) thus leading to hypotension. Frequent blood pressure checking is recommended. Also, niacin, in combination with some beta-blockers, may decrease its antihyperlipidemic efficacy.
Niacin can increase the risk of bleeding by exerting an additive effect. Niacin has shown to not only cause a reduction in platelet counts (mean of -11% with 2000 mg) but to increase prothrombin time (mean of approximately +4%), leading to bleeding, especially when combined with anticoagulants such as apixaban, caplacizumab, or warfarin. Thus, a blood coagulation panel should be a routine test.
Niacin also exerts an additive effect when combined with ceritinib, diazoxide leading to hyperglycemia.
Phosphorus levels also require monitoring in patients at risk for hypophosphatemia as niacin can cause a decrease in phosphorus levels (mean of -13% with 2000 mg).
Harm may result in a nursing baby as niacin can pass into breast milk; therefore, nursing mothers should avoid the drug.
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