Niacin (a combination of nicotinic acid and nicotinamide), a B vitamin (vitamin B3), is a pharmacotherapeutic agent that has been used since 1955, making it the oldest, pleiotropic hypolipidemic agent.[1] The vitamin plays a role in both neuroprotection and neuronal death, giving it the utmost importance in the proper functioning of the central nervous system (CNS), neuronal development, and function.[2]

Niacin has seen extensive use, alone or in combination, with statin medications (hydroxymethyl glutaryl coenzyme A reductase inhibitors) in the reduction of total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, very-low-density lipoprotein (VLDL), and lipoprotein levels.  Moreover, niacin is the most potent agent used to increase plasma high-density lipoprotein (HDL) cholesterol.[3][1][4] 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.[1][4]

Niacin being such a pleiotropic agent still possesses properties that remain uncovered. Some other studied uses of niacin other than the ones stated above are[5][6][7][8][9][10][11][12][13][14][15]:

• Decreases  the incidence of cardiovascular events, premature aging, age-associated neurological disorders such as:
  • Alzheimer disease
  • Huntington disease
  • Amyotrophic lateral sclerosis
  • 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[14]
• Circadian rhythm and metabolism regulation through sirtuins
• Intracellular calcium regulation

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:

1. Lipid metabolism: Lipid-lowering ability of niacin is very diverse and still under investigation. 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.[16] 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.[17]
2. 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.[18]
3. Aging-related process and pathologies: 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.[6] 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.[6][18]
4. Malignant glioma: 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.[12][13]

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.[18][19]

Research showed that a formulation of modified release niacin and with crystalline immediate-release niacin offered similar results.[5]

 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 FFA were observed with acute administration of niacin.[18]

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.

Recommended dosage:

Pellagra:

Oral dosage (nicotinic acid or nicotinamide/niacinamide)

Adults

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.

Children

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 IV or V:

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. 

Of note: 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.

The adverse effects of pharmacological doses of nicotinic acid are continuously under research in clinical research trials.

Some common reactions are:

Flushing: Niacin often causes generalized pruritus, and a burning sensation is usually limited to the face and chest and lasts 20 to 30 minutes.  This side effect, however, is one that decreases not only in frequency but severity with time.[5] 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.[20]

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.[21] 

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.[18][4]

Other side effects include hyperuricemia, gastrointestinal disorders, rash, increase in homocysteine levels, hypotension, dyspepsia, elevations in AST and ALT, nausea, vomiting, and paresthesias.[4][1]

Serious adverse reactions:

Peptic ulcer disease, arrhythmias, anaphylaxis, hepatotoxicity, hepatic necrosis, fulminant, macular edema.[1]

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