Niacin

Mechanism of Action

After undergoing biochemical reactions in the mitochondria with nicotinamide and tryptophan, niacin 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, participate 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 challenging to fully grasp its mechanism of action. 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 increasing HDL-cholesterol levels is that niacin decreases the degradation of ApoA-I-containing lipoproteins and increases peroxisome proliferator-activated receptor γ (PPARγ) expression and enhances PPARγ transcriptional activity in macrophages.[11] 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.[12]
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 shown to increase their local glucose uptake when GPR109a gets stimulated by niacin, which may contribute to loss of glycemic control.[13]
3. Aging-related process and pathologies: Though yet 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 the loss of a cell's power to undergo division and growth, leading to cell aging and death. NAD-dependent enzymes such as sirtuin proteins and poly(ADP-ribose) polymerase (PARP) provide continuous protection of the genome and 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, mediated by sirtuins, have been associated with premature aging and disorders like Huntington and other age-associated neurological disorders in cells with defective sirtuins.[14]
4. Malignant glioma: Niacin may inhibit glioma cell invasion 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 give them the ability to recur and 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.[15][16]

Administration

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, 750 mg, 1000 mg, and 3000 mg strengths. Dosing of 1 to 3 grams/day was found to reduce serum LDL cholesterol and increase serum HDL cholesterol.[17] Research showed that a formulation of modified release niacin and crystalline immediate-release niacin offered similar results.[4]
• Immediate-release tablets are available in formulation ranging from 50 mg to 500 mg. 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.[13]
• At the time of niacin administration, patients should avoid alcohol as it may increase the risk of pruritus and flushing. In addition, niacin therapy is not recommended in patients who chronically misuse alcohol due to an increased risk of hepatotoxicity.

Recommended Dosage for Pellagra

Adults

• 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.

Children

• Dosing is up to 300 mg/day given by slow intravenous infusion, depending on the severity of niacin deficiency.

Recommended Dosage for Hypercholesterolemia, Mixed Dyslipidemia or Hypertriglyceridemia, Type IV or V

• Normal dosing is 1500 to 3000 mg/day orally, divided 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 4 weeks, with a maximum of 6000 mg/day. 
• Note: 325 mg aspirin 30 minutes before a dose may reduce flushing; The medication should be given without food.

Pregnancy Considerations

• 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.

Breastfeeding Considerations

• Harm may result in a nursing baby as niacin can pass into breast milk; therefore, nursing mothers should avoid the drug.

Adverse Effects

Common Reactions

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 adverse reaction, however, decreases in frequency and severity with time.[4] Pretreatment of 30 minutes with aspirin (up to 325 mg) can help 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.[18]

One reaction to consider is niacin’s effects (whether used alone or combined with statin medications) on glycemic control in patients with dyslipidemia, regardless of their diabetes mellitus status. 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.[19] Also, niacin administration has been demonstrated to increase fasting glycemic levels in patients with diabetes. Avoiding niacin therapy has been recommended in patients with metabolic syndrome or diabetes.[13][5]

Other adverse effects include hyperuricemia, gastrointestinal disorders, rash, increased homocysteine levels, hypotension, dyspepsia, elevations in AST and ALT, nausea, vomiting, and paresthesias.[5][1]

Serious Adverse Reactions

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

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

Monitoring

• 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. Patients on diabetic medications, such as acarbose, albiglutide, alogliptin, glipizide, or insulin, should also have blood glucose monitored frequently.[19] 
• Niacin can cause an increase in uric acid, thus exerting an antagonist effect on medications for gouts, 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).

Toxicity

In pharmacological doses (e.g., 1000 to 3000 mg/day), 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.[4] Other symptoms of toxicity may include dizziness, upset stomach, redness, itching, nausea, and vomiting.

Enhancing Healthcare Team Outcomes

Niacin is a pharmacotherapeutic pleiotropic agent with properties still yet to be fully understood. It is encouraged that interprofessional healthcare team members (clinicians, pharmacists, nurse practitioners, physician assistants, primary care providers, nurses) stay updated on niacin's properties and side effects uncovered by ongoing research. Niacin can cause flushing, a significant adverse impact that significantly affects its compliance in patients. Knowing how to titrate from a minimal dose will help minimize such unwanted effects and benefit patient health outcomes. Close monitoring and periodic blood work on initiating or increasing the dosage of niacin is necessary as it is known to increase the risk of bleeding, hypotension, hyperuricemia, and cause alterations in glycemic control. Its adverse effect on glycemic control in patients with dyslipidemia, both with or without diabetes, is one of its most concerning effects as it may cause diabetes in predisposed patients or make the management of diabetes a challenge. Using an interprofessional approach with each discipline contributing from their area of expertise will result in better patient outcomes and fewer adverse effects from niacin. [Level 5]