Introduction
Niacin, also known as nicotinic acid or vitamin B3, is a water-soluble vitamin that has been used clinically for decades to manage dyslipidemia. While it functions as an essential nutrient at lower doses, at pharmacological doses (≥1 g/day), niacin demonstrates significant lipid-modifying effects that have made it an important therapeutic agent in cardiovascular risk management.
Mechanism of Action
Niacin exerts its effects through multiple mechanisms:
- Lipid effects: Reduces hepatic synthesis of very low-density lipoprotein (VLDL) and subsequent low-density lipoprotein (LDL) production
- Receptor-mediated: Acts as an agonist at the hydroxycarboxylic acid receptor 2 (HCA2), inhibiting adipose tissue lipolysis and reducing free fatty acid flux to the liver
- HDL modulation: Increases high-density lipoprotein (HDL) cholesterol by reducing hepatic uptake of apolipoprotein A-I
- Vascular effects: Improves endothelial function and possesses anti-inflammatory properties
Indications
FDA-approved indications:- Primary hypercholesterolemia (as monotherapy or in combination)
- Mixed dyslipidemia
- Hypertriglyceridemia
- Secondary prevention of cardiovascular events in combination with other lipid-lowering agents
- Pellagra treatment and prevention (at nutritional doses)
- Adjunctive therapy in peripheral vascular disease
Dosage and Administration
Standard dosing:- Immediate-release: Start with 100-250 mg orally twice daily, gradually increase to 1.5-2 g/day in divided doses
- Extended-release: Start with 500 mg orally at bedtime, increase by 500 mg every 4 weeks to maximum of 2 g/day
- Renal impairment: Use with caution; dose adjustment may be necessary
- Hepatic impairment: Contraindicated in active liver disease
- Geriatric: Start with lower doses due to increased risk of adverse effects
- Pediatric: Safety and efficacy not established for lipid management
- Take with food to minimize gastrointestinal upset
- Avoid alcohol around dosing time to reduce flushing risk
- Extended-release formulations should be swallowed whole
Pharmacokinetics
- Absorption: Rapid and extensive (>60-70%) from GI tract; food may delay but not reduce absorption
- Distribution: Widely distributed to body tissues; minimal protein binding
- Metabolism: Extensive first-pass metabolism via conjugation pathways in liver
- Elimination: Primarily renal excretion (88%) as metabolites; half-life approximately 20-45 minutes
Contraindications
- Active liver disease or unexplained persistent liver transaminase elevations
- Active peptic ulcer disease
- Arterial bleeding
- Hypersensitivity to niacin or any product component
- Significant gout or hyperuricemia
Warnings and Precautions
Black Box Warning:- Severe hepatotoxicity can occur with extended-release formulations, particularly with doses ≥2 g/day or when substituted for equivalent immediate-release doses
- Hepatotoxicity: Monitor liver function tests regularly
- Myopathy: Increased risk when combined with statins
- Glucose intolerance: May increase fasting glucose and HbA1c
- Atrial fibrillation: Increased risk reported in some studies
- Ophthalmologic effects: May cause toxic amblyopia and macular edema
Drug Interactions
- Statins: Increased risk of myopathy and rhabdomyolysis
- Bile acid sequestrants: May decrease niacin absorption (separate administration by 4-6 hours)
- Antihypertensive agents: Potentiates vasodilatory effects
- Alcohol: Increases flushing and hepatotoxicity risk
- Warfarin: May potentiate anticoagulant effect (monitor INR)
Adverse Effects
Common (≥10%):- Flushing (up to 90% of patients, often diminishes with continued use)
- Pruritus, rash
- Gastrointestinal distress (nausea, vomiting, diarrhea)
- Headache
- Hepatotoxicity (elevated transaminases, jaundice)
- Myopathy/rhabdomyolysis
- Atrial fibrillation and other arrhythmias
- Macular edema
- Glucose intolerance and worsened diabetes control
- Gout attacks
Monitoring Parameters
Baseline:- Lipid profile
- Liver function tests (ALT, AST)
- Fasting glucose and HbA1c
- Uric acid levels
- Renal function
- Liver function tests every 3-6 months
- Lipid profile at 4-8 weeks and periodically thereafter
- Glucose parameters every 3-6 months in diabetic patients
- Symptoms of myopathy (muscle pain, weakness)
- Flushing severity and frequency
Patient Education
- Flushing management: Take with low-fat snack, premedicate with aspirin 325 mg 30 minutes before dose, avoid alcohol and hot beverages around dosing time
- Adherence: Importance of gradual dose titration and consistent dosing
- Symptom recognition: Report any muscle pain, weakness, dark urine, jaundice, or visual changes
- Lifestyle: Emphasize that niacin complements but does not replace diet and exercise
- Timing: Extended-release formulations must be taken at bedtime
- Persistence: Flushing typically diminishes after several weeks of consistent use
References
1. Grundy SM, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110(2):227-239. 2. AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365(24):2255-2267. 3. HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371(3):203-212. 4. FDA prescribing information for niacin extended-release tablets. 5. Guyton JR, et al. Effectiveness of once-nightly dosing of extended-release niacin alone and in combination for hypercholesterolemia. Am J Cardiol. 1998;82(6):737-743. 6. McKenney JM, et al. A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients. JAMA. 1994;271(9):672-677.
This monograph is intended for educational purposes only and should not replace clinical judgment. Always consult current prescribing information and guidelines before initiating therapy.