Nicotinic acid derivatives

I. Introduction

Nicotinic acid derivatives—also referred to as niacin derivatives—are a class of pharmacologic agents primarily derived from niacin (nicotinic acid, vitamin B3). These compounds are structurally related to pyridine carboxylic acids and are recognized for their potent lipid-modifying effects, vasodilatory properties, and therapeutic roles in treating dyslipidemia, pellagra, and other metabolic or vascular conditions.

Nicotinic acid and its derivatives occupy a distinctive position among lipid-lowering therapies because they simultaneously reduce low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and lipoprotein(a) while raising high-density lipoprotein cholesterol (HDL-C)—a profile not matched by most other classes like statins or fibrates. Their use has, however, declined with the advent of newer agents due to concerns regarding flushing, hepatotoxicity, and limited cardiovascular outcome benefits demonstrated in large trials.

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II. Classification and Derivatives

The major agents categorized under nicotinic acid derivatives include:

1. Immediate-release (IR) Nicotinic Acid

   • Pure niacin

   • Short half-life; significant flushing

2. Extended-release (ER) Nicotinic Acid

   • Niaspan® (US branded ER formulation)

   • Reduced flushing, but risk of hepatotoxicity

3. Sustained-release (SR) Nicotinic Acid

   • Non-prescription formulations (e.g., Slo-Niacin®)

   • Higher liver risk than IR

4. Nicotinamide (Niacinamide)

   • Amide form of niacin; lacks lipid-lowering effects

   • Used in pellagra, topical cosmeceuticals, and dermatology

5. Inositol Hexanicotinate (IHN)

   • “No-flush niacin,” a compound of niacin and inositol

   • Marketed as a supplement; minimal cholesterol-lowering effect

6. Acipimox

   • Synthetic niacin derivative used in Europe and Japan

   • Similar lipid effects with improved tolerability

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III. Mechanism of Action

Nicotinic acid derivatives exert their lipid-lowering effects through multiple pathways:

1. Inhibition of hepatic diacylglycerol acyltransferase-2 (DGAT2)

   • ↓ triglyceride synthesis → ↓ very-low-density lipoprotein (VLDL) production → ↓ LDL

2. Activation of GPR109A (HM74A) receptor on adipocytes

   • Inhibits hormone-sensitive lipase → ↓ free fatty acid release → ↓ hepatic lipid flux

3. Reduction in apolipoprotein B-100 synthesis

   • Contributes to ↓ VLDL and LDL levels

4. Inhibition of HDL catabolism

   • ↑ HDL via reduced hepatic uptake

5. Suppression of lipoprotein(a) synthesis

   • One of the few agents to reduce Lp(a), an independent cardiovascular risk factor

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IV. Lipid Profile Modulation

Lipid Parameter	Effect
LDL-C (bad cholesterol)	↓ 10–25%
HDL-C (good cholesterol)	↑ 15–35%
Triglycerides	↓ 20–50%
Lipoprotein(a)	↓ 15–30%

Note: These effects are dose-dependent and vary based on the specific formulation.

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V. Therapeutic Indications

1. Dyslipidemia (as adjunctive therapy)

   • Combined hyperlipidemia (↑ LDL, TG; ↓ HDL)

   • Isolated low HDL with atherogenic dyslipidemia

   • Hypertriglyceridemia

2. Pellagra

   • Caused by niacin deficiency

   • Characterized by dermatitis, diarrhea, dementia

3. Peripheral Vascular Disease (PVD)

   • Improves walking distance and blood flow via vasodilation

4. Atherosclerosis / Secondary prevention (historical use)

   • Previous use based on HDL raising and Lp(a) lowering

   • Currently not first-line due to outcome trials

5. Dermatologic uses

   • Niacinamide used topically for acne, hyperpigmentation, and anti-aging

6. Adjunct in some psychiatric or cognitive disorders (investigational)

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VI. Dosage and Administration

Agent	Typical Dose Range	Notes
IR Niacin	1,000–3,000 mg/day in divided doses	Higher flushing risk
ER Niacin (Niaspan)	500–2,000 mg at bedtime	Titrated slowly; improved tolerability
SR Niacin	250–750 mg twice daily	Avoid in hepatic disease
Acipimox	250 mg twice or three times daily	Used in Europe and Asia; not FDA approved in the US
Nicotinamide	300–500 mg/day (nutritional use)	No lipid effect
Inositol hexanicotinate	250–500 mg (supplement form)	No evidence for lipid effects

VII. Adverse Effects

A. Common

• Flushing (prostaglandin D2-mediated vasodilation)

• Pruritus

• Warmth or tingling sensation

• Nausea, vomiting

• Gastrointestinal discomfort

B. Serious

• Hepatotoxicity (elevated liver enzymes, hepatitis)

• Hyperglycemia (especially in diabetics)

• Hyperuricemia and gout

• Acanthosis nigricans (with insulin resistance)

• Hypotension (in vasculopathic patients)

• Atrial arrhythmias (rare)

• Myopathy (especially when combined with statins)

Risk of hepatotoxicity is highest with sustained-release forms and high doses.

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VIII. Contraindications

• Active liver disease or unexplained transaminase elevations

• Active peptic ulcer disease

• Gout

• Hypersensitivity to nicotinic acid

• Severe hypotension

• Pregnancy (high doses not recommended)

• Uncontrolled diabetes mellitus (relative contraindication)

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IX. Precautions and Monitoring

Parameter	Monitoring Frequency
Liver function tests (LFTs)	Baseline, every 6–12 weeks
Fasting glucose / HbA1c	Baseline, periodically
Uric acid	If history of gout
Lipid panel	Every 4–12 weeks
Creatine kinase (CK)	If symptoms of myopathy

Patients should be titrated gradually to minimize flushing and hepatotoxicity. Co-administration with aspirin (81–325 mg) 30 minutes prior can reduce flushing.

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X. Drug Interactions

Interacting Drug/Class	Effect / Concern
Statins (e.g., simvastatin)	↑ risk of myopathy or rhabdomyolysis
Bile acid sequestrants	↓ absorption of niacin; separate by 4–6 hrs
Antidiabetic agents	Niacin may blunt glycemic control
Alcohol	↑ risk of hepatotoxicity
Allopurinol or uricosurics	May antagonize effect (↑ uric acid)

Combination therapy with statins is effective but must be used with extreme caution due to muscle toxicity risk.

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XI. Clinical Trials and Evidence

A. AIM-HIGH Trial (2011)

• Evaluated niacin added to statin therapy

• No significant reduction in cardiovascular events

• Terminated early due to increased stroke risk

B. HPS2-THRIVE Trial (2014)

• Tested ER niacin + laropiprant vs placebo in statin-treated patients

• No cardiovascular benefit

• Increased adverse events (liver, GI, glucose, infection)

These trials shifted niacin derivatives from frontline use in atherosclerotic cardiovascular disease (ASCVD) prevention.

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XII. Current Role in Therapy

Due to limited outcome benefit and adverse effects, guidelines from AHA/ACC, ESC, and NICE no longer recommend routine niacin use in combination with statins for cardiovascular prevention.

However, nicotinic acid derivatives still hold niche roles:

• Patients with statin intolerance

• Severe hypertriglyceridemia

• Low HDL with residual cardiovascular risk

• Cases of familial dyslipidemia

• Adjunctive use in selected individuals after risk-benefit analysis

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XIII. Summary of Nicotinic Acid Derivatives

Agent/Class	Lipid Effects	Flushing	Hepatic Risk	Unique Points
IR Niacin	Strong	High	Moderate	Best lipid efficacy
ER Niacin (Niaspan)	Strong	Moderate	Higher	Prescribed, better tolerated
SR Niacin	Mild–Moderate	Low	High	OTC; not recommended
Acipimox	Moderate	Low	Low	Less flushing, Europe-only
Niacinamide	None (lipids)	None	None	Pellagra, topical uses
Inositol hexanicotinate	Unproven	None	Unclear	Marketed as "flush-free"