- ACRONYMS AND DEFINITIONS
- A1C - Hemoglobin A1C
- CAD - Coronary artery disease
- CVD - Cardiovascular disease
- CIMT - Carotid Intima-Media Thickness (a measure carotid artery wall thickness and atherosclerosis)
- ER - Extended-release
- RCT - Randomized controlled trial
- ULN - Upper limit of normal
- DRUGS IN CLASS
- Niacin standard-release
- Prescription: Niacor®
- Over-the-counter: Available from many manufacturers. Inositol hexanicotinate, sometimes called "Flush-free" niacin should be avoided because it does not appear to release any active niacin [9]
- Niacin extended-release
- Prescription: Niaspan®
- Over-the-counter: Available from many manufacturers. Slo-Niacin®, a brand of OTC niacin, has been studied in clinical trials.
- MECHANISM OF ACTION
- The exact mechanism of niacin is not completely understood
- Niacin may inhibit the release of free fatty acids from adipose tissue. Niacin may also increase lipoprotein lipase activity which increases the rate of chylomicron triglyceride removal from plasma.
- Niacin decreases the rate of hepatic synthesis of VLDL and LDL, but does not appear to affect fecal excretion of fats, sterols, or bile acids [1]
- FDA-APPROVED INDICATIONS
- Niacor®
- Reduction of elevated total and LDL cholesterol
- Adjunctive therapy for the treatment of adult patients with very high serum triglyceride levels (≥ 1000 mg/dl)
- Niaspan®
- Reduction of elevated total cholesterol, LDL cholesterol, Apo B, and triglycerides
- Increase HDL levels
- In patients with a history of myocardial infarction and hyperlipidemia, niacin is indicated to reduce the risk of recurrent nonfatal myocardial infarction
- In patients with a history of CAD and hyperlipidemia, niacin, in combination with a bile acid binding resin, is indicated to slow progression or promote regression of atherosclerotic disease
- Adjunctive therapy for the treatment of adult patients with very high serum triglyceride levels (≥ 1000 mg/dl)
- CHOLESTEROL EFFECTS
Niaspan dose (mg at bedtime) | Triglycerides | HDL | LDL | Total |
---|---|---|---|---|
500 mg | -5% | +10% | -3% | -2% |
1000 mg | -11% | +15% | -9% | -5% |
1500 | -28% | +22% | -14% | -11% |
2000 | -35% | +26% | -17% | -12% |
- SECONDARY CVD PREVENTION
- Overview
- The two large studies detailed below looked at the effects of niacin in the secondary prevention of CVD
- The AIM-HIGH study enrolled 3414 patients with a history of CVD
Main inclusion criteria
- Age ≥ 45 years
- Documented CVD
- HDL ≤ 42 mg/dl for men, ≤ 53 mg/dl for women
- Triglycerides 100 - 400 mg/dl
- LDL ≤ 180 mg/dl
Main exclusion criteria
- Acute coronary syndrome within 4 weeks
- CABG within 1 years
- Stroke within 8 weeks
- HgA1C > 9%
- EF < 30%
- AST or ALT > 2 X ULN
- Recent acute gout
- Serum creatinine ≥ 2.5 mg/dl
Baseline characteristics
- Average age 64 years
- History of myocardial infarction - 56%
- History of stroke or cerebrovascular disease - 21%
- History of peripheral vascular disease - 14%
- Diabetes - 34%
- Taking statin - 93%
- Average LDL - 76 mg/dl
- Average HDL - 35 mg/dl
- Median triglyceride level - 163 mg/dl
Randomized treatment groups
- Group 1 (1696 patients) - Placebo + Simvastatin
- Group 2 (1718 patients) - Niaspan® 1500 - 2000 mg a day + Simvastatin
- Simvastatin was dosed to achieve an LDL level between 40 - 80 mg/dl
- Ezetimibe (Zetia®) could be added to both groups if needed to keep LDL ≤ 80 mg/dl
- Nonstudy lipid-lowering drugs were not allowed
Primary outcome: Composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke,
hospitalization for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization
Results
Duration: The trial was stopped early after an average follow-up of 3 years due to a lack of efficacy | |||
Outcome | Placebo | Niaspan | Comparisons |
---|---|---|---|
Primary outcome | 16.2% | 16.4% | HR 1.02, 95%CI [0.87 - 1.21], p=0.80 |
Nonfatal myocardial infarction | 5.5% | 6.1% | HR 1.11, 95%CI [0.84 - 1.47], p=0.46 |
Ischemic stroke | 1.1% | 1.7% | HR 1.61, 95%CI [0.89 - 2.90], p=0.11 |
Overall mortality | 4.8% | 5.6% | HR 1.16, 95%CI [0.87 - 1.56], p=0.32 |
Average LDL at 3 years | 68 mg/dl | 65 mg/dl | N/A |
Average HDL at 3 years | 39 mg/dl | 44 mg/dl | N/A |
Median triglycerides at 3 years | 152 mg/dl | 120 mg/dl | N/A |
Flushing/itching causing discontinuation | 2.5% | 6.1% | N/A |
Drug discontinuation | 20.1% | 25.4% | p<0.001 |
Findings: Among patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of less than 70 mg per deciliter (1.81 mmol per liter), there was no incremental clinical benefit from the addition of niacin to statin therapy during a 36-month follow-up period, despite significant improvements in HDL cholesterol and triglyceride levels
- The HPS2-THRIVE study enrolled 25,673 patients with a history of CVD
Main inclusion criteria
- Age 50 - 80 years
- History of CVD or diabetes with evidence of symptomatic CAD
Main exclusion criteria
- Acute coronary syndrome or stroke within 3 months
- Planned revascularization
- ALT > 1.5 X ULN
- Serum creatinine > 2.3 mg/dl
- CK > 3 X ULN
Baseline characteristics
- Average age 65 years
- History of myocardial infarction - 68%
- History of cerebrovascular disease - 32%
- History of peripheral artery disease - 13%
- Diabetes - 32%
- Average LDL - 63 mg/dl
- Average HDL - 44 mg/dl
Randomized treatment groups
- Group 1 (12,838 patients) - Niacin extended-release 2000 mg + laropiprant 40 mg a day
- Group 2 (12,835 patients) - Placebo
- All patients received simvastatin 40 mg ± ezetimibe to keep total cholesterol < 135 mg/dl
- All patients went through a run-in phase where tolerance to study medications was proven
- Laropiprant is an antagonist of the prostaglandin D2 receptor DP1 that has been shown to improve adherence to niacin therapy by reducing flushing in up to two thirds of patients
Primary outcome: First major vascular event defined as major coronary event (nonfatal myocardial infarction or death from coronary causes),
stroke of any kind, or coronary or noncoronary revascularization
Results
Duration: Median of 3.9 years | |||
Outcome | Niacin | Placebo | Comparisons |
---|---|---|---|
Primary outcome | 13.2% | 13.7% | RR 0.96, 95%CI [0.90 - 1.03], p=0.29 |
Major coronary event | 5.2% | 5.4% | RR 0.96, 95%CI [0.87 - 1.07], p=0.51 |
Any stroke | 3.9% | 3.9% | RR 1.0, 95%CI [0.88 - 1.13], p=0.56 |
Any revascularization | 6.3% | 7.0% | RR 0.90, 95%CI [0.82 - 0.99], p=0.03 |
Overall mortality | 6.2% | 5.7% | RR 1.09, 95%CI [0.99 - 1.21], p=0.08 |
New-onset diabetes | 5.7% | 4.3% | RR 1.32, 95%CI [1.16 - 1.51], p<0.001 |
GI side effect | 3.1% | 2.2% | RR 1.39, 95%CI [1.20 - 1.62] |
Myopathy | 0.6% | 0.1% | RR 3.54, 95%CI [2.36 - 5.33] |
Any serious bleeding event | 2.5% | 1.9% | RR 1.38, 95%CI [1.17 - 1.62], p=0.0002 |
Drug discontinuation | 25.4% | 16.6% | p<0.001 |
|
Findings: Among participants with atherosclerotic vascular disease, the addition of extended-release niacin-laropiprant to statin-based LDL cholesterol-lowering therapy did not significantly reduce the risk of major vascular events but did increase the risk of serious adverse events
- Professional recommendations
- See cholesterol treatment guidelines for recommendations from various professional organizations
- Summary
- Several older studies found that niacin improved carotid intima-media thickness (CIMT), a surrogate outcome for vascular disease. These findings served as a basis for the AIM-HIGH and HPS2-THRIVE studies. Unfortunately, niacin had no effect on CVD outcomes like heart attack or stroke when added to statin therapy. Niacin was also potentially harmful in the HPS2-THRIVE study because it increased the incidence of diabetes and worsened control of existing diabetes.
- Niacin may have a benefit in patients who cannot take statins, but this has not been studied extensively
- After the AIM-HIGH and HPS2-THRIVE studies were published, the use of niacin to treat dyslipidemia fell out of favor
- SIDE EFFECTS
- Flushing (skin warmth, redness, itching and/or tingling)
- Flushing is the most common side effect with niacin
- Greater than 60% of patients experience flushing with niacin
- Flushing tends to decrease with continued use (4 weeks and beyond)
- Extended-release niacin has been shown to elicit fewer episodes of flushing when compared to standard-release niacin
- In one study, the average number of flushing events per week was 8.6 for standard niacin versus 1.9 for Niaspan®
- Tips to decrease flushing:
- Taking an aspirin or other NSAID (ex. ibuprofen, naproxen) 30 minutes before the niacin dose can reduce the length and intensity of flushing
- Extended-release niacin
- Taking niacin at bedtime can minimize flushing
- Taking niacin with a low-fat snack (wheat crackers or skim milk) may help reduce flushing and stomach upset
- Avoid alcohol, hot beverages, and spicy foods when taking niacin
- Gradually increase niacin doses over a period of weeks to months [9]
- Gastrointestinal side effects
- In placebo-controlled trials, patients on niacin have had a significantly higher incidence of gastrointestinal side effects and events
- In the HPS2-THRIVE study, 4.8% of patients on niacin reported serious gastrointestinal events compared to 3.8% on placebo (RR 1.28, 95%CI [1.13 - 1.44], p<0.001)
- Gastrointestinal events included dyspepsia (upset stomach), diarrhea, and peptic ulcer disease [14]
- Niacin is contraindicated in active peptic ulcer disease [1,8]
- Blood sugar elevation (diabetes)
- Niacin can raise blood sugar levels
- In the HPS2-THRIVE study, patients on niacin had a higher incidence of new-onset diabetes (Niacin - 5.7%, Placebo - 4.3%), and diabetics had a higher incidence of uncontrolled blood sugar events (Niacin - 11.1%, Placebo 7.5%) [14]
- Results from a study that was designed specifically to look at the effects of niacin on blood sugars are summarized below
- STUDY
- Design: Randomized, placebo-controlled trial (N=468 | length = 48 weeks) in patients with peripheral artery disease
- Treatment: Niacin with a target dose of 1500 mg twice a day vs Placebo
- Primary outcome: Change in HgA1C and fasting blood sugar from baseline
- Results:
- Primary outcome (diabetics)
- Change in fasting glucose: Niacin +8.1 mg/dl, Placebo -8.7 mg/dl (p=0.04)
- Change in HgA1C: Niacin 0%, Placebo -0.3% (p=0.05)
- Primary outcome (nondiabetics)
- Change in fasting glucose: Niacin +6.3 mg/dl, Placebo +0.5 mg/dl (p≤0.001)
- Change in HgA1C: Niacin +0.1%, Placebo +0.1% (p=0.38) [5]
- Findings: Our study suggests that lipid-modifying dosages of niacin can be safely used in patients with diabetes and that niacin therapy may be considered as an alternative to statin drugs or fibrates for patients with diabetes in whom these agents are not tolerated or fail to sufficiently correct hypertriglyceridemia or low HDL-C levels.
- Uric acid elevation
- Niacin may raise uric acid levels which can affect patients with gout
- In the study that looked at the effects of niacin on blood sugars (see blood sugar elevation above), changes in uric acid levels were assessed. Patients who received niacin (N=237) at an average dose of 2600 mg a day for 48 weeks saw an average increase in uric acid levels of 0.80 - 0.90 mg/dl from baseline
- Patients with gout may want to avoid niacin if possible
- Liver enzyme elevations
- Niacin may raise liver enzymes
- In placebo-controlled trials, no increased risk of elevated liver enzymes (> 3 X ULN) was seen in patients with normal baseline liver enzymes
- When added to statin therapy, the risk of elevated liver enzymes may be higher (about 1% of patients in trials) [1]
- In the AIM-HIGH study, liver function abnormalities were seen in 0.8% of niacin-treated patients and 0.5% of placebo-treated patients [13]
- The manufacturers of niacin products recommend periodic monitoring of liver enzymes [1, 8]
- Muscle toxicity
- Muscle toxicity including muscle aches and rhabdomyolysis have been reported in patients taking niacin
- The risk appears to be higher when niacin is taken with a statin, but overall, it is still very low
- In the HPS2-THRIVE study, 3.7% of niacin-treated patients had a serious musculoskeletal event compared to 3.0% of placebo-treated patients. Chinese patients had a much higher incidence of myopathy when compared to European patients. [14]
- Other laboratory effects
- Niacin may cause a small reduction in platelet count (average -11% with 2000 mg)
- Niacin may prolong the prothrombin time (PT) (average +4%)
- Niacin may decrease phosphorus levels (average -13% at 2000 mg) [1]
- CONTRAINDICATIONS
- Active liver disease or unexplained persistent elevations in hepatic transaminases
- Active peptic ulcer disease
- Arterial bleeding
- Known hypersensitivity [1,8]
- PRECAUTIONS
- Kidney disease
- Niacin has not been studied extensively in patients with kidney disease
- Manufacturer makes no specific dosage recommendations. Use caution. [1]
- Liver disease
- Niacin has not been studied extensively in patients with liver disease
- Manufacturer makes no specific dosage recommendation
- Niacin is contraindicated in patients with active liver disease [1]
- Diabetes
- Niacin can raise blood sugar levels (see blood sugar elevations above)
- Niacin should be used with caution in diabetics and in patients who are at increased risk for diabetes
- Gout
- Niacin can raise uric acid levels (see uric acid increases above)
- Niacin should be used with caution in patients with uncontrolled gout
- Bleeding disorders
- Niacin can prolong the prothrombin time (PT) (see laboratory effects above)
- Niacin should be used with caution in patients with active bleeding or bleeding disorders
- Peptic ulcer disease
- Niacin has been associated with a slight increased risk of peptic ulcer disease (see gastrointestinal side effects above)
- Niacin is contraindicated in patients with active peptic ulcer disease
- DRUG INTERACTIONS
- NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.
- Drug interactions
- Bile Acid Sequestrants (Questran®, Welchol®) - Bile acid Sequestrants may interfere with the absorption of niacin. Niacin should not be taken within 4 - 6 hours of bile acid sequestrants. [1]
- Statins (Lipitor®, Crestor®, etc.) - The risk of muscle toxicity may be increased when niacin is taken with statins (see muscle toxicity above)
- Vitamins with niacin (Vitamin B3) - vitamin supplements that contain niacin (also called vitamin B3) may potentiate the side effects of niacin products
- Metabolism and clearance
- CYP2D6 - inhibitor [15]
- DOSING
- Dosage forms
- Niacin standard-release (Niacor®): 500 mg tablet | No generic. Costs > $150/month.
- Niacin extended-release (Niaspan®): 500, 750, 1000 mg tablet | Generic available. Costs < $50/month.
- Dosing
- Standard-release (Niacor®)
- Starting: 250 mg once daily following evening meal
- Maintenance: 1000 - 2000 mg two to three times a day
- Max: 6000 mg/day
- Increase dose at intervals of 4 - 7 days for doses up to 2000 mg/day
- Increase dose at intervals of 2 - 4 weeks for doses > 2000 mg/day
- Dosing for standard-release and extended-release niacin is not equivalent. When switching from standard-release to extended-release products, the dose will likely need to be lowered.
- Taking with food may decrease stomach upset
- Extended-release (Niaspan®)
- Week 1 - 4: 500 mg at bedtime
- Week 5 - 8: 1000 mg at bedtime
- Maintenance: 1000 - 2000 mg at bedtime
- Max: 2000 mg/day
- Dosing for standard-release and extended-release niacin is not equivalent. When switching from standard-release to extended-release products, the dose will likely need to be lowered.
- Take at bedtime after low-fat snack
- Flushing
- Pretreatment with aspirin (325 mg 30 minutes before) or other NSAID may decrease flushing
- Tolerance to flushing typically develops over several weeks
- LONG TERM SAFETY
- Niacin has been used since the 1970s to treat high cholesterol
- Niacin has been shown to be safe in long-term use, but it can have significant side effects
- BIBLIOGRAPHY
- 1 - Niaspan PI
- 2 - PMID 2215615
- 3 - PMID 15537681
- 4 - PMID 19874992
- 5 - PMID 10979113
- 6 - PMID 19915217
- 7 - PMID 18375237
- 8 - Niacor PI
- 9 - PMID 20360295
- 10 - PMID 17368274
- 11 - PMID 15653014
- 12 - PMID 12485966
- 13 - PMID 22085343
- 14 - PMID 25014686
- 15 - PMID 15081432