NIACIN

• 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)
• HR - Hazard ratio
• ULN - Upper limit of normal

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• DRUGS IN CLASS

• Niacin standard-release
• Prescription - Niacor®
• Over-the-counter - many brands


• Niacin extended-release
• Prescription - Niaspan®
• Over-the-counter - Slo-Niacin® and many others

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• 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 increase lipoprotein lipase activity which may increase 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]

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• 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)

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• EFFECTIVENESS

• EFFECT ON LIPID PARAMETERS

• Tris = triglycerides
• Values are presented as average percent decrease/increase from baseline
• Study was a dose-escalation study. Same group of subjects for all doses (N=87).
• Women tend to have a greater response to niacin than men
• Reference [1]

Niaspan dose (mg at bedtime)	Tris	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%

• PREVENTION OF CARDIOVASCULAR DISEASE
• Several large studies have evaluated niacin in the secondary prevention of CVD


• AIM-HIGH Study - Niaspan vs Placebo for Secondary Prevention of CVD, NEJM (2011) [PubMed abstract]
• The AIM-HIGH study enrolled 3414 patients with a history of CVD
• Main inclusion criteria: age ≥ 45 years; documented CVD defined as stable coronary heart disease, cerebrovascular or carotid disease, or peripheral arterial disease; HDL ≤ 42 mg/dl for men, ≤ 53 mg/dl for women; triglycerides 100 - 400 mg/dl; LDL ≤ 180 mg/dl adjusted for dose of baseline statin
• 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 CABG - 35%; history of PCI - 62%; 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
• Patients were randomized to 1 of 2 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
• The trial was stopped early after an average follow-up of 3 years due to a lack of efficacy with Niaspan
• Primary outcome: Group 1 - 16.2%, Group 2 - 16.4% (HR 1.02, 95%CI [0.87 - 1.21], p=0.80)
• Nonfatal myocardial infarction: Group 1 - 5.5%, Group 2 - 6.1% (HR 1.11, 95%CI [0.84 - 1.47], p=0.46)
• Ischemic stroke: Group 1 - 1.1%, Group 2 - 1.7% (HR 1.61, 95%CI [0.89 - 2.90], p=0.11)
• Overall mortality: Group 1 - 4.8%, Group 2 - 5.6% (HR 1.16, 95%CI [0.87 - 1.56], p=0.32)
• Average LDL at 3 years: Group 1 - 68 mg/dl, Group 2 - 65 mg/dl
• Average HDL at 3 years: Group 1 - 39 mg/dl, Group 2 - 44 mg/dl
• Median triglycerides at 3 years: Group 1 - 152 mg/dl, Group 2 - 120 mg/dl
• Flushing or itching leading to drug discontinuation: Group 1 - 2.5%, Group 2 - 6.1%
• Drug discontinuation: Group 1 - 20.1%, Group 2 - 25.4% (p<0.001) [13]


• HPS2-THRIVE Study - Niacin + Laropiprant vs Placebo for Secondary Prevention of CVD, NEJM (2014) [PubMed abstract]
• The HPS2-THRIVE study enrolled 25,673 patients with a history of CVD
• Main inclusion criteria: age 50 - 80 years; history of myocardial infarction, cerebrovascular disease, peripheral arterial disease, or diabetes mellitus with evidence of symptomatic coronary disease
• 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
• Patients were randomized to 1 of 2 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
• After a median follow-up of 3.9 years, the following was seen:
• Primary outcome: Group 1 - 13.2%, Group 2 - 13.7% (RR 0.96, 95%CI [0.90 - 1.03], p=0.29)
• Major coronary event (nonfatal myocardial infarction and death from coronary cause): Group 1 - 5.2%, Group 2 - 5.4% (RR 0.96, 95%CI [0.87 - 1.07], p=0.51)
• Any stroke: Group 1 - 3.9%, Group 2 - 3.9% (RR 1.0, 95%CI [0.88 - 1.13], p=0.56)
• Any revascularization: Group 1 - 6.3%, Group 2 - 7.0% (RR 0.90, 95%CI [0.82 - 0.99], p=0.03)
• Overall mortality: Group 1 - 6.2%, Group 2 - 5.7% (RR 1.09, 95%CI [0.99 - 1.21], p=0.08)
• New-onset diabetes: Group 1 - 5.7%, Group 2 - 4.3% (RR 1.32, 95%CI [1.16 - 1.51], p<0.001)
• Peptic ulcer/other upper GI: Group 1 - 3.1%, Group 2 - 2.2% (RR 1.39, 95%CI [1.20 - 1.62])
• Myopathy: Group 1 - 0.6%, Group 2 - 0.1% (RR 3.54, 95%CI [2.36 - 5.33])
• Any serious bleeding event: Group 1 - 2.5%, Group 2 - 1.9% (RR 1.38, 95%CI [1.17 - 1.62], p=0.0002)
• Drug discontinuation: Group 1 - 25.4%, Group 2 - 16.6% (p<0.001)
• In Group 1, LDL decreased by 10 mg/dl on average and triglycerides decreased by 33 mg/dl while HDL increased by 6 mg/dl [14]


• Professional guidelines:
• The AHA 2013 cholesterol treatment guidelines and the American College of Cardiology 2016 guidelines on non-statin therapy do not recommend the use of niacin
• StraightHealthcare analysis:
• 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
• Since the AIM-HIGH and HPS2-THRIVE studies were published, the use of niacin to treat dyslipidemia has fallen out of favor

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• 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 ADMIT study detailed below, the effects of niacin on blood sugars was evaluated in diabetics and nondiabetics


• ADMIT Study - Niacin vs Placebo for Glycemic Control, JAMA (2000) [PubMed abstract]
• The ADMIT study enrolled 468 patients with peripheral artery disease
• Main inclusion criteria: ABI < 0.85 or a history of lower extremity revascularization
• Main exclusion criteria: HgA1C > 9%; kidney disease; liver disease; gout; hyperuricemia; peptic ulcer disease; triglycerides > 400 mg/dl; LDL > 190 mg/dl
• Baseline characteristics: average age 66 years; diabetes - 27%; average HgA1C - 7.8% (diabetics), 5.3% (nondiabetics); average uric acid level - 5.6 mmol/L (diabetics), 6.3 mmol/L (nondiabetics); average fasting glucose - 168 mg/dl (diabetics), 95 mg/dl (nondiabetics)
• Patients were randomized to 1 of 2 groups:
• Group 1 (237 patients) - Niacin immediate-release target dose of 1500 mg twice a day
• Group 2 (231 patients) - Placebo twice a day
• All participants went through a run-in phase where niacin was titrated to 500 mg twice a day
• The average daily dose of niacin at Week 18 was 2553 mg in patients with diabetes and 2626 mg in patients without diabetes
• PRIMARY OUTCOME: Change in HgA1C and fasting blood sugar from baseline
• After 48 weeks, the following was seen:
• Diabetics (125 patients)
• Change in fasting glucose: Group 1 +8.1 mg/dl, Group 2 -8.7 mg/dl (p=0.04)
• Change in HgA1C: Group 1 0%, Group 2 -0.3% (p=0.05)
• Nondiabetics (343 patients)
• Change in fasting glucose: Group 1 +6.3 mg/dl, Group 2 +0.5 mg/dl (p≤0.001)
• Change in HgA1C: Group 1 +0.1%, Group 2 +0.1% (p=0.38) [5]


• StraightHealthcare analysis:
• Niacin raises blood sugar levels
• The effect may be more pronounced in diabetics
• 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]
• In general, diabetics should avoid niacin


• URIC ACID ELEVATION
• Niacin may raise uric acid levels which can affect patients with gout
• In the ADMIT study detailed 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
• StraightHealthcare analysis:
• Niacin raises uric acid levels
• Patients with uncontrolled gout should avoid niacin until their uric acid levels are under control


• 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]

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• CONTRAINDICATIONS

• Active liver disease or unexplained persistent elevations in hepatic transaminases
• Active peptic ulcer disease
• Arterial bleeding
• Known hypersensitivity [1,8]

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• PRECAUTIONS

• KIDNEY DISEASE
• Niacin has not been studied extensively in patients with kidney disease
• Niacin should be used with caution in patients with kidney disease
• Manufacturer makes no specific dosage recommendations [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 increases 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

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• DRUG INTERACTIONS

• NOTE: The drug interactions presented here are NOT A COMPREHENSIVE LIST of all known interactions. Other interactions exist. The interactions below 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.


• HIGH ALERT INTERACTIONS


• None known


• METABOLISM AND ELIMINATION
• NOTE: Drugs can be metabolized by more than one enzyme. Drugs may be metabolized by an enzyme and inhibit/induce the enzyme at the same time. Drug transporters (ex. p-glycoprotein) can play a role in drug metabolism. Not all drug interactions are clinically significant. Consult your physician or pharmacist if you are taking medications together and are concerned about a possible interaction.


• Niacin
• CYP2D6 - inhibitor [15]


• OTHER
• 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)
• The increased risk, if any, is very low. Statins and niacin are commonly prescribed together.
• Vitamins with niacin (Vitamin B3) - vitamin supplements that contain niacin (also called vitamin B3) may potentiate the side effects of niacin products

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• 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

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• DOSING

• Niacin dosing chart

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• GENERIC AVAILABILITY

• Generic available:
• Niaspan®
• Niacor®

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• OVER-THE-COUNTER NIACIN

• Extended-release
• Slo-Niacin® is available over-the-counter
• It is made by Upsher-Smith® and has been studied in clinical trials
• Slo-Niacin® may be cheaper than prescription extended-release niacin


• Standard-release
• Standard-release niacin is available over-the-counter from many manufacturers
• Products from reputable manufacturers should be safe and effective
• Inositol hexanicotinate, sometimes called "Flush free" niacin should be avoided because it does not appear to release any active niacin [9]

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• DIFFERENCES BETWEEN DRUGS IN CLASS

• Extended-release niacin has been shown to have a lower incidence of flushing (see flushing above)

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• BIBLIOGRAPHY

• What is PMID?
• PI = Manufacturer's Package Insert

• #     PMID
  
• 1 - Niaspan PI
• 2 - 2215615
• 3 - 15537681
• 4 - 19874992
• 5 - 10979113
• 6 - 19915217
• 7 - 18375237
• 8 - Niacor PI
• 9 - 20360295
• 10 - 17368274
• 11 - 15653014
• 12 - 12485966
• 13 - 22085343
• 14 - 25014686
• 15 - 15081432