Niacin

Introduction

Niacin, or nicotinic acid, is an older drug. One of the earliest cholesterol-lowering drug cardiovascular trials was the Coronary Drug Project (CDP), which found a modestly reduced rate of nonfatal myocardial infarction (MI) in the niacin group during the trial, and lower mortality over long-term follow-up. Subsequent angiographic regression trials found that niacin, when used in combination with a bile acid sequestrant or statin, slowed progression and promoted regression of coronary atherosclerosis compared with placebo. Much of the enthusiasm for niacin over the subsequent years was focused on the non– low-density lipoprotein cholesterol (LDL-C) effects of niacin, such as raising high-density lipoprotein cholesterol (HDL-C) and lowering lipoprotein(a) (Lp(a)) levels.

Enthusiasm waned for niacin after the AIM-HIGH and HPS2-THRIVE trials. AIM-HIGH found no incremental cardiovascular risk reduction benefit from the additional reduction in non–HDL-C, apolipoprotein B, triglycerides, lipoprotein (a), and increase in HDL-C with niacin. HPS2-THRIVE found no incremental cardiovascular risk reduction benefit when niacin/laropiprant (an anti-flushing agent) was added to background statin therapy, and an excess of significant adverse events occurred in the niacin group. In retrospect, the modest reduction in coronary artery disease (CAD) events in the CDP was consistent with the modest magnitude of LDL-C lowering, compared with the Cholesterol Treatment Trialists’ meta-analysis, which found that each 39 mg/dL (1 mmol/L) reduction in LDL-C with statins reduced major cardiovascular events by about 20%

Niacin is available over the counter in crystalline or immediate release (IR) and extended or sustained release forms. Crystalline or IR niacin can cause significant flushing and must be administered two or three times a day. Sustained-release niacin should never be used due to serious hepatoxicity and liver failure reported for doses ≥1.5 g daily.

Prescription extended-release niacin has less flushing and can be administered once or twice daily. It appears to have no liver toxicity in doses up to 2 g daily when used as monotherapy or in combination with a statin.

Inositol hexanicotinate, or “no-flush” niacin, is inactive and has no lipid effects.

Clinical Highlight I

Statin-treated patients:

• Consider niacin a only after other guideline-recommended options (statins, ezetimibe, PCSK9 inhibitors and bempedoic acid) have failed in high-risk patients with familial hypercholesterolemia or ASCVD who do not have diabetes whose LDL-C remains ≥130 mg/dL. Benefit may be marginal when LDL-C is lower due to the increased risk of adverse events.
• Discontinue niacin if LDL-C is not lowered by at least another 15% when added to background therapy. No significant ASCVD event reduction has occurred in clinical trials with lesser LDL-C reductions (e.g., SEARCH and A to Z).

Appropriate Uses

The FDA has approved the following indications for extended-release niacin.

LDL-C Lowering

Niacin extended-release 1 to 2 g daily can be used to lower LDL-C (and apolipoprotein B and total cholesterol) in patients with primary hyperlipidemia or mixed dyslipidemia.

Triglyceride Lowering

Niacin extended-release 1 to 2 g daily can be used to lower triglycerides in patients with primary hyperlipidemia, mixed dyslipidemia and severe hypertriglyceridemia.

Cardiovascular Event Reduction

Niacin extended-release 1 to 2 g daily can be used as monotherapy to reduce the risk of recurrent myocardial infarction in patients with a history of myocardial infarction and hyperlipidemia.

Angiographic Stabilization/Regression

Niacin extended-release 1 to 2 g daily can be used in combination with a bile acid binding agent to slow progression or regress atherosclerosis in patients with a history of CAD and hyperlipidemia.

The 2018 multi-society cholesterol guideline recommends consideration of nonstatins in high-risk patients who may benefit from additional LDL-C lowering, with nonstatins shown to reduce ASCVD events in clinical trials preferred. Niacin as monotherapy can be considered in patients with statin-associated side effects. However, the 2018 multi-society cholesterol guideline does not list niacin as an LDL-lowering drug, nor is it considered in the 2022 ACC/AHA expert consensus decision pathway for nonstatins. Subgroup analyses of AIM-HIGH and HPS2-THRIVE suggest niacin may reduce cardiovascular events in selected subgroups of statin-treated patients, although cardiovascular morbidity and mortality were not reduced in patients treated with simvastatin and niacin in AIM-HIGH. Furthermore, the adverse event profile of niacin limits its clinical use.

Mechanisms and Metabolism

Niacin alters most lipid fractions through a variety of mechanisms, not all of which have been elucidated. Decreased apoB synthesis and increased apoB degradation lowers LDL-C and very low-density lipoprotein cholesterol (VLDL-C). Triglyceride reductions result from partially inhibiting fatty acid release from adipose tissue, which leads to decreased hepatic triglyceride synthesis, as well as increased lipoprotein lipase activity, leading to enhanced chylomicron triglyceride removal from plasma. Increases in HDL-C levels are likely related at least in part to decreased triglyceride levels, but decreased hepatic uptake and catabolism of HDL-C may also contribute.

Niacin undergoes extensive first-pass metabolism in the liver through enzymatic pathways other than those metabolizing statins and is rapidly excreted in urine.

Efficacy

Individual response to niacin is highly variable, so only continue niacin if the desired treatment objectives are achieved. For extended release (ER) niacin, maximal lipid effects are achieved at 1.5 to 2 g daily (Table 25-1). ER niacin doses should not exceed 2 g daily due to concerns about hepatotoxicity. Higher doses of crystalline or immediate release (IR) niacin can be used and have greater lipid efficacy. Niacin efficacy may be attenuated when used with a statin.

Each 500-mg increase in dose lowers LDL-C on average by an additional 5%. Women seem to experience slightly greater LDL-C and triglyceride-lowering efficacy than men.

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Cardiovascular Outcomes Trials

A number of trials have evaluated the effects of niacin on cardiovascular outcomes (Table 25-2). Numerous trials have also evaluated the effect of niacin on progression of angiographic coronary artery disease or carotid intimal thickness. Meta-analysis of the niacin trials has found no association between on-treatment HDL-C or triglyceride changes and cardiovascular risk reduction.

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CDP (Coronary Drug Project)

This trial compared niacin (n = 1,073) to placebo (n = 2,695) in men aged 30-64 years with hypercholesterolemia and a history of myocardial infarction. Two other arms evaluated clofibrate and estrogen. The mean dose of crystalline niacin during the trial was approximately 2 g and the approximate reduction in LDL-C and non–HDL-C was about 15%.Niacin reduced the risk of coronary heart disease by 13% (Figure 25-1) and cerebrovascular events by 21% compared with placebo over a mean follow-up period of 5 years. Follow-up 11 years after the trial ended found an 11% reduction in total mortality in the group of patients treated with niacin during the trial.

The estrogen arm was stopped early due to excess harm from fatal and nonfatal thrombotic events and unacceptable adverse effects such as breast swelling. The clofibrate arm showed no cardiovascular benefit and an excess of mortality.

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AIM-HIGH

AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes) was a randomized, placebo-controlled trial in 3414 patients with stable cardiovascular disease, low HDL-C and high triglycerides. All participants received simvastatin 40-80 mg daily, with ezetimibe 10 mg added to maintain LDL-C levels of 40-80 mg/dL. Patients were randomized to extended-release niacin 1.5 to 2 g daily or placebo with 100-150 mg niacin to maintain blinding due to the flushing effect.

AIM-HIGH achieved lipid values are shown in Table 25-3. Significant additional reductions in triglycerides, non–HDL-C, apoB, lipoprotein (a) and increases in HDL-C and HDL-C subfractions occurred in the niacin group. Nonetheless, no difference in cardiovascular outcomes occurred (HR 1.02, 95% CI 0.87-1.21; P=0.79) (Figure 25-2), and the trial was stopped early for futility (mean follow-up 3 years).

Post hoc analyses found reductions in Lp(a), apoB and favorable changes in other lipids and apolipoproteins were not related to a reduction in cardiovascular risk. One post hoc subgroup analysis did find a trend toward cardiovascular risk reduction in the subgroup with triglycerides ≥198 mg/dL and HDL-C <33 mg/dL (HR 0.74, P=.073).

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HPS-2 THRIVE

HPS2-THRIVE (Heart Protection Study 2 –Treatment of HDL to Reduce the Incidence of Vascular Events) randomized 25,673 men and women with clinical cardiovascular disease on background simvastatin therapy to ER niacin 2 g given with laropiprant (an anti-flushing agent) or placebo. Baseline LDL-C was 63 mg/dL and HDL-C was 44 mg/dL. During the trial, LDL-C was 10 mg/dL lower, triglycerides were 33 mg/dL lower, and HDL-C was 6 mg/dL higher in the niacin/laropiprant group. There was no reduction in major cardiovascular events in the niacin/laropiprant group (HR 0.96, 95% CI 0.90-1.03, P=0.29) over the median 3.9 years of follow-up (Figure 25-3). Subgroup analyses suggested there may have been a modest (approximately 10%) reduction in major cardiovascular events in those with baseline LDL-C above 58 mg/dL (Figure 25-4).

The niacin/laropiprant group had more serious adverse events: disturbances of diabetes control, increased incidence of diabetes, and gastrointestinal, musculoskeletal, skin, infection and bleeding adverse events.

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Angiographic Regression Trials

Trials of niacin used in combination with colestipol or a statin have demonstrated a benefit on coronary or carotid atherosclerotic plaque. Two of these very small trials reported a significant reduction in cardiovascular events.

CLAS

CLAS (Cholesterol-lowering Atherosclerosis Study) randomized 162 men with previous coronary artery bypass grafting surgery to niacin plus colestipol or placebo. After 2 years, the niacin-colestipol group had less angiographic progression and more regression in the native arteries and vein grafts.

FATS

FATS (Familial Atherosclerosis Treatment Study) randomized 146 men ≤62 years with CAD, apoB levels ≥125 mg/dL and a family history of vascular disease to conventional therapy, niacin plus colestipol, or lovastatin plus colestipol. The niacin-colestipol group had 32% lower LDL-C and 43% higher HDL-C than placebo. Compared to placebo, less progression and more regression was seen in the niacin-colestipol group, with a trend toward fewer CAD events over the 2.5-year treatment period.

HATS

The 3-year HATS (HDL Atherosclerosis Treatment Study) randomized 160 patients with low HDL-C and “normal” LDL-C levels to one of four treatment regimens. The simvastatin plus niacin (slow-release 1000 mg twice daily) group had 42% lower LDL-C and 26% higher HDL-C. Compared to placebo, the simvastatin-niacin group had angiographic regression of coronary atherosclerosis and fewer cardiovascular events. Of note, antioxidant vitamins attenuated the benefits of simvastatin-niacin therapy on regression and events.

Dosing

Tolerance to flushing develops over the course of several weeks so patients should be started at a low dose and gradually uptitrated as tolerated.

Patients may find it helpful to hear a description of niacin flushing symptoms prior to the first use: flushing symptoms usually start 30-120 minutes after taking ER niacin, and 15-30 minutes after taking IR niacin. Episodes typically last 5 to 60 minutes. Chewing an aspirin or taking diphenhydramine may decrease severity of an episode. Flushing rates usually substantially lessen after 4 weeks of ER niacin use, and uncommonly occur after 1 year of use.

Reducing Flushing

• Flushing, pruritus and gastrointestinal distress are lessened by gradually increasing the dosage.
• Take niacin with food. This slows absorption.
• Premedication with aspirin 325 mg (not enteric coated) 30 minutes before taking niacin.
• Nonsteroidal anti-inflammatory agents should be avoided due to increased risk of heart attack and stroke even with short-term use. The FDA has insufficient data to determine if there are some NSAIDs that are safer than others.
• Evening dosing of ER niacin may result in less flushing perception during sleep.
• Avoid spicy foods, alcoholic and hot drinks and hot showers near the time of niacin ingestion.
• Do not break, crush or chew tablets.
• If dosing is interrupted for an extended period of time, the physician should be contacted prior to reinitiating the therapy; re-titration is recommended, using the titration schedule below.
• Niacin should be re-titrated when switching between brands or forms of niacin.

Extended-Release (ER) Niacin

• Take at bedtime with a low-fat snack.
• Start with 500 mg at bedtime.
• Increase by 500 mg once every 4 weeks as tolerated.
• Maximum dosage is 2,000 mg daily.
• Four 500 mg tablets may be better tolerated than two 1,000-mg tablets.

Crystalline or Immediate-Release (IR) Niacin

• Start with 125-250 mg twice daily or 100 mg three times daily.
• Take before meals.
• Titrate every 2 weeks by 100-250 mg in two or three divided doses up to 3 g daily.

Contraindications

• Active liver disease or significant or unexplained hepatic dysfunction
• Unexplained hepatic transaminase elevations
• Active peptic ulcer disease
• Arterial bleeding
• Known hypersensitivity to niacin or other product components

Safety

Pregnancy

Effects on the fetus are unknown. Niacin should be discontinued if pregnancy occurs in a woman treated for primary hypercholesterolemia. In a woman with hypertriglyceridemia who becomes pregnant, the benefits of continued niacin therapy should be determined on an individual basis. Niacin is excreted in breast milk. Because of the potential for serious adverse effects in nursing infants from lipid-altering doses of niacin, whether to discontinue nursing or to discontinue the drug should take into account the importance of the drug to the mother.

Discontinuation

About 12% of patients in clinical trials discontinue ER niacin due to adverse effects, with flushing or rash (7%) the most frequent reason for niacin discontinuation, along with GI adverse effects (nausea, vomiting, diarrhea) the cause in about 4% of patients.

Flushing, Itching, Rash

Almost all patients will experience some degree of flushing or other cutaneous symptoms when starting crystalline niacin, as do about half of patients receiving extended-release niacin. With careful uptitration, most will develop tolerance over time. Women are more likely to experience flushing than men.

For some patients, flushing episodes may be quite alarming and can be accompanied by dizziness, tachycardia, palpitations, shortness of breath, sweating, burning sensation, chills, edema and, in rare cases, syncope. Patients should be forewarned what they might expect prior to starting niacin. Diphenhydramine and aspirin (not enteric coated) may alleviate the effects of an acute flushing episode.

Liver

Do not use niacin if hepatic transaminase levels are ≥2 to 3 times the upper limit of normal.

Persistent hepatic transaminase elevations can occasionally occur with niacin therapy. Regularly monitor serum transaminase levels, including AST and ALT (SGOT and SGPT). Evaluate before treatment begins, then every 6 to 12 weeks for the first year and periodically thereafter (e.g., at approximately 6-month intervals).

Carefully evaluate patients who develop elevated serum transaminase levels during niacin therapy. Measurements should be repeated promptly and then performed more frequently. If the transaminase levels show evidence of progressive rise, particularly if they persistently increase to ≥3 times ULN, bilirubin is
≥3 mg/dL, prothrombin time is elevated, or if they are associated with symptoms of nausea, fever and/or malaise, or jaundice, the drug should be discontinued. Niacin rechallenge should be undertaken only with careful monitoring, if at all, in these patients. Niacin should be used with caution in patients who consume a substantial quantity of alcohol or with a past history of liver disease.

Extended-release niacin in doses >2 g/day are not recommended due to serious concerns about hepatoxicity.

Immediate-release niacin in doses up to 3 g/day appears to have no significant hepatoxicity.

Severe hepatic toxicity, including fulminant hepatic necrosis, has occurred in patients substituting sustained-release (modified-release, time-release) niacin for crystalline or IR niacin at equivalent doses.

Muscle

Niacin increases the risk of myopathy. Patients treated with a statin, elderly patients and patients with diabetes, renal failure, or uncontrolled hypothyroidism are at increased risk of myopathy and rhabdomyolysis from niacin therapy. Patients of Chinese descent are at significantly increased risk of myopathy when niacin ≥1 g is used concomitantly with simvastatin ≥40 mg.

Hyperglycemia and Diabetes

Niacin can increase glucose levels and worsen glucose control in patients with diabetes. Niacin can cause diabetes in previously normoglycemic or prediabetic patients, which is typically reversible upon niacin discontinuation. Closely monitor glucose during the first few months of niacin therapy or after a dose adjustment.

Atrial Fibrillation

New onset atrial fibrillation has occurred in the long-term trials of niacin. Niacin should be used with caution in patients with paroxysmal atrial fibrillation.

GI Symptoms

Niacin can cause unexplained abdominal pain and other GI symptoms. Niacin should not be used in patients with active peptic ulcer disease or GI bleeding. Gastrointestinal distress is greatly reduced by slowly increasing the dose of niacin and avoiding administration on an empty stomach.

Acute Coronary Syndromes

Use with caution in patients with unstable angina or in the acute phase of myocardial infarction.

Renal Impairment

No studies have been performed in patients with renal impairment. Niacin should be used with caution in these patients.

Acanthosis Nigricans

Marked hyperpigmentation of the axillary folds may occur.

Increased Uric Acid/Gout

Niacin commonly increases uric acid levels. Use with caution in patients predisposed to gout.

Low Platelet Count

Modest reduction in platelet count can occur. Carefully monitor patients receiving concomitant niacin and anticoagulation therapy, and monitor platelet counts in these patients.

Increased INR/Prothrombin Time

Niacin can very modestly increase prothrombin time. Carefully monitor patients receiving concomitant niacin and anticoagulation therapy, and monitor INR in these patients.

Decrease in Phosphorus

Niacin can transiently reduce phosphorus levels. Monitor phosphorous levels in patients with hypophosphatemia.

Eye

Blurred vision due to cystoid macular degeneration has been reported with niacin >3 g.

Drug-Drug Interactions

Statins

Concomitant use with a statin increases the risk of myopathy and rhabdomyolysis. Niacin does not affect the pharmacokinetics of fluvastatin and modestly increases the plasma levels of lovastatin and simvastatin.

Bile Acid Sequestrants

Niacin is extensively bound to colestipol (98%) and to a lesser extent cholestyramine (10%-30%). Administer niacin 4 to 6 hours after cholestyramine.

Antihypertensive Therapy

Niacin can cause postural hypotension by potentiating the effects of ganglionic blocking agents and vasoactive drugs.

Laboratory Test Interactions

Niacin can cause false elevations in some tests of urine or plasma catecholamines, and false-positive tests for urine glucose.