Niacin is used as an adjunct to nondrug therapies (i.e., lifestyle modifications) for prevention of cardiovascular events and for the management of dyslipidemias.
The American College of Cardiology (ACC)/American Heart Association (AHA) guideline for management of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults states that nondrug therapies (i.e., lifestyle modifications), which include adherence to a heart-healthy diet, regular exercise, avoidance of tobacco products, and maintenance of a healthy weight, are the foundation of atherosclerotic cardiovascular disease (ASCVD) prevention. Drug therapy is not a substitute for but an adjunct to these nondrug therapies and measures, which should be continued when drug therapy is initiated. Because drug therapy is likely to continue for many years or a lifetime, the patient should be apprised of the goals and potential adverse effects of drug therapy. For additional details on lifestyle modifications, consult the most recent AHA/ACC Guidelines on Lifestyle Management to Reduce Cardiovascular Risk (available at http://www.cardiosource.org or http://my.americanheart.org).
Prevention of Cardiovascular Events
Niacin is used as an adjunct to dietary therapy in patients with a history of myocardial infarction (MI) and hypercholesterolemia to reduce the risk of recurrent nonfatal MI. Extended-release niacin in fixed combination with lovastatin is used in patients for whom treatment with both extended-release niacin and lovastatin is appropriate.
The ACC/AHA cholesterol management guideline states that nonstatin therapies (e.g., niacin) do not provide acceptable ASCVD risk reduction benefits compared to their potential for adverse effects in the routine prevention of ASCVD. The guideline states nonstatin drugs may be useful as adjuncts to hydroxymethyl-glutaryl-CoA (HMG-CoA) reductase inhibitor (statin) therapy in certain high-risk patients (e.g., patients with ASCVD, patients with low-density lipoprotein (LDL)-cholesterol concentrations of 190 mg/dL or higher, patients with diabetes mellitus) who have a less-than-anticipated response to statins, are unable to tolerate even a less-than-recommended intensity of a statin, or are completely intolerant to statin therapy. However, data from several large randomized studies indicate that the addition of niacin to simvastatin-based therapy did not further reduce the incidence of major cardiovascular events but did increase the risk of severe adverse effects. For additional details on prevention of ASCVD, and also consult the most recent ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (available at http://www.cardiosource.org or http://my.americanheart.org).
Efficacy of niacin in reducing the risk of recurrent MI has been established in a large, multicenter, placebo-controlled study (Coronary Drug Project). During 5-8.5 years of observation in men with previous MI, therapy with 3 g of niacin daily was shown to reduce the incidence of definite, nonfatal MI. During this period, niacin therapy had no effect on overall or cause-specific mortality rates when compared with placebo, although the 5-year rate of death secondary to coronary heart disease (CHD) was slightly lower in the niacin-treated group. However, follow-up of surviving patients 5-9 years after discontinuance of drug therapy indicated that previous niacin therapy was associated with a long-term overall reduction in mortality when compared with placebo, possibly secondary to the reduction in nonfatal MI observed during the treatment period or to a long-term benefit from the drug's effects on lipoproteins.
The addition of niacin to statin-based therapy has not been shown to provide an incremental benefit on cardiovascular morbidity and mortality beyond that already demonstrated with statin-based therapy. In the Impact on Global Health Outcomes (AIM-HIGH) study, the combination of extended-release niacin (1.5-2 g daily) and statin-based therapy (simvastatin 40-80 mg once daily, with or without ezetimibe 10 mg daily) was compared with statin-based therapy alone in patients with established cardiovascular disease (i.e., documented stable CHD, cerebrovascular or carotid disease, peripheral arterial disease). Despite a favorable effect on serum lipid concentrations (median high-density lipoprotein [HDL]-cholesterol concentration increased from 35 to 42 mg/dL, triglyceride concentration decreased from 164 to 122 mg/dL, and LDL-cholesterol concentration decreased from 74 to 62 mg/dL), the addition of niacin to simvastatin-based therapy did not further reduce the incidence of the primary end point (i.e., composite of death from CHD, nonfatal MI, ischemic stroke, hospitalization for more than 23 hours for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization) compared with statin-based therapy alone over a follow-up period of 36 months. The addition of extended-release niacin to existing simvastatin-based therapy, however, did increase the risk of adverse effects (e.g., pruritus, flushing, adverse GI effects, increased blood glucose concentrations). The investigators of this study stated that whether such combination therapy provides incremental benefit in higher-risk patients or in those receiving suboptimal statin therapy remains to be established.
Data from another large randomized, double-blind, multicenter study involving 25,673 adults with cardiovascular disease confirmed findings of the AIM-HIGH study. In the Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE), the combination of extended-release niacin/laropiprant (2 g/40 mg daily) (no longer commercially available) and statin-based therapy (simvastatin 40 mg once daily, with or without ezetimibe 10 mg daily) was compared with statin-based therapy alone in patients with established cardiovascular disease (i.e., history of MI, cerebrovascular disease, peripheral arterial disease, diabetes mellitus with evidence of symptomatic coronary disease). Despite a favorable effect on serum lipid concentrations (additional 6-mg/dL increase in HDL-cholesterol concentration, 33-mg/dL reduction in triglyceride concentration, and 10-mg/dL reduction in LDL-cholesterol concentration), the addition of niacin/laropiprant to simvastatin-based therapy did not further reduce the incidence of major cardiovascular events (i.e., nonfatal MI, death from coronary causes, stroke of any type, coronary or noncoronary revascularization) compared with simvastatin-based therapy alone over a median follow-up of 3.9 years. The addition of niacin/laropiprant to existing simvastatin-based therapy, however, did increase the risk of severe adverse effects, including disturbances in glycemic control requiring hospitalization, development of diabetes mellitus, adverse GI effects, myopathy, gout, rash, skin ulceration, and, unexpectedly, infection and bleeding. In light of these findings, some clinicians state that niacin should be reserved as a fourth-line agent (after intensive lifestyle modifications, fibric acid derivatives, and omega-3-acid ethyl esters) for patients with severe hypertriglyceridemia in whom the primary goal of treatment is prevention of pancreatitis.
Reducing Progression of Coronary Atherosclerosis
Niacin, in combination with a bile acid sequestrant, also is used to slow the progression or promote regression of atherosclerosis in patients with clinical evidence of CHD who have elevated cholesterol concentrations. Extended-release niacin in fixed combination with lovastatin is used in patients for whom treatment with both extended-release niacin and lovastatin is appropriate.
In the Familial Atherosclerosis Treatment Study (FATS), combined therapy with a bile acid sequestrant (colestipol) and either niacin or lovastatin for 2.5 years resulted in decreased progression of coronary atherosclerosis, an increased frequency of coronary atherosclerotic regression, and a reduced incidence of cardiovascular events (e.g., death, myocardial infarction, or the need for revascularization procedures for worsening symptoms) in high-risk men with CHD. Although coronary artery stenosis was reduced by an average of only 1.1 or 0.3% by combined niacin-colestipol or lovastatin-colestipol therapy, respectively, the incidence of clinical cardiovascular events in the 2 drug treatment groups combined was reduced by 73% compared with the placebo group. This disproportionality between the extent of improvement in coronary artery stenosis resulting from cholesterol reduction and decreases in cardiovascular morbidity and mortality also has been noted in other studies, suggesting that other effects of cholesterol reduction (e.g., stabilization of atherosclerotic plaque against rupture, improved coronary endothelial vasomotor function) may potentially contribute to a reduction in ischemic events in patients receiving antilipemic therapy.
In the Cholesterol-Lowering Atherosclerosis Study (CLAS), combined therapy with immediate-release niacin (average dosage 4.3 g daily) and colestipol (average dose 29.5 g daily) for 2-4 years in hypercholesterolemic men with previous coronary bypass surgery resulted in decreased progression of coronary atherosclerosis (measured as the number of lesions that progressed, formation of new lesions in native coronary arteries or in bypass grafts, or any adverse change in bypass grafts) and an increased frequency of coronary atherosclerotic regression.
Intolerable adverse effects may limit the usefulness of niacin therapy in patients with dyslipidemia, and some clinicians reserve niacin as alternative therapy when drugs with fewer and less severe adverse effects do not achieve the desired result.
Primary Hypercholesterolemia and Mixed Dyslipidemia
Niacin is used as an adjunct to dietary therapy to decrease elevated serum total and LDL-cholesterol, apo B, and triglyceride concentrations, and to increase HDL-cholesterol concentrations in the treatment of primary hypercholesterolemia and mixed dyslipidemia, including heterozygous familial hypercholesterolemia and other causes of hypercholesterolemia (e.g., polygenic hypercholesterolemia).
Niacin, in combination with a bile acid sequestrant, is used as an adjunct to dietary therapy to decrease elevated serum total and LDL-cholesterol concentrations in patients with primary hypercholesterolemia in whom a regimen of diet with or without pharmacologic therapies has not resulted in normal serum cholesterol concentrations.
Extended-release niacin in combination with lovastatin is used in the treatment of primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia in adults receiving lovastatin who require further reductions in triglyceride or increases in HDL-cholesterol concentrations or in patients receiving niacin who require further reductions in LDL-cholesterol concentrations. When such combination therapy is appropriate, the fixed-combination preparation containing extended-release niacin and lovastatin may be used.
A statin generally is considered the initial drug of choice when drug therapy is indicated for the management of hypercholesterolemia in most adults with increased LDL-cholesterol concentrations. Although the Third Report of the National Cholesterol Education Program (NCEP) (Adult Treatment Panel [ATP] III) stated that a bile acid sequestrant or niacin also could be useful as initial therapy or in combination with statin therapy, data from several large randomized studies indicate that the addition of niacin to simvastatin-based therapy did not further reduce the incidence of major cardiovascular events but did increase the risk of severe adverse effects.
(See Secondary Prevention under Uses: Prevention of Cardiovascular Events.)
Reductions in cholesterol and triglyceride concentrations produced by usual dosages of niacin substantially exceed those achieved with placebo. Mean reductions of 3-18% in plasma LDL-cholesterol concentration, 5-38% in triglyceride concentration, and increases of 10-32% in HDL-cholesterol concentration have been reported in various controlled studies in patients with primary hypercholesterolemia or mixed dyslipidemia who received extended-release niacin (Niaspan) 500-2000 mg daily at bedtime for at least 4 weeks. An analysis of pooled data from these studies indicate that women may exhibit a greater antilipemic response to Niaspan than men; LDL-cholesterol and triglyceride concentrations were reduced by 5-18 and 9-36%, respectively, in women and 2-15 and 3-30%, respectively, in men. Increases in HDL-cholesterol concentrations also were greater among women than men (8-26% versus 11-23%).
The addition of a bile acid sequestrant or a statin to niacin therapy further reduces LDL-cholesterol concentrations in patients with primary hypercholesterolemia or mixed dyslipidemia. In a long-term, open-label study in such patients, combined therapy for 48-96 weeks with extended-release niacin and a bile acid sequestrant or a statin was associated with overall LDL-cholesterol reductions of 20-28 and 32%, respectively; these reductions averaged 2-10 or 14% greater, respectively, than those achieved with niacin monotherapy after 48-96 weeks. In patients with primary hypercholesterolemia or mixed dyslipidemia who received extended-release niacin (1-2 g daily) in fixed combination with lovastatin (20-40 mg daily) for at least 12 weeks, LDL-cholesterol or triglyceride concentrations were reduced by 30-42 or 32-44%, respectively, and HDL-cholesterol concentrations were increased by 20-30%. Additional reductions in total cholesterol, LDL-cholesterol, and triglyceride concentrations also were reported in patients with CHD who received combined therapy with niacin and a statin for 2.5 years. Although combined therapy that includes niacin and a statin may be useful, the safety of this combination, in terms of potential risk for hepatotoxicity, should be considered. It should be noted that, in patients with established cardiovascular disease, the combination of niacin and statin-based therapy has not been shown to provide additional ASCVD risk reduction benefit beyond that already established with statin-based therapy.
(See Secondary Prevention under Uses: Prevention of Cardiovascular Events.)
Niacin is used as adjunctive therapy in the management of severe hypertriglyceridemia in patients at risk of developing pancreatitis (typically those with serum triglyceride concentrations exceeding 2000 mg/dL and elevated concentrations of VLDL-cholesterol and fasting chylomicrons) who do not respond adequately to dietary management. The drug also may be used in patients with triglyceride concentrations of 1000-2000 mg/dL who have a history of pancreatitis or of recurrent abdominal pain typical of pancreatitis. The effect of niacin therapy on risk of pancreatitis in patients with type IV hyperlipoproteinemia and triglyceride concentrations less than 1000 mg/dL who exhibit type V patterns subsequent to dietary or alcoholic indiscretion has not been adequately studied. Niacin is not indicated for use in patients with type I hyperlipoproteinemia who have elevated triglyceride and chylomicron concentrations but normal VLDL-cholesterol concentrations. Extended-release niacin in fixed combination with lovastatin is used in patients for whom treatment with both extended-release niacin and lovastatin is appropriate.
ATP III stated that initiation of therapy and target goals in the management of hypertriglyceridemia depend on initial risk status and preexisting triglyceride concentrations. As in primary or secondary prevention of CHD, LDL-cholesterol is considered the principal target of therapy in most patients with borderline high (150-199 mg/dL) or high (200-499 mg/dL) triglyceride concentrations; in those with high triglyceride concentrations, non-HDL-cholesterol (sum of VLDL-cholesterol plus LDL-cholesterol, calculated as total cholesterol minus HDL-cholesterol) becomes a secondary target of therapy. The principal aim of therapy in patients with very high triglyceride concentrations (500 mg/dL or greater) is to prevent acute pancreatitis through triglyceride lowering; principal and secondary targets similar to those used in patients with borderline high or high triglycerides may be considered in these patients when triglyceride levels are reduced to less than 500 mg/dL.
ATP III stated that nondrug therapies and measures (i.e., weight reduction, increased physical activity, smoking cessation, restriction of excessive alcohol use, avoidance of high-carbohydrate [more than 60% of calories] diets) are considered the initial treatments of choice in the management of patients with borderline high or high triglyceride concentrations. Drug therapy, in addition to nonpharmacologic measures, also may be considered (after LDL-lowering therapy) in patients with high triglyceride concentrations to achieve the non-HDL-cholesterol goal. In these patients, ATP III recommended one of several options: intensifying therapy with an LDL-lowering drug (i.e., statin), initiating therapy with a triglyceride-lowering drug (i.e., fibric acid derivative or, preferably, niacin), or combining moderate doses of statins and triglyceride-lowering drugs.
(See Cautions: Precautions and Contraindicationsand see Drug Interactions.)
Patients with very high triglyceride concentrations should be treated more intensively to prevent development of acute pancreatitis. However, before initiating antilipemic therapy, patients with triglyceride concentrations of 500 mg/dL or greater should be evaluated to rule out secondary causes of hyperlipidemia. ATP III recommended elimination of alcohol from diet and identification and, preferably, discontinuance of drugs that increase triglyceride concentrations. In addition, insulin or oral antidiabetic therapy may be initiated (or dosage increased) in patients with hyperglycemia. In patients with triglyceride concentrations exceeding 1000 mg/dL, a very low-fat diet (less than 15% of total daily calories as fat) should be initiated immediately to improve chylomicronemia that contributes to hypertriglyceridemia. Weight reduction and increased physical activity as components of therapeutic lifestyle changes should be emphasized. Pharmacologic therapy with triglyceride-lowering drugs (i.e., niacin or, preferably, a fibric acid derivative) usually is required in patients with very high triglyceride concentrations, and often can prevent acute pancreatitis. Because niacin may worsen hyperglycemia (and thus increase triglyceride concentrations), high doses (greater than 2 g daily) of the drug generally should be used with caution in patients with elevated serum glucose concentrations. For most patients with very high triglyceride concentrations, therapy is considered successful if triglyceride concentrations are reduced to less than 500 mg/dL; triglyceride concentrations often cannot be normalized in these patients. The principal aim of therapy is to prevent acute pancreatitis; efforts to modify CHD risk (by lowering LDL- and/or non-HDL-cholesterol concentrations) may be considered once triglyceride concentrations have been reduced to less than 500 mg/dL.
Patients with very high triglyceride and chylomicron concentrations usually have a genetic form of the disease and generally are unresponsive to triglyceride-lowering drugs. Treatment for these patients includes very low-fat diets, which may be supplemented with medium-chain triglycerides to minimize production of chylomicrons.
Niacin is recommended for use in high-risk patients with isolated low HDL-cholesterol concentrations in whom drug therapy is deemed appropriate. In patients with documented CHD who had HDL-cholesterol concentrations of 40 mg/dL or less, reductions in LDL-cholesterol and triglyceride concentrations following treatment with extended-release niacin for at least 19 weeks averaged 3% and 33%, respectively, and increases in HDL-cholesterol averaged 27%. Niacin also is used as an adjunct to dietary therapy for the treatment of patients with primary dysbetalipoproteinemiawho do not respond adequately to diet.
For additional information on the role of niacin and other antilipemic agents in the treatment of lipoprotein disorders, see General Principles of Antilipemic Therapy in the HMG-CoA Reductase Inhibitors General Statement 24:06.08. For the use of niacin as a vitamin and as a vasodilator, see Niacin/Niacinamide 88:08.