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Niacin as a Component of Combination Therapy for Dyslipidemia

  • Author Footnotes
    1 Dr Miller receives grant support from AstraZeneca Pharmaceuticals; Merck & Co, Inc; Bristol-Myers Squibb Company; Kos Pharmaceuticals, Inc; and Schering-Plough Corp.
    Michael Miller
    Correspondence
    Address reprint requests and correspondence to Michael Miller, MD, Division of Cardiology, Rm S3B06, University of Maryland Hospital, 22 S Greene St, Baltimore, MD 21201
    Footnotes
    1 Dr Miller receives grant support from AstraZeneca Pharmaceuticals; Merck & Co, Inc; Bristol-Myers Squibb Company; Kos Pharmaceuticals, Inc; and Schering-Plough Corp.
    Affiliations
    Center for Preventive Cardiology, University of Maryland Medical Center, Baltimore
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  • Author Footnotes
    1 Dr Miller receives grant support from AstraZeneca Pharmaceuticals; Merck & Co, Inc; Bristol-Myers Squibb Company; Kos Pharmaceuticals, Inc; and Schering-Plough Corp.
      Dyslipidemia is one of the most important modifiable risk factors for coronary disease. Despite the availability of highly effective lipid-modifying agents, many patients still do not reach lipid targets established by national guidelines. Niacin has been known to be an effective treatment of dyslipidemia for almost half a century. Niacin substantially increases high-density lipoprotein cholesterol (HDL-C) levels while lowering levels of low-density lipoprotein cholesterol (LDL-C), triglycerides, and lipoprotein(a). In addition, niacin converts small LDL particles into more buoyant, less atherogenic LDL particles. Combined with other agents, niacin offers an important treatment option for patients with dyslipidemia. In particular, niacin complements LDL-C-lowering drugs; it is the most effective agent available for increasing HDL-C levels while lowering levels of LDL-C and triglycerides and improving other lipid risk factors such as lipoprotein(a). Combining niacin with statins or bile acid sequestrant therapy is safe and effective for improving lipid levels and decreasing coronary risk. Differences in niacin formulations dictate tolerability profiles and should be considered when selecting niacin as part of lipid therapy. Furthermore, adverse effects on glucose and insulin sensitivity should be considered when selecting candidates for niacin therapy. Adding niacin to lipid-lowering regimens is a valuable option for physicians treating patients with dyslipidemia and should be considered in appropriate patients.
      A1C (glycosylated hemoglobin), BAS (bile acid sequestrant), CHD (coronary heart disease), ER (extended-release), FATS (Familial Atherosclerosis Treatment Study), FBG (fasting blood glucose), GI (gastrointestinal), HATS (HDL [high-density lipoprotein]-Atherosclerosis Treatment Study), HDL-C (high-density lipoprotein cholesterol), LDL-C (low-density lipoprotein cholesterol), Lp(a) (lipoprotein(a)), MI (myocardial infarction), NCEP III (National Cholesterol Education Program III), TC (total cholesterol), TG (triglyceride), VA-HIT (Veterans Affairs HDL Intervention Trial), VLDL (very low-density lipoprotein)
      Coronary heart disease (CHD) is the single largest cause of death in American men and women, and dyslipidemia is one of the major modifiable risk factors.
      • National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
      Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): final report.
      Despite efforts by the medical and public health communities to increase awareness of the risks of dyslipidemia and encourage lipid screening, patients often are inadequately treated, and less than 40% reach National Cholesterol Education Program (NCEP) low-density lipoprotein cholesterol (LDL-C) targets with monotherapy.
      • Pearson TA
      • Laurora I
      • Chu H
      • Kafonek S
      The Lipid Treatment Assessment Project (L-TAP): a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals.
      Furthermore, risk assessment limited to LDL-C fails to identify a substantial number of patients at risk for coronary events. Most patients with CHD have multiple lipid abnormalities, ie, mixed dyslipidemia. The Veterans Affairs HDL Intervention Trial (VA-HIT) group
      • Rubins HB
      • Robins SJ
      • Collins D
      • Department of Veterans Affairs HDL Intervention Trial Study Group
      • et al.
      Distribution of lipids in 8,500 men with coronary artery disease.
      found that 87% of 8500 patients with established CHD had suboptimal LDL-C levels (=100 mg/dL), and 33% had hypertriglyceridemia (triglyceride [TG] levels >200 mg/dL). In addition, approximately 60% of the study population had low levels of high-density lipoprotein cholesterol (HDL-C) (=40 mg/dL).
      Because of its effects on all components of the lipid profile, niacin has gained attention as an important therapeutic option for patients with multiple lipid abnormalities and for those not achieving treatment targets while receiving monotherapy. This article discusses (1) the importance of measuring and improving lipoprotein levels other than LDL-C to reduce coronary risk and (2) the role of niacin as both monotherapy and in combination with other lipidmodifying agents in the treatment of dyslipidemia.

      IMPORTANCE OF NON-LDL LIPID FRACTIONS IN CHD EVENTS

      The importance of improving the overall lipid profile is becoming increasingly understood. The NCEP III has identified non-HDL-C, the sum of all atherogenic lipoproteins, as a secondary target of therapy for patients with TG levels of 200 mg/dL or higher.
      • National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
      Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): final report.
      Non-HDL-C, calculated by subtracting the HDL-C value from the total cholesterol (TC) value, is considered a predictor of CHD risk. The new guidelines emphasize that, although LDL-C remains the primary target of therapy, once goals have been achieved, focus must turn to other lipid abnormalities.
      Low levels of HDL-C are strong independent predictors of CHD risk. Each 1 mg/dL increase in HDL-C is associated with a 2% to 3% decrease in CHD risk, even after adjustment for other risk factors, and predicts coronary risk regardless of LDL-C levels.
      • Castelli WP
      Cholesterol and lipids in the risk of coronary artery disease—the Framingham Heart Study.
      The NCEP III has identified HDL-C levels less than 40 mg/dL as a risk factor for CHD, although no goal has been set.
      • National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
      Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): final report.
      In a recently published editorial, Sacks et al,
      • Sacks FM
      • Expert Group on HDL Cholesterol
      The role of high-density lipoprotein (HDL) cholesterol in the prevention and treatment of coronary heart disease: expert group recommendations [editorial].
      on the basis of current clinical research, proposed an HDL-C goal of 40 mg/dL or higher in patients with, or at high risk for, CHD.
      Recent research also stresses the importance of elevated TG levels as an independent risk factor for CHD events. The VA-HIT was the first trial to show that improvements in levels of HDL-C (6% increase) and TG (31% decrease) with gemfibrozil, without substantial reductions in LDL-C levels, decreased CHD death, nonfatal myocardial infarction (MI), and stroke by 24%.
      • Rubins HB
      • Robins SJ
      • Collins D
      • Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group
      • et al.
      Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol.
      The NCEP identifies TG levels of less than 150 mg/dL as optimal and recommends treatment for TG levels of 200 mg/dL or higher.
      • National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
      Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): final report.
      Lipoprotein(a) [Lp(a)] is a modified form of LDL with a distinctive glycoprotein [apo(a)] that shares structural homology with plasminogen; consequently, increased levels of Lp(a) may impair fibrinolysis, thereby increasing plaque development and thrombotic events.
      • Danesh J
      • Collins R
      • Peto R
      Lipoprotein(a) and coronary heart disease: meta-analysis of prospective studies.
      To date, no data show that lowering Lp(a) levels leads to clinical benefit; however, a meta-analysis of 27 prospective studies showed that, although Lp(a) levels were not correlated with other classic CHD risk factors, they were associated with CHD risk. Patients with Lp(a) levels in the highest tertile had an approximate 70% increase in CHD risk over patients with Lp(a) levels in the lowest tertile.
      • Danesh J
      • Collins R
      • Peto R
      Lipoprotein(a) and coronary heart disease: meta-analysis of prospective studies.

      TC/HDL-C RATIO: PARAMETER OF CHD RISK

      Both the LDL-C/HDL-C ratio and the TC/HDL-C ratio predict CHD risk. However, the LDL-C/HDL-C ratio may underestimate the degree of CHD risk in some patients.
      • Lemieux I
      • Lamarche B
      • Couillard C
      • et al.
      Total cholesterol/HDL cholesterol ratio vs LDL cholesterol/HDL cholesterol ratio as indices of ischemic heart disease risk in men: the Quebec Cardiovascular Study.
      Investigators from the Quebec Cardiovascular Study
      • Lemieux I
      • Lamarche B
      • Couillard C
      • et al.
      Total cholesterol/HDL cholesterol ratio vs LDL cholesterol/HDL cholesterol ratio as indices of ischemic heart disease risk in men: the Quebec Cardiovascular Study.
      reported that variations in the TC/HDL-C ratio might be more predictive of CHD risk than the LDL-C/HDL-C ratio (Figure 1). This may be because there is more cholesterol in the very low-density lipoprotein (VLDL) fraction in patients with hypertriglyceridemia than in the LDL-C component.
      • Lemieux I
      • Lamarche B
      • Couillard C
      • et al.
      Total cholesterol/HDL cholesterol ratio vs LDL cholesterol/HDL cholesterol ratio as indices of ischemic heart disease risk in men: the Quebec Cardiovascular Study.
      In the 6 clinical end point trials that used statin therapy,
      • Downs JR
      • Clearfield M
      • Weis S
      • et al.
      Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS.
      Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).
      • Sacks FM
      • Pfeffer MA
      • Moye LA
      • Cholesterol and Recurrent Events Trial Investigators
      • et al.
      The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels.
      • Shepherd J
      • Cobbe SM
      • Ford I
      • West of Scotland Coronary Prevention Study Group
      • et al.
      Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia.
      • Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group
      Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.
      Heart Protection Study Collaborative Group
      MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.
      significant reduction in the TC/HDL-C ratio (Figure 2) coincided with clinical event reduction, ranging between 25% and 35%.
      Figure thumbnail gr1
      Figure 1Odds ratios for ischemic heart disease during 5-year follow-up in 2103 men in the Quebec Cardiovascular Study, classified according to quintiles of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol (LDL-C/HDL-C) ratios (top) and total cholesterol to HDL-C (TC/HDL-C) ratios (bottom). Reprinted with permission from Lemieux et al.
      • Lemieux I
      • Lamarche B
      • Couillard C
      • et al.
      Total cholesterol/HDL cholesterol ratio vs LDL cholesterol/HDL cholesterol ratio as indices of ischemic heart disease risk in men: the Quebec Cardiovascular Study.
      Copyright 2001, American Medical Association.
      Figure thumbnail gr2
      Figure 2Changes in total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C) ratio in major statin trials.
      • Downs JR
      • Clearfield M
      • Weis S
      • et al.
      Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS.
      Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).
      • Sacks FM
      • Pfeffer MA
      • Moye LA
      • Cholesterol and Recurrent Events Trial Investigators
      • et al.
      The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels.
      • Shepherd J
      • Cobbe SM
      • Ford I
      • West of Scotland Coronary Prevention Study Group
      • et al.
      Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia.
      • Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group
      Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.
      Heart Protection Study Collaborative Group
      MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.
      4S = Scandinavian Simvastatin Survival Study; AFCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS); CARE = Cholesterol and Recurrent Events trial; HPS = MRC/BHF [Medical Research Council/British Heart Foundation] Heart Protection Study; LIPID = Long-term Intervention with Pravastatin in Ischaemic Disease; WOSCOPS = West of Scotland Coronary Prevention Study.

      NIACIN

      Although the exact mechanism is complex and not understood completely, the likely primary action of niacin is to inhibit mobilization of free fatty acids from peripheral adipose tissue to the liver. Consequently, niacin reduces hepatic synthesis of VLDL and TG. Because less VLDL is available as a substrate, LDL-C levels decrease.
      • Piepho RW
      The pharmacokinetics and pharmacodynamics of agents proven to raise high-density lipoprotein cholesterol.
      Niacin is believed to increase serum HDL-C levels by blocking hepatic uptake of apolipoprotein A-I, a major component of HDL-C.
      • Piepho RW
      The pharmacokinetics and pharmacodynamics of agents proven to raise high-density lipoprotein cholesterol.
      Niacin also increases a cardioprotective subfraction of HDL, which enhances reverse cholesterol transport.
      • Sakai T
      • Kamanna VS
      • Kashyap ML
      Niacin, but not gemfibrozil, selectively increases LP-AI, a cardioprotective subfraction of HDL, in patients with low HDL cholesterol.
      Niacin decreases levels of LDL-C by 5% to 25%, TG by 20% to 50%, Lp(a) by 34%,
      • Carlson LA
      • Hamsten A
      • Asplund A
      Pronounced lowering of serum levels of lipoprotein Lp(a) in hyperlipidaemic subjects treated with nicotinic acid.
      and the TC/HDL-C ratio by 27%
      • Luria MH
      Effect of low-dose niacin on high-density lipoprotein cholesterol and total cholesterol/high-density lipoprotein cholesterol ratio.
      ; niacin increases levels of HDL-C by 15% to 35%.
      • National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
      Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): final report.
      The Coronary Drug Project
      Clofibrate and niacin in coronary heart disease.
      was the first trial to study the effect of niacin on cardiovascular end points. After 6 years, treatment with niacin reduced the incidence of nonfatal MI by 26% and cerebrovascular events by 24%. Total mortality was not significantly reduced in the original trial; however, about 9 years after trial termination, the group originally treated with niacin had 11% fewer deaths than did the placebo group (P<.001).
      • Canner PL
      • Berge KG
      • Wenger NK
      • et al.
      Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin.
      It has been hypothesized that the mortality benefit reflects the early effect of niacin on reducing nonfatal cardiovascular events.
      In the Stockholm Ischaemic Heart Disease Secondary Prevention Study,
      • Carlson LA
      • Rosenhamer G
      Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid.
      combination therapy with immediate-release niacin and clofibrate reduced levels of TC by 13% and TG by 19%. Total mortality and CHD mortality were significantly reduced by 26% (P<.05) and 36% (P<.01), respectively, with combination therapy.
      Despite the benefits of niacin therapy, cutaneous flushing has limited its use. Facial and truncal flushing occur in most patients, leading to discontinuation of niacin in up to 25% of patients in studies,
      • Knopp RH
      • Ginsberg J
      • Albers JJ
      • et al.
      Contrasting effects of unmodified and time-release forms of niacin on lipoproteins in hyperlipidemic subjects: clues to mechanism of action of niacin.
      • McKenney JM
      • Proctor JD
      • Harris S
      • Chinchili VM
      A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients.
      • Stein EA
      • Davidson MH
      • Dujovne CA
      • et al.
      Efficacy and tolerability of low-dose simvastatin and niacin, alone and in combination, in patients with combined hyperlipidemia: a prospective trial.
      although these rates are likely to be higher in general practice. Tolerance to the flushing effects of niacin frequently develops with continued use; however, many patients discontinue therapy before this can develop. Several steps can be taken to decrease the severity of flushing and increase patient compliance. First, the patient should be counseled about the importance of continuing therapy and be reminded that interruptions in therapy may diminish any tolerance that has developed. Aspirin (325 mg) or a nonsteroidal anti-inflammatory medication such as ibuprofen (200 mg) taken 30 minutes to 1 hour before the first niacin dose of the day decreases the severity of flushing.
      • Wilkin JK
      • Wilkin O
      • Kapp R
      • Donachie R
      • Chernosky ME
      • Buckner J
      Aspirin blocks nicotinic acid-induced flushing.
      Other precautionary steps include slowly titrating the dose of niacin upward, taking the niacin dose with food, and avoiding spicy foods, hot beverages, and/or hot showers close to taking a dose.
      • Piepho RW
      The pharmacokinetics and pharmacodynamics of agents proven to raise high-density lipoprotein cholesterol.
      Sustained-release formulations of niacin were developed to minimize flushing. Sustained-release niacin is available over the counter as a dietary supplement. In a retrospective study of 63 patients treated with sustained-release niacin, HDL-C levels increased by 18%, and the TC/HDL-C ratio and levels of TC, LDL-C, and TG decreased by 25%, 9%, 13%, and 20%, respectively. The investigators noted a wide range of responses among participants; the changes in HDL-C levels ranged from −5% to 35%, which were not correlated with niacin dose.
      • Squires RW
      • Allison TG
      • Gau GT
      • Miller TD
      • Kottke BA
      Low-dose, time-release nicotinic acid: effects in selected patients with low concentrations of high-density lipoprotein cholesterol.
      Another study showed similar efficacy, including a subgroup of patients with isolated low HDL-C levels, and more marked effects were noted in another subgroup of patients with hypertriglyceridemia.
      • Lavie CJ
      • Mailander L
      • Milani RV
      Marked benefit with sustained-release niacin therapy in patients with “isolated” very low levels of high-density lipoprotein cholesterol and coronary artery disease.
      However, some sustained-release niacin preparations are associated with an increased incidence and severity of hepatotoxicity.
      • McKenney JM
      • Proctor JD
      • Harris S
      • Chinchili VM
      A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients.
      • Dalton TA
      • Berry RS
      Hepatotoxicity associated with sustained-release niacin.
      In a comparative study of 46 adults treated with sequential doses of sustained-release or immediate-release niacin, 52% of patients treated with the sustained-release form exhibited hepatotoxicity. Of these patients, 67% withdrew prematurely because of elevated levels of hepatic enzymes.
      • McKenney JM
      • Proctor JD
      • Harris S
      • Chinchili VM
      A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients.
      The rate of hepatotoxicity appears to differ among products. In the study by Lavie et al,
      • Lavie CJ
      • Mailander L
      • Milani RV
      Marked benefit with sustained-release niacin therapy in patients with “isolated” very low levels of high-density lipoprotein cholesterol and coronary artery disease.
      only 1 of 36 patients (3%) discontinued sustained-release niacin therapy because of elevated levels of hepatic enzymes. Therefore, patients should be treated with only 1 brand of niacin and should not be switched from immediate-release to sustained-release niacin. If switching is necessary because of intolerance, the dose and dosing schedule should be adjusted by the physician and again titrated upward. Niacin can be used safely with proper physician supervision and monitoring; it is probably most important to counsel the patient not to self-treat or change prescribed therapy unless instructed to do so by the physician.
      • Parsons Jr, WB
      The major adverse effects of the various niacin preparations are related to their metabolism and dissolution rate. Niacin is metabolized by 2 processes: (1) a low-affinity, high-capacity pathway in which the drug is conjugated with glycine to form nicotinuric acid and (2) a high-affinity, low-capacity pathway whereby the drug undergoes a series of oxidation-reduction reactions that yield nicotinamide and pyrimidines.
      • Piepho RW
      The pharmacokinetics and pharmacodynamics of agents proven to raise high-density lipoprotein cholesterol.
      The conjugative pathway is associated with flushing, whereas the nonconjugative pathway is associated with hepatotoxicity. Immediate-release products quickly saturate the nonconjugative pathway, resulting in a large fraction being metabolized by the conjugative pathway, whereas the nonconjugative pathway mainly metabolizes the sustained-release products.
      Extended-release (ER) niacin is a Food and Drug Administration-approved intermediate-release preparation given once daily at bedtime. Extended-release niacin has been formulated to distribute drug absorption over 8 to 12 hours to balance metabolism between the 2 metabolic pathways. Its efficacy is comparable to that of immediate-release niacin; however, ER niacin is associated with a lower incidence of flushing than is immediate-release niacin and has a lower risk of hepatotoxicity than does sustained-release niacin.
      • Knopp RH
      • Alagona P
      • Davidson M
      • et al.
      Equivalent efficacy of a time-release form of niacin (Niaspan) given once-a-night versus plain niacin in the management of hyperlipidemia.
      In a study of 223 patients treated with ER niacin or immediate-release niacin,
      • Knopp RH
      • Alagona P
      • Davidson M
      • et al.
      Equivalent efficacy of a time-release form of niacin (Niaspan) given once-a-night versus plain niacin in the management of hyperlipidemia.
      LDL-C levels decreased, respectively, by 12% and 12%, TG levels by 16% and 18%, and Lp(a) levels by 15% and 11%; HDL-C levels increased by 20% and 17%, respectively (all P=.05). Patients treated with ER niacin experienced a lower incidence of flushing (P<.001); aspartate aminotransferase levels increased by 5% and 4.8% (difference between groups not significant) in ER niacin and immediate-release groups, respectively.
      • Knopp RH
      • Alagona P
      • Davidson M
      • et al.
      Equivalent efficacy of a time-release form of niacin (Niaspan) given once-a-night versus plain niacin in the management of hyperlipidemia.
      In addition to flushing and hepatotoxicity, niacin has been associated with gastrointestinal (GI) complaints, including nausea, vomiting, diarrhea, and abdominal pain; activation of peptic ulcer disease; hyperuricemia and gout; hyperglycemia; and acanthosis nigricans.
      • Capuzzi DM
      • Morgan JM
      • Brusco Jr, OA
      • Intenzo CM
      Niacin dosing: relationship to benefits and adverse effects.
      • American Society of Health-System Pharmacists
      ASHP Therapeutic Position Statement on the safe use of niacin in the management of dyslipidemias.
      Niaspan [prescribing information].
      Niacin therapy should be avoided in patients with active peptic ulcer disease, hepatic insufficiency or a history of liver disease, or recent history of acute gout.
      • American Society of Health-System Pharmacists
      ASHP Therapeutic Position Statement on the safe use of niacin in the management of dyslipidemias.
      The hyperglycemic effects of niacin are discussed in the section “Selecting Patients for Niacin Combination Therapy.”

      NIACIN IN COMBINATION THERAPY

      Niacin Plus Bile Acid Sequestrants

      Bile acid sequestrants (BASs) offer a therapeutic option for patients with elevated LDL-C refractory to statin therapy or for patients who are intolerant of statin therapy. The major effect of BASs is to lower LDL-C levels (approximately 15%-30%); however, BASs have only a minor impact on HDL-C levels (3%-5%) and either no effect or a tendency to increase TG levels-a concern for patients with borderline or high TG levels.
      • National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
      Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): final report.
      These elevated levels may be caused by increased hepatic cholesterol synthesis, which also can lead to increased VLDL production.
      Because BASs are not systemically absorbed, systemic adverse reactions are extremely rare. However, these agents are associated with numerous drug interactions and GI adverse effects; constipation, bloating, and flatulence are common.
      • Piepho RW
      The pharmacokinetics and pharmacodynamics of agents proven to raise high-density lipoprotein cholesterol.
      Gastrointestinal effects may be decreased by reducing the dose or using colesevelam, a BAS associated with a lower incidence of GI adverse effects and drug interactions.
      • National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
      Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): final report.
      The efficacy of combination niacin/BAS therapy has been shown in several randomized clinical trials. The Cholesterol Lowering Atherosclerosis Study
      • Blankenhorn DH
      • Nessim SA
      • Johnson RL
      • Sanmarco ME
      • Azen SP
      • Cashin-Hemphill L
      Beneficial effects of combined colestipolniacin therapy on coronary atherosclerosis and coronary venous bypass grafts [published correction appears in JAMA. 1988;259: 2698].
      compared combination immediate-release niacin and colestipol to placebo in 162 patients with previous coronary bypass surgery. After 2 years, niacin/colestipol therapy lowered levels of TC by 26% and LDL-C by 43% and improved levels of HDL-C by 37% (all P<.001). A significant improvement in overall coronary status was seen in 16.2% of patients treated with combination therapy compared with 2.4% in patients who received placebo (P=.002).
      • Blankenhorn DH
      • Nessim SA
      • Johnson RL
      • Sanmarco ME
      • Azen SP
      • Cashin-Hemphill L
      Beneficial effects of combined colestipolniacin therapy on coronary atherosclerosis and coronary venous bypass grafts [published correction appears in JAMA. 1988;259: 2698].
      After 4 years, significantly more patients in the treatment group experienced nonprogression of atherosclerosis than in the placebo group (52% vs 15%; P<.001); likewise, regression occurred more often (18% vs 6%; P=.04) in native coronary lesions.
      • Cashin-Hemphill L
      • Mack WJ
      • Pogoda JM
      • Sanmarco ME
      • Azen SP
      • Blankenhorn DH
      Beneficial effects of colestipol-niacin on coronary atherosclerosis: a 4-year follow-up.
      The Familial Atherosclerosis Treatment Study (FATS),
      • Brown G
      • Albers JJ
      • Fisher LD
      • et al.
      Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B.
      a 2.5-year trial, compared conventional therapy (dietary counseling and placebo or use of colestipol in patients with elevated LDL-C levels) with combination drug therapy plus diet. In the immediate-release niacin plus colestipol group, LDL-C levels decreased by 32%, and HDL-C levels increased by 43%. Regression in at least 1 of 9 proximal lesions was observed in 11% of the patients in the conventional treatment arm and in 39% in the combination therapy arm (P<.005). Although the study was not powered to evaluate clinical events, there was a 73% reduction in event rates (eg, death, MI, or revascularization for worsening symptoms).
      • Brown G
      • Albers JJ
      • Fisher LD
      • et al.
      Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B.
      Studies are presently under way to evaluate the selective cholesterol absorption inhibitor ezetimibe in combination with niacin.

      Niacin/Statin Combination Therapy

      The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are the most effective agents for lowering LDL-C, decreasing levels by 18% to 55%. However, statins have only moderate effects on lowering TG levels (7%-30%) and more modest effects on increasing HDL-C levels (5%-10%).
      • National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
      Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): final report.
      Additionally, dose-response curves are nonlinear, and most of the LDL-C-lowering activity is achieved with lower doses offering less incremental benefit as doses are increased.
      • Schectman G
      • Hiatt J
      Dose-response characteristics of cholesterol-lowering drug therapies: implications for treatment.
      Combination niacin/statin therapy offers the benefits of statins coupled with potent elevation of HDL-C levels, a decrease in Lp(a) levels, and supplemental lowering of LDL-C and TG levels.
      The efficacy of this combination has been well established. In a multicenter randomized trial, combination therapy with simvastatin, 10 mg/d, plus immediate-release niacin, 1.5 g/d, reduced levels of LDL-C by 29% and TG by 31% and increased levels of HDL-C by 31% after 17 weeks of therapy.
      • Stein EA
      • Davidson MH
      • Dujovne CA
      • et al.
      Efficacy and tolerability of low-dose simvastatin and niacin, alone and in combination, in patients with combined hyperlipidemia: a prospective trial.
      In another study, ER niacin plus statin therapy (lovastatin, pravastatin, or simvastatin) lowered levels of TC by 23%, LDL-C by 32%, TG by 30%, and Lp(a) by 19% and increased levels of HDL-C by 26% after 48 weeks of therapy. Combination therapy also reduced the TC/HDL-C ratio by 37%.
      • Guyton JR
      • Goldberg AC
      • Kreisberg RA
      • Sprecher DL
      • Superko HR
      • O'Connor CM
      Effectiveness of once-nightly dosing of extended-release niacin alone and in combination for hypercholesterolemia.
      Most recently, the HDL-Atherosclerosis Treatment Study (HATS) showed clinical benefits with combination niacin/statin therapy in 160 patients with coronary disease, low HDL-C levels, and normal LDL-C levels.
      • Brown BG
      • Zhao XQ
      • Chait A
      • et al.
      Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease.
      Patients were initially prescribed sustained-release niacin and switched to immediate-release niacin if HDL-C level increases were insufficient. Combination therapy reduced levels of LDL-C by 42% and TG by 36% and increased levels of HDL-C by 26%. The TC/HDL-C ratio was reduced from 6.5 to 3.5
      • Brown BG
      • Zhao XQ
      • Chait A
      • et al.
      Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease.
      (Figure 3). Although the average degree of stenosis progressed by 3.9% in individuals in the placebo arm, it regressed 0.4% in those treated with simvastatin and niacin (P<.001). Patients treated with combination therapy experienced a 90% reduction in the composite primary end point of death from coronary causes, confirmed MI or stroke, or revascularization for worsening ischemic symptoms compared with placebo (P=.03). The HATS investigators concluded that combination niacin plus simvastatin represents a substantial advance over current clinical practice for the approximate 40% of patients with CHD who have low HDL-C levels but seldom receive therapy directed at both HDL-C and LDL-C.
      Figure thumbnail gr3
      Figure 3Changes in total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C) ratio in several clinical trials using niacin plus bile acid sequestrant or statin therapy.
      • Blankenhorn DH
      • Nessim SA
      • Johnson RL
      • Sanmarco ME
      • Azen SP
      • Cashin-Hemphill L
      Beneficial effects of combined colestipolniacin therapy on coronary atherosclerosis and coronary venous bypass grafts [published correction appears in JAMA. 1988;259: 2698].
      • Brown G
      • Albers JJ
      • Fisher LD
      • et al.
      Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B.
      • Brown BG
      • Zhao XQ
      • Chait A
      • et al.
      Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease.
      CLAS = Cholesterol Lowering Atherosclerosis Study; FATS = Familial Atherosclerosis Treatment Study; HATS = HDL-Atherosclerosis Treatment Study.
      The combination of niacin plus a statin is well tolerated. Nevertheless, with the withdrawal of cerivastatin, concerns about potential myopathy and hepatotoxicity have been raised by physicians. Fortunately, hepatic effects and myopathy are uncommon with the niacin/statin combination and are similar to the hepatic effects and myopathy reported with statin monotherapy. Recently, simvastatin product labeling was changed, stating that doses of simvastatin higher than 10 mg/d generally should not be used in combination with a fibrate or niacin (>1000 mg/d). However, recent guidelines propose that statin/fibrate and statin/niacin therapy can be used safely if patients are monitored carefully. Data suggest that niacin increases the risk of muscle damage to a lesser degree than fibrates.
      • Pasternak RC
      • Smith Jr, SC
      • Bairey-Merz CN
      • Grundy SM
      • Cleeman JI
      • Lenfant C
      • American College of Cardiology
      • American Heart Association, National Heart, Lung and Blood Institute
      ACC/AHA/NHLBI clinical advisory on the use and safety of statin.
      In a recent study of Food and Drug Administration case reports of statin-related rhabdomyolysis over an approximate 30-month period, statin-niacin-associated rhabdomyolysis occurred in only 4 (0.7%) of 601 reported cases, less than with a statin alone.
      • Omar MA
      • Wilson JP
      FDA adverse event reports on statin-associated rhabdomyolysis.
      Mibefradil (no longer available), fibrates, and cyclosporine (16.5%, 13.3%, and 8.5%, respectively) had the highest association of drug-statin toxicity. Another option is to use a statin with less potential for drug-drug interaction such as those not metabolized by cytochrome P-450 3A4.
      • Pasternak RC
      • Smith Jr, SC
      • Bairey-Merz CN
      • Grundy SM
      • Cleeman JI
      • Lenfant C
      • American College of Cardiology
      • American Heart Association, National Heart, Lung and Blood Institute
      ACC/AHA/NHLBI clinical advisory on the use and safety of statin.

      Niacin-Statin-BAS Therapy

      Use of combination niacin-statin-BAS therapy also has been effective in treating dyslipidemia and decreasing CHD. In a 10-year follow-up to FATS, patients treated with immediate-release niacin, colestipol, and lovastatin were compared with patients returned to the usual care of their physician. After 10 years, combination therapy lowered levels of LDL-C by 43% and TG by 36% and increased levels of HDL-C by 23% compared with −12%, 6%, and 5%, respectively, achieved in the usual care group. Triple therapy also significantly reduced cardiovascular events (5.3% vs 18.8%; P<.001) and all-cause mortality (1.3% vs 19.8%; P<.001).
      • Brown BG
      • Zhao XQ
      • Bardsley J
      • Albers JJ
      Secondary prevention of heart disease amongst patients with lipid abnormalities: practice and trends in the United States.
      However, the Harvard Atherosclerosis Reversibility Project showed that, although the addition of immediate-release niacin to pravastatin produced further improvements in lipid parameters, the further addition of cholestyramine had a negative effect, decreasing HDL-C levels by 8% and increasing TG levels by 46% vs pravastatin/niacin therapy.
      • Pasternak RC
      • Brown LE
      • Stone PH
      • Harvard Atherosclerosis Reversibility Project (HARP) Study Group
      • et al.
      Effect of combination therapy with lipid-reducing drugs in patients with coronary heart disease and “normal” cholesterol levels: a randomized, placebo-controlled trial.

      Combination Products

      A combination ER niacin/lovastatin product is now available by prescription. The efficacy and safety of this combination was recently shown in a 52-week, open label study of 814 men and women with dyslipidemia.
      • Kashyap ML
      • McGovern ME
      • Berra K
      • et al.
      Long-term safety and efficacy of a once-daily niacin/lovastatin formulation in patients with dyslipidemia.
      At 16 weeks, the combination agent significantly decreased levels of LDL-C (47%) and TG (41%) (P<.001). These lipidlowering effects persisted throughout the study. At 16 weeks, HDL-C levels increased 30% over baseline, and by the end of the study, HDL-C levels had increased an additional 11%. Extended-release niacin/lovastatin also decreased Lp(a) levels by 25% (P<.01 vs baseline) and the TC/HDL-C ratio by 48%. In general, treatment was well tolerated. Flushing was the most common adverse event, causing 10% of patients to discontinue the study. Drug-induced myopathy was not reported, and 0.5% of patients had aminotransferase levels that increased by more than 3 times the upper limit of normal.
      • Kashyap ML
      • McGovern ME
      • Berra K
      • et al.
      Long-term safety and efficacy of a once-daily niacin/lovastatin formulation in patients with dyslipidemia.

      SELECTING PATIENTS FOR NIACIN COMBINATION THERAPY

      In appropriate candidates, niacin combined with other hypolipidemic agents potentially can help patients improve their overall lipid profile and reach NCEP III targets. Because niacin is the most powerful agent available for raising HDL-C levels, it is an ideal choice for patients with isolated low HDL-C levels; these patients may be at increased coronary risk due to low HDL-C levels and high TC/HDL-C ratios despite normal TC levels.
      • National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
      Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): final report.
      Combination therapy with niacin and an LDL-C-lowering drug can address multiple lipid abnormalities. Patients with mixed dyslipidemias often require decreases in their LDL-C levels, increases in their HDL-C levels, and/or decreases in their TG levels. The combination may also help patients who are at or near their NCEP III LDL-C goal but need additional LDL-C lowering and/or still have persistent abnormalities of other lipoproteins.
      Niacin is the only lipid-lowering drug presently available that substantially lowers Lp(a); therefore, patients with both elevated LDL-C and Lp(a) levels may be ideal candidates for combination statin/niacin therapy. Because the benefit of specifically decreasing Lp(a) levels is as yet unknown, the primary goal is to reduce the LDL-C level to target, after which, if the Lp(a) level is still elevated, specific Lp(a)-lowering interventions may be considered. African Americans and Asian Indians seem to be especially prone to Lp(a) abnormalities.
      • Drowatzky KL
      • Durstine JL
      • Irwin ML
      • et al.
      The association between physical activity, cardiorespiratory fitness, and lipoprotein(a) concentrations in a tri-ethnic sample of women: the Cross-Cultural Activity Participation Study.
      • Palaniappan L
      • Anthony MN
      • Mahesh C
      • et al.
      Cardiovascular risk factors in ethnic minority women aged ≤30 years.
      Metabolic syndrome has become endemic in the United States. The revised NCEP guidelines emphasize the increased risk seen with this condition and outline diagnosis and management recommendations.
      • National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
      Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): final report.
      Among the associated metabolic factors is atherogenic dyslipidemia, dyslipidemia characterized by low HDL-C levels, high TG levels, and small LDL particles-the lipid triad. Niacin increases HDL-C levels, decreases TG levels, and transforms small LDL particles to normal size.
      • National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
      Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): final report.
      Niacin therapy, although ideal for correcting these abnormalities, traditionally has been avoided in patients with diabetes mellitus because of associated increases in blood glucose levels and insulin resistance. This hyperglycemic response is believed to be due to a rebound in circulating oxidized fatty acids, which may lead to reduced glucose uptake and increased hepatic glucose output.
      • Alvarsson M
      • Grill V
      Impact of nicotinic acid treatment on insulin secretion and insulin sensitivity in low and high insulin responders.
      Furthermore, there is concern about whether patients treated with niacin will develop diabetes or insulin resistance, both important risk factors for cardiovascular disease.
      Recent studies suggest that niacin can be used safely in patients with controlled type 2 diabetes. The Arterial Disease Multiple Intervention Trial
      • Elam MB
      • Hunninghake DB
      • Davis KB
      • et al.
      Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease: the ADMIT study: a randomized trial.
      randomized 468 participants with peripheral arterial disease, including 125 with diabetes (entry glycosylated hemoglobin [A1C] = 7%-9%), to immediate-release niacin or placebo. Niacin therapy increased glucose levels by 8.1 and 6.3 mg/dL in patients with and without diabetes, respectively. Blood glucose levels rose from 165 mg/dL to more than 180 mg/dL as the niacin dose was increased; however, levels began declining (to 173 mg/dL at study end) despite continued therapy. Changes in A1C were significantly different in patients with diabetes treated with niacin compared with placebo (0.3% vs 0%; P=.04); there were no significant changes in A1C in patients without diabetes. After 48 weeks, use of hypoglycemic therapy was not significantly different for patients with diabetes receiving niacin or placebo. Insulin use was increased 13% in patients with diabetes treated with niacin vs 4% in patients with diabetes treated with placebo (P=.09). Perhaps most importantly, of 173 patients treated with niacin who did not have diabetes at entry, 1 reported use of an oral hypoglycemic agent during follow-up.
      Grundy et al
      • Grundy SM
      • Vega GL
      • McGovern ME
      • Diabetes Multicenter Research Group
      • et al.
      Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the assessment of diabetes control and evaluation of the efficacy of niaspan trial.
      randomized 148 patients with diabetes (mean age, about 60 years) with fasting blood glucose (FBG) levels of 200 mg/dL or less and A1C of 9% or less to placebo, ER niacin at 1000 mg, or ER niacin at 1500 mg. There was an initial rise in FBG levels in both niacintreated groups; this difference was significant with ER niacin at 1000 mg at week 4 (P<.05). At the end of the 4-month study, there were no significant differences in FBG vs baseline in any treatment group; the fact that glucose levels returned to baseline with continued niacin use may have been due to adjustments in hypoglycemic therapy. Investigator assessment suggested that a greater percentage of patients treated with the 1500-mg dose required adjustments in hypoglycemic therapy than did those treated with either the 1000-mg dose or placebo. Four patients discontinued niacin therapy because of inadequate glucose control, 3 of whom were receiving the highest dose. There were no differences in A1C with the 1000-mg dose and marginal elevations with the 1500-mg dose vs placebo (0.29% vs −0.02%; P=.048).
      • Grundy SM
      • Vega GL
      • McGovern ME
      • Diabetes Multicenter Research Group
      • et al.
      Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the assessment of diabetes control and evaluation of the efficacy of niaspan trial.
      Recently, the results of the original Coronary Drug Project were analyzed according to baseline fasting and 1hour glucose levels. The analysis found that the beneficial effects of niacin were unaffected by baseline FBG or 1hour glucose levels and that reductions in both nonfatal MI and total mortality were similar to those seen in the original trial and consistent across all levels of glucose. Furthermore, patients with the highest FBG levels (=126 mg/dL) seemed to derive the greatest reduction in nonfatal MI compared with placebo (58%).
      • Canner PL
      • Furberg CD
      • McGovern ME
      Niacin decreases myocardial infarction and total mortality in patients with impaired fasting glucose or glucose intolerance: results from the Coronary Drug Project [abstract].
      This suggests that niacin has a positive effect on clinical outcomes in patients at all baseline glucose levels.
      On the basis of these studies, it seemingly would be most appropriate to initiate therapy in patients with well-controlled glucose and to monitor FBG levels appropriately. Adjustments to hypoglycemic therapy may be necessary; however, risks vs benefits of potential CHD event reduction should be weighed carefully. Furthermore, it appears that the hyperglycemic effects of niacin may be dose dependent. Therefore, the lowest dose possible to produce the desired effect should be used. Unfortunately, niacin use has not been studied extensively in patients with the metabolic syndrome, and further research is needed to determine the full extent of niacin's effects on insulin sensitivity.

      CONCLUSIONS

      Management of dyslipidemia is a central element in reducing the risk of primary and secondary coronary events. Although statin monotherapy is first-line therapy for most patients, less than half the patients treated with statins reach their NCEP targets.
      • Pearson TA
      • Laurora I
      • Chu H
      • Kafonek S
      The Lipid Treatment Assessment Project (L-TAP): a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals.
      Furthermore, statins have limited efficacy in raising HDL-C levels and have no effect on Lp(a) levels. Combination therapy often is needed to correct dyslipidemia in patients with elevated LDL-C levels despite monotherapy or in those with multiple lipid abnormalities. Niacin is an important option for physicians treating these patients because it significantly increases levels of HDL-C and lowers levels of LDL-C, TG, and Lp(a) and the TC/HDL-C ratio. Its ability to increase levels of HDL-C by as much as 30% exceeds that of all other currently available lipoprotein-altering drugs. The combination of a potent LDL-C-lowering drug such as a statin or BAS with niacin therapy represents an important therapeutic option for patients with dyslipidemia. The potential adverse effects associated with niacin therapy, such as flushing, hepatotoxicity, and hyperglycemia, should be considered when selecting patients for niacin therapy and when choosing the specific niacin formulations. Because niacin decreases atherogenic lipoproteins and increases cardioprotective lipoproteins, it is an excellent option for improving the overall lipid profile and TC/HDL-C ratio. Patients who may benefit most from adding niacin to current therapy include those with isolated low HDL-C levels, elevated Lp(a) levels, and atherogenic or mixed dyslipidemia.

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