The almost exclusive focus on low-density lipoprotein level as he major risk factor among lipid abnormalities has recently been questioned. The interest in other lipids, including high-density lipoprotein and triglycerides, has intensified, and the approach to treatment has shifted to include a focus on high-density lipoprotein. A low level of high-density lipoprotein cholesterol is an independent risk factor for coronary heart disease. Increases in high-density lipoprotein have been shown to decrease cardiac mortality and slow the progression of atherosclerosis. To increase high-density lipoprotein, a combination of lifestyle modifications and pharmacotherapy may be needed. Niacin and fibrates are the most effective medications currently available for increasing high-density lipoprotein. In patients with coronary heart disease, use of these medications alone or in combination with a statin has been shown to reduce cardiovascular events. Side effects and adverse reactions are an impediment to the more liberal use of these agents. New options, with improved efficacy and safety profiles, are now being investigated in clinical trials.

The 2002 National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines focus on the reduction of low-density lipoprotein cholesterol (LDL-C) as the primary target to decrease risk for coronary heart disease (CHD).¹ This was underscored in the NCEP’s 2004 update, in which the LDL-C target was reduced from 100 to 70 mg/dL for the secondary prevention of CHD events.² The evidence to support this LDL-C–centric view and the specific LDL-C goals promulgated have recently been questioned.³

In addition, it is widely recognized that many patients present with combined hyperlipidemia, in which LDL-C is elevated only mildly, or not at all, and high-density lipoprotein cholesterol (HDL-C) and/or triglyceride abnormalities predominate. In such patients, therapy targeted at decreasing LDL-C is insufficient to prevent a large variety of cardiovascular (CV) events. In particular, patients with diabetes, metabolic syndrome, and/or obesity frequently present with combined lipid disorders characterized by relatively normal LDL-C levels, increased triglycerides, and decreased HDL-C levels.

The medications useful for increasing HDL-C or reducing triglycerides present special challenges to patients and to clinicians. We review the data supporting HDL-C as a risk factor for CV events, the evidence for various interventions that ameliorate that risk, and the clinical challenges associated with managing patients with below-normal HDL-C levels.

Role of HDL-C in CHD
In the past decade, the treatment of low HDL-C concentrations has slowly emerged as a new therapeutic target that can reduce the incidence of CHD. Epidemiologic studies and randomized clinical trials have shown that a low HDL-C concentration is an independent risk of CV disease (Figure).⁴That both LDL-C and HDL-C levels are independent risk factors with multiplicative effects on the risk for CHD provides the rationale for treating both forms of dyslipidemia, individually and concurrently. Thus, targeting LDL-C alone is insufficient, and treating HDL-C is emerging as an equivalent target in mitigating CV risk factors.

NCEP ATP III recommends the use of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (ie, statins) as the first choice for lowering CHD risk in patients with dyslipidemia.¹ Statins have been shown to be the most potent medications available for decreasing LDL-C, with reductions varying from 20% to 60%; however, the ability of statins to increase HDL-C is modest at best.⁵

Although the NCEP does not identify HDL-C as a treatment target in ATP III, these landmark guidelines do acknowledge that an HDL-C level <40 mg/dL constitutes a risk factor for CHD and that HDL-C levels of ≥60 mg/dL are protective. For persons with diabetes, the American Diabetes Association recommends an HDL-C level of >40 mg/dL in men and >50 mg/dL in women.⁶

Benefits of Increasing HDL-C
It has long been observed that native HDL-C levels of >75 mg/dL are associated with longevity.⁷Although the benefit of raising HDL-C levels for the primary prevention of CV events has not been demonstrated, the benefit of raising HDL-C levels for the secondary prevention of CHD events has been demonstrated in the following randomized, placebo-controlled trials:

• The Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) compared gemfibrozil (Lopid) with placebo in 2531 men (mean age, 64 years) with CHD, all of whom had LDL-C levels of ≤140 mg/dL and HDL-C levels of ≤40 mg/dL.⁸ Despite LDL-C levels remaining virtually constant, HDL-C levels increased by 6%, and triglyceride levels decreased by 31%, in the gemfibrozil group after 1 year. At the end of 5 years, these lipid improvements were associated with a reduced incidence of nonfatal myocardial infarction (MI), death, stroke, transient ischemic attack, and carotid endarterectomy. Subsequent analysis showed that the gemfibrozil-induced increase in the HDL-C levels was strongly correlated with the reduced incidence of nonfatal MI as well as of CHD death.⁹

• More than 6700 men and 1500 women (aged 40 to 72 years) with known CHD were screened for dyslipidemias in the Bezafibrate Infarction Prevention (BIP) trial.¹⁰ Among the one third of participants with total cholesterol levels <200 mg/dL, 50% had HDL-C levels <35 mg/dL, and 50% had HDL-C levels <30 mg/dL. The BIP investigators compared the use of 400 mg/day bezafibrate (not available in the United States) with placebo in 3090 men and women with a history of MI and/or unstable angina.¹¹ Although no difference was found in the primary end point of recurrent MI or CHD mortality over the 6-year study period in the entire study group, a retrospective analysis of the results showed that the subset of treated patients with baseline triglyceride levels of ≥200 mg/dL had an almost 40% reduction in MI events.¹²In addition, risk of CV mortality was reduced by 27% for every 5-mg/dL increase in HDL-C.

• The Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2 trial studied the benefit of combination therapy in 167 patients with CHD (mean age, 67 years). All patients had been taking a statin and had HDL-C levels <45 mg/dL.¹³They were randomized to receive niacin ER (Niaspan) or placebo in combination with their previously prescribed statin. The primary end point was change in carotid intima media thickness, as measured by ultrasound, which was used as an indicator of atherosclerotic progression. Both study groups included patients with low LDL-C levels. The group receiving niacin ER with statin therapy showed an HDL-C increase of 21% and a slower progression of carotid artery intima media thickness compared with the placebo group.

• Another combination therapy study included 160 patients with CHD (average age, 53 years; 13% women) with HDL-C levels <35 mg/dL and LDL-C levels ≤145 mg/dL who were randomized to 1 of 4 regimens: (1) antioxidants alone, (2) simvastatin (Zocor) plus niacin, (3) simvastatin plus niacin plus antioxidants, or (4) placebo.¹⁴At the end of 3 years of follow-up, mean LDL-C and HDL-C were unchanged in the 2 groups using antioxidants and in the placebo group. In the simvastatin-plus-niacin group, LDL-C levels decreased by 42% and HDL-C levels increased by 26%. These changes were associated with a 90% reduction in recurrent CV events, revascularization, and/or death compared with placebo, as well as with angiographic regression of coronary stenosis. The investigators concluded that the magnitude of the reduction in CV clinical events was greater than would be expected with the use of a statin alone.

HDL and Atherosclerosis
A thorough knowledge of the actions and properties of HDL is helpful in understanding the potential of different interventions used to augment HDL-C levels. The main action of HDL particles is to mediate reverse cholesterol transport—the process that removes excess cholesterol from the periphery and delivers it to the liver, where it is eliminated in the bile. HDL also possesses antiatherogenic effects, including antiinflammatory, antioxidant, antithrombotic, and endothelial-stabilizing properties.

HDL particles differ in size, density, and composition. The larger, less-dense particles known as HDL2 are not as atherogenic as the smaller, denser particles of HDL3. The major structural protein in HDL particles is apolipoprotein (Apo) A, which is separated into Apo-AI and Apo-AII. The Apo-AI HDL particles (primarily found in HDL2) have been associated with the cholesterol efflux-promoting effects of HDL-C. In contrast, HDL particles containing both Apo-AI and Apo-AII are less effective in mobilizing cholesterol from nonhepatic cells. Treatment options vary in their effect on HDL composition; the clinical implications of these differences are still being studied.¹⁵

Treatment Options for Suboptimal HDL Levels
Although the treatment goals for patients with low HDL-C have not been firmly established, the NCEP ATP III guidelines have identified high-risk patients as those with HDL-C concentrations <40 mg/dL, particularly if associated with insulin resistance or the fully expressed metabolic syndrome (ie, central obesity, triglycerides ≥150 mg/dL, HDL-C <40 mg/dL in men and <50 mg/dL in women, blood pressure ≥130/85 mm Hg, and fasting blood sugar ≥110 mg/dL).¹

ATP III indicates that the primary target of therapy in patients with combined hyperlipidemia is the reduction of LDL-C and that ideal LDL-C concentrations should be achieved before attempts are made at raising HDL-C. Specific interventions for patients with low HDL-C concentrations include weight reduction, exercise, smoking cessation, and pharmacotherapy with nicotinic acid and fibrates.¹

Lifestyle modifications
Exercise, weight control, smoking cessation, and moderate alcohol intake have all been shown to increase HDL-C levels (Table 1).¹⁶Despite these increases usually being only modest, lifestyle modifications are recommended as initial treatment.

The NCEP guidelines recommend that fat intake be limited to less than 30% of total caloric intake, less than 7% saturated fats, and no trans fats.¹The guidelines encourage use of plant stanol esters and omega-3 fatty acids to reduce triglycerides. More studies are needed to determine any potential benefits of specific oils on HDL-C levels.

Pharmacotherapy
The choice of medication depends largely on the degree of the HDL-C increase needed, patient variables and comorbidities, and drug side-effect profiles (Table 2).Overall, beta-blockers, benzodiazepines, and androgens reduce HDL-C levels; therefore, these medications should be avoided, if at all possible, in patients targeted for HDL-C augmentation therapy.

Niacin. Niacin (nicotinic acid) is the most potent medication available for raising HDL-C, with increases ranging from 15% to 35%.^1,17 Niacin inhibits hepatic uptake of Apo-AI, increases plasma pre-β HDL-C, and preferentially increases Apo-AI and HDL2. It also improves endothelial function.

Widespread use of niacin is limited by its notorious side-effect profile, which includes cutaneous flushing, dyspepsia, and increases in blood glucose and uric acid. When starting niacin therapy, most patients experience cutaneous flushing, more often with the immediate-release formulation. Flushing can be minimized by the use of extended-release niacin, taking the medication with food, taking an aspirin tablet 30 minutes before the niacin, and starting niacin at a low dose and titrating it gradually. Increases in blood glucose and uric acid are dose-related and can be minimized by limiting the dose to 2 g/day. Niacin has also been associated with increases in liver transaminases.¹

Fibrates. Fibrates have been shown to increase HDL-C levels by approximately 10% to 35%, although the primary role of this class is to reduce triglycerides (by 20% to 50%).¹ Fibrates increase HDL-C levels by activating peroxisome-proliferator-activated receptor alpha (PPARα).¹⁸ This receptor stimulates hepatic Apo-AI gene expression and regulates the transcription of genes involved in reverse cholesterol transport.¹⁹ However, even though fibrates increase HDL-C levels, they decrease the size of HDL particles. Fibrates also increase the cholesterol content in Apo-AI and Apo-AII, without preferentially increasing Apo-AI.²⁰

Fibrates are better tolerated than niacin; the most common adverse events are gastrointestinal symptoms, rash, and myalgias. Rhabdomyolysis and hepatotoxicity are rare side effects occurring when fibrates are combined with statins.²¹

Statins. Statins have been shown to increase HDL-C levels only modestly (2% to 10%).⁵ Their primary role is to reduce LDL-C levels. However, a recent study suggests that the baseline level of HDL-C is a stronger predictor of the response to statins than is the baseline level of LDL-C.²²Statins are thought to affect HDL-C by increasing the synthesis of Apo-AI.

The degree of HDL-C increase varies among statins; rosuvastatin calcium (Crestor) appears to have the greatest effects, increasing HDL-C by approximately 15%.²³Some physicians will switch patients to rosuvastatin if the patients do not reach the desired HDL-C goal with another statin.

Statins are associated with rare cases of hepatotoxicity and myalgias, in a dose-related manner.

Thiazolidinediones. The thiazolidinediones rosiglitazone maleate (Avandia) and pioglitazone HCl (Actos) are indicated for the treatment of type 2 diabetes mellitus, but both medications have been shown to increase HDL-C, particularly pioglitazone (by 10% to 20%).²⁴ Patients with low HDL-C levels appear to respond best. The exact underlying mechanism is still unknown. Thiazolidinediones cross-activate PPARα, with side effects similar to those seen with fibrates.²⁴

Rimonabant (Acomplia), the first selective cannabinoid-1 receptor blocker, has been shown to reduce body weight and insulin resistance and to increase HDL-C levels. It is currently available in Europe and has received an “approvable” letter for the treatment of obesity from the US Food and Drug Administration. The Rimonabant in Obesity-Lipids Study Group (RIO-Lipids) demonstrated nearly 25% increases in HDL-C levels with rimonabant.²⁵Although not specifically indicated for the treatment of low levels of HDL-C, rimonabant has beneficial effects on all the NCEP ATP III diagnostic criteria of the metabolic syndrome, except for hypertension. This is significant, since all patients with the metabolic syndrome are at high risk for CV events.

New agents. Work is under way on 2 new classes of drugs designed to promote reverse cholesterol transport, Apo A-1 Milano and a cholesterol ester transfer protein inhibitor. Apo A-1 Milano is a naturally occurring variant of Apo-AI; infusing Apo A-1 Milano is tantamount to infusing HDL-C. Preliminary studies have demonstrated a reduction in coronary atheroma after such infusions.²⁶

In a study of 198 healthy individuals (aged 18 to 65 years), 4 weeks of treatment with the synthetic cholesterol ester transfer protein inhibitor JTT-705 resulted in increases of 34% in HDL-C levels.²⁷

Combination therapy
Combination therapy has been shown to be the most effective option for most patients with mixed dyslipidemia.^1,28,29Combining a statin with a fibrate or with niacin resulted in greater improvements in lipid parameters than monotherapy with a statin, a fibrate, or niacin in patients with combined dyslipidemia. However, combination therapy is underused, presumably because of fears of side effects.

Combination therapy is safe and effective when patients are appropriately monitored, doses are not exceeded, and contraindications are carefully taken into consideration. Combining a statin, at a low-to-moderate dose, with a fibrate or niacin is a generally tolerable option in patients with too-low HDL-C levels.

The SAFARI (Simvastatin plus Fenofibrate for Combined Hyperlipidemia) trial, which randomized 619 patients (aged 21 to 68 years) with mixed hyperlipidemia to simvastatin or to simvastatin plus fenofibrate, showed that increases in HDL-C levels nearly doubled (18.6% versus 9.7%) in the combination therapy arm.³⁰

Caution should be exercised when combining fibrates and statins, particularly if the fibrate is gemfibrozil. In addition to a propensity for side effects, gemfibrozil increases the plasma concentration of statins and thus also the risk for myopathies and hepatotoxicity. For this reason, fenofibrate is preferred for concurrent fibrate–statin therapy. It is important to closely adhere to the NCEP ATP III monitoring parameters and follow-up schedules for statins and for fibrates, particularly when these are used in combination. In addition, patients should be counseled about the warning signs of myopathy, such as muscle pain, weakness, and dark urine.

The combination of niacin and lovastatin (Mevacor) has been studied in patients with low HDL-C levels in 2 trials.

A 52-week open-label study investigated the niacin ER/lovastatin combination agent (Advicor) in 814 men and women (average age, 59 years) with combined dyslipidemia.³¹The dosage was titrated up to niacin ER 2000 mg/lovastatin 40 mg at week 16. Dose-dependent side effects were observed for all major lipid parameters. Compared with baseline levels, HDL-C increased by 30% at week 16 and by 41% at week 52. Only 10% of patients withdrew from the study because of flushing (the most common side effect). No drug-induced myopathy occurred. Significant transaminase elevations (ie, more than 3 times normal) were rare, with an incidence rate of 0.5%.

The second study compared the combined niacin ER/lovastatin agent with standard doses of atorvastatin (Lipitor) and simvastatin in 315 patients (aged 18 to 70 years) with elevated LDL-C (defined as ≥160 mg/dL in those without CHD and ≥130 mg/dL in those with CHD) and low HDL-C levels (<45 mg/dL in men and <50 mg/dL in women).³² At 16 weeks, HDL-C increased significantly more (from 17% to 32%, depending on dose) with niacin ER/lovastatin therapy than with atorvastatin (6%) or with simvastatin (7%) monotherapy at all compared doses. Only 6% of patients withdrew because of flushing. No differences were seen among the 3 groups in discontinuations as a result of elevated liver enzymes, and no drug-induced myopathy was reported.

Conclusion
The weight of evidence suggests that HDL-C is an independent risk factor for atherosclerotic vascular disease, and that interventions to increase HDL-C above baseline levels reduces the risk for CV events. HDL-C can be raised with lifestyle modifications aimed at reducing saturated fat consumption and excess body weight, and with the addition of pharmacotherapy, most notably niacin and fibrates.

Self-assessment test
1.All the following statements are correct, except:
A. The main action of HDL particles is to mediate reverse cholesterol transport
B. Fibrates are better tolerated than niacin
C. Rosiglitazone is the only thiazolidinedione that increases HDL-C
D. The American Diabetes Association recommends an HDL-C level >40 mg/dL in men with diabetes and >50 mg/dL in women with diabetes

2.What is the first treatment option for patients with low HDL-C?
A. Lifestyle modifications
B. Niacin
C. Fibrates
D. Rimonabant

3.All of the following methods can reduce niacin-related flushing, except:
A. Using the extended-release formulation
B. Taking the medication with food
C. Taking aspirin 30 minutes after taking niacin
D. Starting at a low dose and titrating gradually

4.Which of the following medications or classes produces the greatest increase in HDL-C?
A. Statins
B. Fibrates
C. Niacin
D. Thiazolidinediones

5.Which statement about combination therapy for improving HDL-C levels is true?
A. Gemfibrozil decreases the plasma concentration of statins
B. Fenofibrate is preferred when combining a fibrate with a statin
C. Niacin should not be combined with a statin
D. Combination therapy is best for patients whose only lipid abnormality is low HDL-C

(Answers at end of references list)

References
1. 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. Circulation. 2002;106:3143-3421.

2. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239.

3. Hayward RA, Hofer TP, Vijan S, et al. Lack of evidence for recommended low-density lipoprotein treatment targets: a solvable problem. Ann Intern Med. 2006;145:520-530.

4. Castelli WP, Anderson K, Wilson PW, et al. Lipids and risk of coronary heart disease: the Framingham Study. Ann Epidemiol. 1992;2:23-28.

5. Joseph PH, Davidson MH, Stein EA, for the STELLAR Study Group. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses. Am J Cardiol. 2003;92:152-160.

6. American Diabetes Association. Standards of medical care in diabetes—2007. Diabetes Care. 2007;30(suppl 1): S4-S41.

7. Glueck CJ, Gartside P, Fallat RW, et al. Longevity syndromes: familial hypobeta and familial hyperalpha lipoproteinemia. J Lab Clin Med. 1976;88:941-957.

8. Rubins HB, Robins SJ, Collins D, et al, for the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med. 1999;341:410-418.

9. Robins SJ, Collins D, Wittes JT, et al. Relation of gemfibrozil treatment and lipid levels with major coronary events. VA-HIT: a randomized controlled trial. JAMA. 2001;285:1585-1591.

10. The Bezafibrate Infarction Prevention (BIP) Study Group, Israel. Lipids and lipoproteins in symptomatic coronary artery disease. Distribution, intercorrelations, and significance for risk classification in 6,700 men and 1,500 women. Circulation. 1992;86:839-848.

11. The BIP Study Group. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study. Circulation. 2000;102:21-27.

12. Goldenberg I, Goldbourt U, Boyko V, et al. Relation between on-treatment increments in serum high-density lipoprotein cholesterol levels and cardiac mortality in patients with coronary heart disease (from the Bezafibrate Infarction Prevention trial). Am J Cardiol. 2006;97: 466-471.

13. Taylor AJ, Sullenberger LE, Lee HJ, et al. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation. 2004;110:3512-3517.

14. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345:1583-1592.

15. Meyers CD, Kashyap ML. Pharmacologic elevation of high-density lipoproteins: recent insights on mechanism of action and atherosclerosis protection. Curr Opin Cardiol. 2004;19:366-373.

16. Rosenson RS. Low HDL-C: a secondary target of dyslipidemia therapy. Am J Med. 2005;118:1067-1077.

17. Vega GL, Grundy SM. Lipoprotein responses to treatment with lovastatin, gemfibrozil and nicotinic acid in normolipidemic patients with hypoalphalipoproteinemia. Arch Intern Med. 1994;154:73-82.

18. Schoonjans K, Staels B, Auwerx J. Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. J Lipid Res. 1996;37:907-925.

19. Fruchart JC, Brewer HB Jr, Leitersdorf E. Consensus for the use of fibrates in the treatment of dyslipoproteinemia and coronary artery disease. Am J Cardiol. 1998;81:912-917.

20. Vu-dac N, Schoonjans K, Kosykh V, et al. Fibrates increase human apolipoprotein A-II expression through activation of the peroxisome proliferator-activated receptor. J Clin Invest. 1995;96:741-750.

21. Duell PB, Connor WE, Illingworth DR. Rhabdomyolysis after taking atorvastatin with gemfibrozil. Am J Cardiol. 1998;81:368-369.

22. Olsson AG, Schwartz GG, Szarek M, et al. High-density lipoprotein, but not low-density lipoprotein cholesterol levels influence short-term prognosis after acute coronary syndrome: results from the MIRACL trial. Eur Heart J. 2005;26:890-896.

23. Nissen SE, Nicholls SJ, Sipahi I, et al, for the ASTEROID Investigators. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295: 1556-1565.

24. Chiquette E, Ramirez G, Defronzo R. A meta-analysis comparing the effect of thiazolidinediones on cardiovascular risk factors. Arch Intern Med. 2004;164:2097-2104.

25. Després JP, Golay A, Sjöström L, for the Rimonabant in Obesity-Lipids Study Group. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 2005;353: 2121-2134.

26. Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA. 2003;290: 2292-3000.

27. de Grooth GJ, Kuivenhoven JA, Stalenhoef AF, et al. Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study. Circulation. 2002;105:2159-2165.

28. Davidson MH. Combination therapy for dyslipidemia: safety and regulatory considerations. Am J Cardiol. 2002;90(suppl 10B):50K-60K.

29. Xydakis AM, Ballantyne CM. Combination therapy for combined dyslipidemia. Am J Cardiol. 2002;90(suppl 10B): 21K-29K.

30. Grundy SM, Vega GL, Yuan Z, et al. Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial). Am J Cardiol. 2005;95:462-468.

31. Kashyap ML, McGovern ME, Berra K, et al. Long-term safety and efficacy of a once-daily niacin/lovastatin formulation for patients with dyslipidemia. Am J Cardiol. 2002;89:672-678.

32. Bays HE, Dujovne CA, McGovern ME, et al. Comparison of once-daily niacin extended-release/lovastatin with standard doses of atorvastatin and simvastatin (the ADvicor Versus Other Cholesterol-Modulating Agents Trial Evaluation (ADVOCATE). Am J Cardiol. 2003;91: 667-672.

Answers: 1. C; 2. A; 3. C; 4. C; 5. B.