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Abstract

There is abundant epidemiologic evidence to support the independent, inverse relationship between low levels of high-density lipoprotein cholesterol (HDL-C) and incident cardiovascular (CV) risk, the clinical importance of which is underscored by the high prevalence of low HDL-C in populations with coronary heart disease (CHD), with or without elevated levels of low-density lipoprotein cholesterol (LDL-C). The National Cholesterol Education Program recommended that optimal treatment for high-risk patients includes both lowering LDL-C and non-HDL-C to risk stratified levels and raising HDL-C when it is <40 mg/dL, although no target level for the latter lipoprotein was suggested. Niacin is the most powerful agent currently available for raising low levels of HDL-C. It also induces significant reductions in triglycerides, lipoprotein(a), and LDL-C levels while also favorably altering LDL particle size and number. In the Coronary Drug Project, niacin treatment was associated with significant reductions in CV events and long-term mortality, similar to the reductions seen in the statin monotherapy trials. In combination trials, niacin plus a statin or bile acid sequestrant produces additive reductions in CHD morbidity and mortality and promotes regression of coronary atherosclerosis. Recently, 2 clinical outcome trials (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes [AIM-HIGH] and Second Heart Protection Study [HPS-2 THRIVE]) failed to show a reduction in CV events in patients treated to optimally low levels of LDL-C. Despite favorable effects on HDL-C and triglycerides, these studies did not demonstrate incremental clinical benefit with niacin when added to simvastatin, although notable limitations were identified in each of these trials. Thus, there is insufficient evidence from clinical trials to recommend HDL-targeted therapy for additional event reduction at the present time. However, niacin should continue to be used as an adjuvant therapy for reducing atherogenic lipoprotein burden in patients who have not reached their risk stratified LDL-C and non-HDL-C targets.

Keywords

atherosclerosis coronary artery disease high-density lipoprotein niacin reverse cholesterol transport statin

Introduction

Although coronary heart disease (CHD) survival has increased appreciably in the past 3 decades, CHD remains the leading cause of death among both men and women in the western world.¹ Currently, over 16.3 million Americans have been diagnosed with CHD and, despite significant advances in pharmacologic and interventional management over the past decade, both morbidity and mortality remain unacceptably high.^1,2 A recent Framingham Heart Study analysis estimates that lifetime risk of cardiovascular (CV) disease at the age of 50 years is actually about 1 (51.7%) in 2 for men and 2 (39.2%) in 5 for women and that cumulative risk increases with time, particularly for individuals with greater than 2 risk factors.³

Elevated low-density lipoprotein cholesterol (LDL-C) has long been recognized as a major predictor of CHD risk. Importantly, during the last decade, introduction of the hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) has revolutionized the treatment of hypercholesterolemia by significantly reducing major vascular events. In primary and secondary prevention trials using a statin, plasma LDL-C was reduced by 25% to 55%, and CHD event rates by 24% to 45%, as compared with placebo.^{4

–13}

Recent clinical trials and meta-analyses have focused on aggressive LDL-C reduction with high doses of statin monotherapy.^9,10,14 Multiple trials including the Heart Protection Study (HPS) of cholesterol lowering with simvastatin in 20 536 high-risk individuals,¹⁵ the Pravastatin in elderly individuals at risk of vascular disease (PROSPER)¹⁶ the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT),¹⁷ the prevention of coronary and stroke events with atorvastatin in patients with hypertension who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA),¹⁸ and the Pravastatin or Atorvastatin Evaluation and Infection Therapy: Comparison of intensive and moderate lipid lowering with statins after acute coronary syndromes trial (PROVE IT-TIMI 22)¹⁹ all demonstrated favorable outcomes with more aggressive LDL-C reduction. The favorable outcomes associated with these trials prompted changes to the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) guidelines²⁰ encouraging aggressive LDL reductions to ≤100 mg/dL in high-risk individuals and, as a therapeutic option, ≤70 mg/dL in patients at very high risk (eg, recent acute coronary syndrome [ACS], diabetes with established CHD and patients with prior stroke and vascular disease, etc). Despite these aggressive goals, treating to the recommended LDL targets (and maintaining optimal levels) has been a challenge outside of the controlled setting of clinical trials. In the Multi-Ethnic Study of Atherosclerosis (MESA) study,²¹ a multicenter cohort of 6814 individuals aged 45 to 84, only 54% of individuals with CHD received lipid-lowering therapy, and only 40% of those on lipid-lowering therapy had their blood cholesterol levels under control per the NCEP guidelines. Overall, when one analyzes the aggregate effectiveness of treatment in all primary and secondary prevention trials, morbidity and mortality rates among statin-treated patients still remain approximately two thirds to three quarters of those found in patients randomized to placebo.²²

Importantly, early population studies have demonstrated that LDL lowering is not the only predictor of favorable CHD outcomes.^23
–25 Low levels of high-density lipoprotein cholesterol (HDL-C) are also recognized as a major independent predictor of CHD risk due to the strong inverse association observed between HDL-C levels and CHD event rates.²⁶ The Veteran Affairs HDL Intervention Trial (VA-HIT) was the first prospective randomized controlled trial to provide strong evidence that raising low levels of HDL-C in patients with CHD was associated with significant reductions in CHD events, notably CHD death, myocardial infarction (MI), and stroke despite the absence of significant LDL change over 5.1 years of follow-up.²⁷ Subsequently, multivariate analyses of clinical trials in patients with hypercholesterolemia have shown that raising HDL-C levels was associated with reductions in CHD events.^28,29 An analysis of 4 large studies demonstrated a 2% to 3% reduction in CHD risk for every 1 mg/dL increase in HDL.³⁰ More recently, the HDL-Atherosclerosis Treatment Study (HATS) demonstrated that treatment of the total lipid profile with a combination of simvastatin and niacin was associated with significant regression of coronary atherosclerosis and incremental reductions in clinical events in patients with a mean baseline lipid profile that included an LDL-C of 124 mg/dL, HDL-C of 34 mg/dL, and triglycerides of 160 mg/dL.³¹

The growing numbers of patients with low HDL-C and normal LDL-C levels (as many as 40%-45% of all patients with CHD),^32,33 as well as those with diabetes mellitus (DM), the metabolic syndrome, or multiple lipid abnormalities, comprise an expanding population of patients for whom statin monotherapy may not be the optimal therapeutic approach. Statin therapy only raises HDL-C levels modestly by 5% to 10%.³⁴ These effects on HDL-C levels appear to be similar across all statins studied and do not appear to be dose dependent.

Niacin is the most effective therapeutic agent for raising low HDL-C levels. Niacin also produces moderate reductions in triglycerides (TG), lipoprotein (a) [Lp(a)], and, at higher doses, LDL-C levels.³⁵ Despite these multiple therapeutic actions, its clinical use has, historically, been limited by a relatively poor tolerability profile primarily due to flushing associated with older, immediate-release (IR) formulations that have lessened with newer extended-release niacin (ERN) preparations. This review will focus on the possible cardioprotective role of HDL-C levels and the clinical efficacy and safety of niacin as a therapeutic option to modify all components of the lipid profile.

Cardioprotective Role of HDL-C

Effects on Lipid Homeostasis

Elevated HDL-C correlates highly with reduced risk of CHD in cohorts observed throughout the world; however, until recently, the exact mechanism by which HDL-C exerts its “protective” benefits was poorly understood. Clearly, the cholesterol cargo of an HDL particle does not exert antiatherogenic effects. The HDLs are highly diverse polymolecular complexes comprising many different proteins, enzymes, apoproteins, globulins, sphingolipids, phospholipids, microRNAs, complement components, and acute phase reactants that can impact HDL functionality. Likely the most important antiatherogenic mechanism regulated by HDL is reverse cholesterol transport (RCT), a series of reactions by which cholesterol is returned from peripheral tissue pools back to the liver for active reprocessing or elimination (Figure 1).^36,37 The removal of excess cholesterol is mediated via adenosine triphosphate (ATP)-binding membrane cassette transport proteins A1 (ABCA1) and G1 (ABCG1) expressed on the surface of macrophages.^38
–40 Specifically, ABCA1 transfers intracellular cholesterol and phospholipids from macrophages to small, nascent HDL particles, while ABCG1 transfers intracellular cholesterol to larger, more spherical HDL particles.⁴¹

Figure 1.

Model of reverse cholesterol transport (reprinted with permission)¹⁴⁴. Macrophages resident within the intima of arterial walls transform into foam cells as they accumulate larger and larger amounts of cholesterol and other lipids. Macrophages are unable to catabolize cholesterol. In order to limit the amount of internalized cholesterol, these cells express multiple ATP-binding membrane cassette transport proteins (ABCA1 and ABCG1) that externalize intracellular UC and phospholipid. Nonlipidated ApoA-I and the ApoA-I in ndHDL bind to ABCA1 and promote sterol mobilization. The UC is esterified to CEs by LCAT using PC as an acyl chain donor. The CE is taken up into the hydrophobic core of ndHDL, making the particle progressively larger and more spherical, resulting in the formation of HDL₃. As more CE is loaded into HDL₃, it is converted into large HDL₂ particles. High-density lipoprotein₂ particles can bind to ABCG1, further promoting cholesterol mobilization and externalization. The various HDL species can undergo condensation and exchange reactions. For example, PLTP can catalyze the condensation of ndHDL with HDL₃ to form an HDL₂. Reverse cholesterol transport is a manifestation of 2 distinct pathways. In direct RCT, HDL particles dock with SR-BI on the surface of hepatocytes. The SR-BI selectively delipidates HDL particles and then releases them back into the circulation in order to initiate another round of RCT. In indirect RCT, the HDL particle exchanges CE for triglyceride from ApoB-containing lipoproteins (VLDL, IDL, and LDL), a reaction catalyzed by cholesterol ester transfer protein. High-density lipoprotein particles so enriched with triglyceride become better substrates for lipolysis and catabolism by HL. As the particle becomes smaller and thermodynamically more unstable, ApoA-I is released and bound by megalin or cubulin and eliminated in the glomerular ultrafiltrate. The CE transferred into these lipoproteins can be taken up either by blood vessel walls or by LDL (LDL-R) and VLDL receptors on the hepatocyte surface. Cholesterol delivered back to the liver can undergo multiple fates: it can be converted into bile acids by 7-α hydroxylase and secreted into the gut via ABCB11, packaged back into VLDL and secreted into plasma, or secreted into the biliary tree via ABCG5/G8. ApoA indicates apolipoprotein; ATP, adenosine triphosphate; CE, cholesterol ester; HDL, high-density lipoprotein; ndHDL, nascent discoidal HDL; LCAT, lecithin–cholesteryl acyltransferase; PC, phosphatidylcholine; PLTP, phospholipid transfer protein; RCT, reverse cholesterol transport; LDL, low-density lipoprotein; VLDL, very-LDL; IDL, intermediate-density lipoprotein; HL, hepatic lipase; SR-BI, scavenger receptor type B class I; UC, unesterified cholesterol.

The liver, intestine, and visceral adipose tissue lipidate free apolipoprotein A-I (ApoA-I), the primary apoprotein constituent of HDL, and hence are important sources of HDL biogenesis. High-density lipoprotein particles dock with ABCA1 and ABCG1 on the surface of foam cells in the subendothelial space and stimulate the externalization of excess intracellular unesterified cholesterol and phospholipids. The cholesterol is esterified by lecithin–cholesterol acyltransferase, and the cholesterol ester (CE) is taken up into the hydrophobic core of the lipoprotein particle. As more and more CE is packaged into the particle’s core, the HDLs become larger and progressively more spherical. Approximately 50% of CE in the core of HDL particles is directly transported to the liver via scavenger receptor BI (direct RCT) and is repackaged into very-LDL particles or excreted as bile acids by the catalytic action of 7-α hydroxylase. The other 50% is exchanged for triglyceride from apolipoprotein B (ApoB)-containing lipoproteins—very-LDLs (VLDL), intermediate-density lipoproteins (IDLs), and LDL—by the action of cholesteryl ester transfer protein (CETP).^36,37,42,43 The cholesterol transferred into ApoB-containing lipoproteins can either be cleared via LDL and VLDL receptors (indirect RCT) or be taken up by macrophages in arterial walls.

High-density lipoprotein particles may provide further antiatherogenic efficacy by reducing expression of adhesion proteins and other inflammatory markers, increasing fibrinolysis, and inhibiting LDL oxidation. The inhibition of adhesion molecules and selectins reduces the influx of neutrophils and monocytes into the subendothelial space. Oxidized LDL particles contain a variety of proinflammatory and proatherogenic fatty acids and phospholipids. High-density lipoprotein also helps to reverse endothelial dysfunction. Dysfunctional endothelial cells release oxygen-free radicals that can oxidize and peroxidize LDL. Endothelial dysfunction is also associated with reduced nitric oxide release, a state associated with vasoconstriction as well as abnormal flow and shear stress.^{36,37,42
–44} High-density lipoproteins promote endothelial cell nitric oxide production. Experimental animal models have shown that raising HDL-C levels, through a variety of mechanisms, can decrease formation of new atherosclerotic plaque, stabilize existing plaque, and inhibit thrombosis.^{45

–54}

The clinical benefits of consistently elevated HDL levels have been demonstrated in longitudinal population and observation studies, as well as in recent controlled clinical trials, which have shown stabilization and even regression of atherogenic plaques through targeted elevation of HDL-C levels. However, the cardioprotective role of raising HDL has become clouded following the early termination of the Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events (ILLUMINATE) trial with the CETP-inhibitor torcetrapib in patients with high risk for CHD events.⁵⁵ In combination with atorvastatin, torcetrapib increased HDL-C by 72% and further lowered LDL-C by 25% but caused a significantly higher rate of CV events and mortality, compared to atorvastatin monotherapy. Although adverse events associated with torceptrapib may be due to “off-target toxicity” (eg, increased blood pressure, electrolyte abnormalities, and increased expression of aldosterone synthase), the ILLUMINATE trial illustrates that increasing the quantity of HDL-C may not provide cardioprotection per se.

The proteome (ie, its protein cargo) of HDL is extremely complex. Numerous studies have established that HDL particles can become dysfunctional. In patients with CHD or chronic heightened systemic inflammatory states, HDL particles can become pro-oxidative and proinflammatory because of changes in their proteome.^56
–58 Antioxidative enzymes can be displaced as constituents of the acute phase response (serum amyloid A, fibrinogen) bind to HDL particles. In patients who have sustained an acute coronary event⁵⁹ or who have chronic kidney disease,⁶¹ HDL particles are markedly dysfunctional. Other recent studies demonstrated that the protein composition of HDL particles could be adversely altered in disease states^46,60 and favorably altered by using a combination of statin and niacin therapy,⁵⁰ prompting an emphasis on evaluating the impact of therapies on HDL functionality and not just the magnitude in rise of HDL-C.⁴⁵

Population-Based Studies and the Importance of HDL-C

One-quarter century ago, the Framingham Heart Study reported that HDL-C levels were inversely related to the incidence of CHD in both men and women (P < .01) even after controlling for other established risk factor covariates.²³ Subsequent reports have shown that HDL-C is a better predictor of CHD risk than LDL-C.²⁴ Levels of HDL-C less than 35 mg/dL were associated with an 8-fold greater risk of CV events than levels greater than 65 mg/dL.^23
–25 Similarly, in the Lipid Research Clinics Program Prevalence Study, men with HDL-C of less than 35 mg/dL had almost 6 times the CHD rates of those with HDL-C of at least 45 mg/dL.²⁵ In the Tromso Heart study, 1952 men and women aged 25 to 82 years, with baseline carotid artery disease in 1997, were reevaluated after 7 years.⁶² At follow-up, patients with the least amount of plaque progression had the highest levels of HDL-C, independent of all other risk factors.⁶²

Gender is also an important determinant of serum HDL-C levels.⁶³ On average, women have a 10-mg/dL higher level of HDL-C than that of age- and weight-matched men.²⁰ High-density lipoprotein cholesterol also appears to have more impact on CHD risk in women than in men. In the Framingham Study, men in the lowest quartile for HDL-C (<36 mg/dL) had a 60% to 70% greater risk of MI compared with those in the highest HDL-C quartile (>53 mg/dL), while women in the lowest HDL-C quartile (<46 mg/dL) had an approximately 600% greater risk (rate of MI in lowest HDL-C quartile of 10.6/100 vs 1.4/100 in the highest HDL-C quartile) of MI compared with those in the highest quartile (>67 mg/dL).⁶⁴

Approximately 39% of men and 15% of women in the United States have low-serum HDL-C levels,¹ and the prevalence is substantially higher among those with CHD. In a survey of over 8500 men with documented CHD who were screened for eligibility in VA-HIT, 64% had HDL-C levels <40 mg/dL, 87% had LDL-C ≥100 mg/dL, and 33% had TG ≥200 mg/dL.³² Furthermore, 41% of patients with low HDL-C levels (<35 mg/dL) had near normal LDL-C (<130 mg/dL) and, therefore, were considered equivocal candidates for lipid-lowering pharmacotherapy based on their LDL-C levels alone.³²

In a similar analysis of 8353 high-risk women in a managed care setting, 83% had an LDL-C ≥100 mg/dL at baseline. Over a 3-year period, approximately one-third of members studied were placed on lipid-lowering therapy; however, 71% still had persistently elevated LDL-C levels.⁶⁵ At baseline, 57% of patients had optimal levels of HDL-C (≥50 mg/dL) and TG (≤150 mg/dL).^65
–67 At the end of the analysis, this level of control changed to 56% and 60% for each lipid parameter, respectively. The percentage of women who achieved optimal values of all 3 parameters combined (HDL-C, LDL-C, and TG) improved from 7% at baseline to only 12% upon study completion.⁶⁵

Recognizing the importance of identifying persons with low levels of HDL-C, the NCEP revised upward the limit for low HDL-C from <35 mg/dL to <40 mg/dL,²⁰ with a similar recommendation supported by the ADA guidelines.^68,69 The American Heart Association (AHA) Women’s Prevention Guidelines go even further and suggest a minimum HDL level of ≥50 mg/dL in females.⁶⁶

Low HDL-C is also frequently associated with elevated TG and variable levels of small, dense LDL-C, an atherogenic lipid triad typically found in persons with type 2 diabetes and the metabolic syndrome.⁷⁰ Over 23 million Americans have type 2 diabetes,^1,61,71 ^, ⁷² while an estimated 68 million have metabolic syndrome,^61,73 with over 65% of diabetes-related deaths due to late-stage effects of cardiac or blood vessel disease.^1,2 These numbers are expected to increase in the next 10 years, due in large part to the alarming rise in obesity, which is reaching epidemic proportions in the United States.^1,74 An analysis of the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial showed that low HDL-C levels coupled with DM were the greatest predictor of increased CV risk in patients with the metabolic syndrome compared to LDL-C, hypertension, elevated body mass index, or hypertriglyceridemia.⁷⁵ Although evidence of aggressively treating LDL-C with statins has proved to be beneficial in patients with DM,⁷⁶ some concern has been raised about potential adverse effects on glucose metabolism with high-dose statin therapy.⁷⁷

Clinical Effects of Raising HDL-C

Determining the best method to increase HDL-C levels remains undefined. Modifiable lifestyle changes such as smoking cessation,^78,79 increased physical activity,⁸⁰ and weight control with reductions in insulin resistance⁸¹ can produce small increases in HDL-C (2-7 mg/dL), although results vary⁸² and are frequently disappointing in those with low baseline HDL-C levels.^83,84 Although all forms of lifestyle modification likely impact the risk of CHD in a positive manner, the precise quantitative contribution of resulting HDL-C elevations by specific approaches is not yet established. Given the challenges of instituting comprehensive, sustainable lifestyle changes, many patients with low levels of HDL-C, particularly those at high risk of CHD, require pharmacotherapy to raise HDL-C.

Nicotinic Acid

Mechanism of Action

Effects on HDL metabolism

In clinical studies, niacin on average raised HDL-C levels 15% to 35%, lowered TG 20% to 50%, Lp(a) 24% to 38%, and LDL-C 5% to 25%.^20,85,86 Prescription niacin is the most powerful HDL-raising drug currently available.³⁴ The mechanisms by which niacin impacts serum levels of HDL-C are complex and involve both synthesis and catabolism of this lipoprotein. Niacin increases the level and production rate of Apo-A1 without effects on ApoA-II in patients with CHD and combined dyslipidemia.^87,88 In the human monocyte cell line MM6sr, niacin increases expression of ABCA1, which facilitates transfer of cholesterol from macrophages to nascent HDL and thereby increases HDL-C.⁴⁹ In human Hep G2 cells and in CETP transgenic mice, niacin reduces the catabolic rate of ApoA-I and inhibits CETP expression and activity (Figure 2).^89,90 As CETP catalyzes a stoichiometric 1:1 exchange of CE from HDL in exchange for TG in VLDL, IDL, and LDL, inhibition of CETP leads to increased CE contents of HDL and decreased catabolism of TG-rich HDL particles by hepatic lipase. In HepG2 cells, niacin reduces the expression of HDL holoparticle receptors, such as the β-chain of F₁ATP synthase,⁹¹ thereby preventing the uptake and catabolism of HDL particles from plasma and increases levels of the larger, buoyant HDL₂ subclass.^92,93 Niacin also selectively augments removal of CE from HDL particles by hepatic scavenger receptor type B class I, thereby increasing circulating cholesterol-depleted HDL particles that may once again engage in RCT.¹⁴⁴

Effects on TG, LDL, and VLDL

Some of the impact of niacin on TG as well as on LDL and VLDL particles may involve the inhibition of free fatty acid (FAA) release from adipose tissue and reduction of TG-rich VLDL production in the liver.⁸⁸ In adipose tissue, niacin activates GPR-109A, a G_i-protein-coupled receptor, which inhibits adenylate cyclase activity and lowers intracellular cyclic adenosine monophosphate (cAMP). As the lipolysis of stored TG by hormone-sensitive triglyceride lipase is dependent on cAMP levels, a reduction in cAMP reduces the formation and release of FAA into plasma.^89,94 In rodents, reduced FFA release attenuated the activity of peroxisome proliferator-activated receptor γ coactivator, Apo-CIII (an inhibitor of lipoprotein lipase), and assembly of TG-rich VLDL in the liver.⁹⁵ Since VLDL is converted into IDL and then LDL by lipoprotein lipase, reductions in VLDL lead to lower LDL-C levels and increase intracellular degradation of ApoB.⁸⁸ In patients with combined dyslipidemia and nonalcoholic hepatic steatosis, niacin also decreased the production rate, secretion rate, and increased fractional clearance rate of VLDL particles^{48,88,94,96

–102} and shifted the subclass distribution of LDL from small dense particles to larger, more buoyant particles.^{87,103

–106}

Role of GRP-109A

The role of GPR-109A in mediating the lipid effects of niacin in man remains unclear. Highly expressed in adipose tissue and cutaneous Langerhans cells, the GPR-109A receptor binds niacin with high affinity and is thought to mediate both flushing and lipid responses to niacin. Niacin does not induce serum lipid changes in GPR-109A knockout mice, suggesting a critical role of GPR-109A in this species.¹⁰⁷ It is of interest to note that MK-0354 (laropiprant), a partial agonist of GPR-109A with a diminished flushing response compared to niacin, reduced plasma FFA from adipose tissue as effectively as niacin, but it did not reduce LDL-C, TG, or elevate HDL-C after 4 weeks of treatment in man.¹⁰⁸ It has been reported that VLDL production rates were unchanged after FAA levels had returned to baseline.⁹⁸ These data suggest that the activation of GPR-109A and reduction of FFA release from adipose tissue are insufficient to elicit the lipid modification responses of niacin in man. Additional actions in the liver, such as the inhibition of both diacylglycerol acyltransferase 2 and reduced synthesis of TG, may also be involved.⁹⁷

Figure 2.

Model of niacin mechanism of action (reprinted with permission from Kamanna and Kashyap⁹⁶). ER indicates endoplasmic reticulum, FA, fatty acids; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SR-BI, scavenger receptor type B class I, TG, triglyceride; VLDL, very-low-density lipoprotein.

Pleiotropic Effects of Niacin on Inflammation and Endothelial Function

Atherosclerosis is a chronic inflammatory disease. Niacin has demonstrable efficacy in reducing inflammation in patients with diabetes, CHD, peripheral artery disease, and metabolic syndrome.^87,109,110 In one study, 27 patients with stable CHD had LDL-C levels treated to 80 mg/dL with statin therapy at baseline. The addition of ERN (1 g/d) for 3 months decreased the serum levels of high-sensitivity C-reactive protein (hsCRP) by 15% and lipoprotein-associated phospholipase A2 by 20% compared to placebo.⁸⁷ Another study in 35 patients with diabetes, CHD or PAD showed that 12 months of treatment with ERN (2 g/d) reduced hsCRP by 50%.¹⁰⁹ Among lipid-lowering drugs, niacin is uniquely effective in reducing levels of Lp(a), a risk factor for CHD,¹¹¹ whose level is not improved by statins.

Niacin may also exert antiinflammatory responses independent of changes in plasma lipids. In a rabbit model, niacin supplementation administered in amounts that did not change serum levels of HDL-C, LDL-C, or TG reduced expression of multiple inflammatory cytokines (intercellular adhesion molecule 1 [ICAM-1], vascular cell adhesion molecule 1 [VCAM-1], and monocyte chemoattractant protein 1 [MCP-1]), attenuated intima–media neutrophil infiltration, improved endothelial-dependent vasorelaxation, and protected against tumor necrosis factor α-induced vascular inflammation.¹¹²

Patients with DM are at increased risk of CHD, and ATP III defines DM as a CHD risk equivalent. A recent study of HDL particles isolated from diabetic patients (n = 33) showed reduced ability to stimulate nitric oxide formation, affect endothelium-dependent vasodilation and progenitor cell-mediated endothelial repair compared with HDL isolated from healthy individuals. After 3 months of treatment with ERN (1500 mg/d), HDL particles isolated from niacin-treated diabetic patients (n = 15) showed improvements in nitric oxide production, endothelial-dependent vasodilation, and progenitor cell-mediated endothelial repair.⁵³

In summary, the ability of niacin to increase both HDL quantity and function, reduce LDL and TG, reduce inflammatory responses, and improve endothelial vasorelaxation^112,113 could possibly contribute to slowing the development and progression of atherosclerotic plaque and reduce CV morbidity and mortality as seen in older studies.

Cardiovascular Outcome Studies With Niacin

The first large clinical trial of lipid-lowering pharmacotherapy, the Coronary Drug Project (CDP),¹¹⁴ randomized 8341 men with CHD to 4 lipid-altering regimens (estrogen, thyroxine, clofibrate, and niacin) for 6.2 years. Only niacin significantly reduced the incidence of nonfatal MI (26%) and stroke (24%) compared with placebo (Table 1). Mortality rates during the course of the trial were high, with 2333 patients of the original 8414 member cohort having died by the end of the study. All-cause mortality was not reduced significantly by niacin during the course of the trial (24.8% vs 25.9%). A 15-year follow-up in the CDP (6.2 years on study drug followed by 8.8 years after study conclusion) found an 11% reduction (69 fewer deaths; 52% vs 58.2%, P = .0004) in total mortality in the original niacin cohort compared with the placebo group.¹¹⁵ The follow-up was performed in order to more fully ascertain whether specific treatments such as estrogen or clofibrate were associated with increased risk of mortality. The median survival time from entry into the CDP was 13.03 years for patients in the niacin group compared to 11.40 years for patients randomized to treatment with placebo (P = .0012) due for the most part to reductions in CAD-related mortality. The investigators attributed the mortality benefit to reductions in risk for MI and the cholesterol-lowering effects of the niacin.¹¹⁵

Table 1.

Review of Niacin Clinical Trials on Atherosclerosis and/or Clinical Events.

Study	N (% F)	Treatment	Entry requirement	Duration, year	Baseline				% Change in lipids			Atherosclerosis change by angiography or carotid US (treatment vs control)			% Reduction in clinical events
Study	N (% F)	Treatment	Entry requirement	Duration, year	Age,^a year	HDL-C, mg/dL	LDL-C/(TC)^b	TG	HDL-C, mg/dL	LDL-C/(TC)^b	TG	Regression, %	Progression, %	Stenosis	CHD death + nonfatal MI	PTCA or CABG	All cause mortality
CDP (1975)	3908 (0)	Niacin 3 g versus placebo	MI	5	45		(252)^b	7 meq/L		(–10)^b	–26.1				15^c	47^c	4 (NS)
CDP follow-up (1986)	3467		MI	15	51										−12.4		11^d
SIHD secondary prevention (1988)	555 (20)		MI	5	61	48	161 (251)	208		(−13)	−19				36^c		26^e
CLAS (1987)	162 (0)	Niacin 4 g + colestipol 30 g versus placebo	CABG	2	54	45	171	151	37	−43	−22	16.2^c vs 2.4	39 vs 61
CLAS II (1990)	103 (0)		CABG	2	54	44	171	154	37	−40	−18	18 vs 6^e	48 vs 85^f
UCSF-SCOR (1990)	72 (57)	Niacin 0-7.5 g + colestipol 15-20 g versus usual care	HFHC	2	42	47	283	133	28	–38	–19	33 vs 13 (NS)	20 vs 41 (NS)	–1.53^evs 0.8
FATS (1990)	146 (0)	Niacin 4 g + colestipol 230 g versus usual care	Angiographic CHD	2.5	46	39	190	194	43	−32	−29	39 vs 11^c	25 vs 46^c	–0.9^cvs 2.1	+2 (NS)	75
FATS follow-up (1998)	176 (0)		Angiographic CHD	10		43	202	210	23	−48	−36				72^e		93^d
HATS (2001)	160 (13)	Niacin 1-4 g + simvastatin 10-20 mg versus placebo	Angiographic CHD	3	53	31	125	213	26	−42	−36			−0.4^dvs 3.9	60	57
AFREGS (2005)	143 (9)	Niacin 0.25-3.0 g + gemfibrozil 1200 mg + cholestyramine versus placebo + diet + cholestyramine 16 g	Angiographic CHD	3	63	34	126	169	38	−22	−46			−2.16	13.7	11	1.4
ARBITER 2 (2004)	167 (7)	ERN 0.5-1 g + statin versus placebo + statin	CHD on statin and HDL < 45	1	67	39	87	154	21	−2.3	−13		CIMT 1.6 vs 5.1^d
ARBITER 3 (2006)	130 (8)		Open-label ARBITER 2 patients switched to ERN	2	67	40	88	165	23	−9.5	−20	−4.6% decrease in CIMT, P = .008
ARBITER 6 (2009)	208 (22)	ERN 2 g/d versus ezetimibe 10 mg	CHD and HDL <50 for men and <55 for women	14 months	64	43	81	126	18	−20	−18	−1.58% decrease in CIMT. P = .001 versus baseline
Oxford (2009)	63 (94%)	ERN 2 g statin versus placebo + statin	T2DM with CHD or carotid/peripheral atherosclerosis HDL-C < 40 mg/dL niacin 2 g/d	1	65	39	85	168	23	19	11	−1.1 mm² for ERN vs +1.2 mm² for placebo		−1.64 mm² in carotid wall area by MRI, P = .03	9/165 in ezetimibe vs 2/160 in ERN-treated patients

Abbreviations: NS, not significant; CDP, coronary drug project; ERN, extended-release niacin; SIHD, Stockholm Ischemic Heart Disease; CLAS, Cholesterol Lowering Atherosclerosis Study; UCSF-SCOR, University of California, San Francisco, Atherosclerosis Specialized Center of Research; FATS, Familial Atherosclerosis Treatment Study; HATS, HDL-Atherosclerosis Treatment Study; MI, myocardial infarction; CABG, coronary artery bypass grafting; PTCA, percutaneous coronary angioplasty; HFHC, heterozygous familial hypercholesterolemia; CHD, coronary heart disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglyceride; ERN = extended released niacin; TG, triglyceride; US, ultrasonography; DM, diabetes mellitus.

^a Mean.

^b If LDL-C not available, total cholesterol value given in parentheses.

^c P < .01.

^d P ≤ .001.

^e P ≤ .05.

^f P < .0001.

The effects of niacin on improving CV outcomes have been further investigated in numerous combination trials evaluating diverse, high-risk populations. The Stockholm Ischaemic Heart Disease Secondary Prevention Study randomized men and women (N = 555) to treatment with niacin plus clofibrate or placebo.¹¹⁶ After 5 years of treatment, nonfatal CV events were reduced by 33% and total mortality by 26% overall in the drug treatment group compared to placebo. In patients older than 60 years of age, total mortality decreased by 28% in the niacin plus clofibrate group compared to placebo.¹¹⁶

In addition to the positive clinical outcomes associated with niacin therapy, a number of recent studies have shown beneficial effects of niacin on atherosclerotic lesions. The Cholesterol-Lowering Atherosclerosis Studies (CLAS and CLAS II) were the first randomized angiographic studies to demonstrate a clear treatment effect on atherosclerotic lesions.^117,118 After 2 years of treatment, 162 men randomized to niacin plus colestipol had significant increases in stenosis regression and decreases in progression compared to those on placebo.¹¹⁷ After 4 years of follow-up, regression and nonprogression rates continued to improve with active treatment.¹¹⁸ Another angiographic study randomized both men and women with heterozygous familial hypercholesterolemia to colestipol and niacin combination therapy, lovastatin, or “usual care.” After 2 years of treatment, there was regression of coronary atherosclerosis. The difference in the dimensions of lesions between controls and treated patients was slightly more than 2% of the cross-sectional area, which represents a 4.5% difference in the size of the average atherosclerotic lesion (P = .05).¹¹⁹

The single-site Familial Atherosclerosis Treatment Study (FATS) randomized men (n = 146) to treatment with colestipol and niacin, colestipol and lovastatin, or usual care (43% received colestipol).¹²⁰ After 2.5 years of treatment, combination therapy was associated with significant decreases in coronary stenosis and a substantial 73% relative reduction in death, MI, or refractory ischemic symptoms, requiring surgical or percutaneous intervention. Moreover, during a 10-year follow-up, patients who continued on triple therapy experienced sustained reductions in outcomes and a 93% reduction in total mortality compared with those who had returned to usual care.¹²¹

Similar findings were demonstrated in the HDL Atherosclerosis Treatment Study (HATS) patients, which included 160 men and women who had an ApoB level ≥125 mg/dL at baseline.³¹ After 3 years, treatment with simvastatin (mean dose: 13 mg/d) plus niacin (mean dose: 2400 mg/d) was associated with significant regression of atherosclerotic plaque as measured by quantitative coronary angiography as well as a 90% reduction in the composite end point of death, MI, stroke, or revascularization (P = .03) compared to placebo. Of note, the addition of antioxidants tended to mitigate the angiographic and clinical efficacy of combination therapy because it attenuated the capacity of statin/niacin therapy to raise HDL-C.¹²² Both the FATS and HATS trials suggest that LDL-C lowering coupled with HDL-C raising provides additive reductions in morbidity and mortality.^31,114,120 Multiple meta-analyses evaluating the impact of aggressive LDL-C lowering and HDL-C raising on CV event rates¹²³ and progression of atherosclerotic disease^124,125 suggest that both are important. The GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) Study demonstrated that even after adjusting for 24 established covariates for CHD (including LDL-C), the hazard ratio for an acute coronary event in patients treated with atorvastatin is 0.85 (95% confidence interval [CI]: 0.76-0.94; P = .002) for every 4 mg/dL increase in HDL-C.¹²⁶ In the Treating to New Targets Study, even among patients who had attained an LDL-C <70 mg/dL, risk of the primary composite end point continued to increase continuously as HDL-C levels decreased.¹²⁷

The Armed Forces Regression Study (AFREGS) randomized 143 military retirees under the age of 76 years with documented CHD to placebo or aggressive lipid-lowering treatment with gemfibrozil, niacin, and cholestyramine.¹²⁸ Patients were enrolled if they had a baseline HDL-C of less than 40 mg/dL following an AHA Step II diet intervention for 6 months. Changes in coronary stenosis (primary end point) and hospitalization for cardiac events (secondary end points) were assessed at the end of 30 months of treatment. In the drug therapy group, HDL-C increased by 36% (CI 28.4%-43.5%, P < .001); LDL-C and TG decreased by 26% (CI 19.1%-33.7%) and 50% (CI 40.5%-59.2%), respectively (P < .001).⁹⁴ Coronary stenosis increased by 1.35% in the placebo group and decreased by 0.81% in the treatment arm (P = .04).¹²⁸ The composite CV event rate end point was reached in 26% of patients in the placebo group and 13% of those in the intervention group (difference 13.7% [CI 0.0%-26.5%]). In the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2 trial, 167 patients with known CHD and low HDL-C (<45 mg/dL) were randomized to ERN, 1000 mg at bedtime, or placebo.¹²⁹ All patients were required to be on statin therapy with an LDL-C entry criterion of <130 mg/dL. The primary end point for this 1-year study was the change in carotid intima–media thickness (CIMT), a standardized method of measuring plaque progression. At 12 months, the ERN-treated patients had almost no change in CIMT (0.014 ± −0.104 mm; P = .23), whereas the placebo group on statin therapy alone exhibited a significant increase in CIMT (0.044 ± 0.100 mm; P < .001).¹²⁹

Following the completion of ARBITER 2, patients were continued in an open-label, 12-month follow-up (ARBITER-3).¹³⁰ In all, 104 patients completed follow-up for an additional year: 47 that were crossed over from placebo and started on ERN, and 57 that continued ERN for a total of 24 months. At the completion of the 2-year treatment period, patients converted from placebo to ERN experienced significant regression of CIMT (−0.095 ± 0.019 mm; P < .001 vs placebo phase). In the patients receiving ERN + statin for a total of 24 months, CIMT regression was also significant (−0.041 ± −0.021 mm; P = .001 vs placebo phase). The ARBITER 2 and 3 studies are the first to demonstrate stabilization and subsequent regression of atherosclerosis with the addition of niacin adjuvant therapy to stable statin treatment with well-controlled LDL-C.^129,130

In the ARBITER 6 trial, 363 patients with CHD or a CHD risk equivalent on statin treatment with an average LDL-C of 80 mg/dL were randomized to ezetimibe (10 mg/d) or ERN (2000 mg/d). The objective of this trial was to compare the effectiveness of therapy directed at lowering LDL-C (ezetimibe) vs therapy directed at raising HDL-C (niacin) on atherosclerosis measured by CIMT.¹³¹ The study was terminated early after 14 months due to consistent superiority of niacin (N = 97) over ezetimibe (N = 111) on CIMT measured at both 8 and 14 months. After 14 months, ezetimibe reduced LDL-C more than niacin (−17.6 ± 20.1 mg/dL vs −10 ± 24.5 mg/dL, P = .01), while niacin increased HDL-C more than ezetimibe (7.5 ± 9.2 mg/dL vs −2.8 ± 5.7 mg/dL, P < .001). At 8 and 14 months, ezetimibe treatment did not show significant changes in mean CIMT from baseline (0.0014 ± 0.0020 mm, P = .38; 0.0007 ± 0.0035 mm, P = .84; respectively). By comparison, niacin significantly reduced the mean CIMT from baseline at both 8 and 14 months (−0.0102 ± 0.0030 mm, P = .004; and −0.0142 ± 0.0041 mm, P < .001; respectively). The superiority of niacin over ezetimibe was maintained after inclusion of data from additional 107 patients who completed a closeout assessment.¹³² The ARBITER 6 trial shows the superiority of niacin and its effects on both HDL-C and LDL-C in regression of atherosclerosis monitored by CIMT, as compared with ezetimibe, which modulates primarily LDL-C. However, the following must be pointed out. First, ARBITER 6 was designed to assess the impact of different lipid-modifying medications in patients with well-controlled LDL-C and a low HDL-C. Such patients would be expected to benefit more from niacin than ezetimibe. Second, the patients enrolled in ARBITER 6 were already receiving aggressive statin therapy for approximately 6 years by the time of randomization, which would be expected to impact the ability to induce incremental CIMT regression with additional LDL-C lowering in the absence of an HDL-C elevation. Finally, the trial was discontinued prematurely with more than 40% of patients not having received a follow-up CIMT evaluation, which could have significantly impacted the ability of the study to detect a difference in the ezetimibe-treated group over the time course evaluated.¹³²

The Oxford Niaspan Study evaluated the effects of ERN 2000 mg/d on atherosclerosis measured by magnetic resonance imaging (MRI) in patients (n = 71) with type 2 DM and CHD or carotid/peripheral artery disease who achieved their LDL-C target with statin therapy but still had low HDL-C levels (<40 mg/dL).¹³³ After 1 year, ERN increased HDL-C (23%) and decreased LDL-C (19%). Extended-release niacin also significantly decreased TG, hsCRP, Apo-B, and Lp(a) and increased Apo-A1 and adiponectin. After 12 months, MRI showed niacin significantly reduced plaques in the carotid wall area compared with placebo (adjusted treatment difference: −1.64 mm², 95% CI: −3.12 to −0.16; P = .03). Mean changes in carotid wall area was −1.1 ± 2.6 mm² for ERN compared with +1.2 ± 3.0 mm² for placebo.¹³³ Both the Oxford Niaspan and ARBITER 6 studies were conducted in patients on statin therapy and well-managed LDL-C levels at baseline, and each demonstrated that niacin, by elevating HDL-C, reducing TG, LDL-C, and inflammation, could reduce atherosclerotic plaque burden.^132,133

Recent Clinical Trials Directed at Clinical Event Reduction

The AIM-HIGH Trial

Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH) was a randomized, placebo-controlled clinical trial in patients with a history of CHD and atherogenic dyslipidemia (low HDL-C and high triglycerides).¹³⁴ The AIM-HIGH investigators hypothesized that raising HDL-C with ERN would reduce the risk of CV events among patients who had achieved target levels of LDL-C (40 to 80 mg/dL) with intensive simvastatin ± ezetimibe therapy 10 mg daily, as needed, in either arm. Following a 4- to 8-week open-label run-in with simvastatin 40 mg daily and rapid up-titration of progressively increasing dosages of ERN (500 mg daily during week 1; 1000 mg daily during week 2; 1500 mg/daily during week 3; 2000 mg daily during week 4), participants tolerating at least 1500 mg daily were randomly assigned to a double-blind 1:1 randomization scheme to ERN or matching placebo. In this event-driven trial, it was projected that 800 adjudicated primary events during a 2.5- to 7-year (mean: 4.6 year) follow-up would provide 85% power to detect a relative 25% treatment difference between the ERN and placebo groups. Follow-up was scheduled to conclude in December 2012. A total of 3414 men and women, mean age 64 years, were recruited from 92 enrolling centers across the United States and Canada and followed for an average of 36 months. At entry, 3196 (94%) patients were taking a statin, with a mean baseline LDL-C of 71 mg/dL, HDL-C was 35 mg/dL, and triglyceride (TG) level was 161 mg/dL; by contrast, only 218 (6%) patients were statin-naive at trial entry. In this small cohort, mean baseline LDL-C was 125 mg/dL, HDL-C was 33 mg/dL, and TG was 215 mg/dL.¹³⁴

During a 36-month follow-up period, compared to placebo, ERN raised mean HDL-C by 25% (to 42 mg/dL), lowered TG by 29% (to 122 mg/dL), while LDL-C further declined from 74 mg/dL to 62 mg/dL. As noted previously, the trial was stopped at a formal interim analysis by the Data Safety Monitoring Board due to lack of efficacy of ERN. The primary end point (time to first event for the composite of CHD death, non-fatal MI, ischemic stroke, hospitalization for ACS, or symptom-driven coronary or cerebral revascularization) occurred in 282 ERN-treated patients (16.4%) as compared to 274 placebo-treated patients (16.2%; hazards ratio 1.02, 95% CI, 0.87-1.21; P = .80).¹³⁴

Second Heart Protection Study

A much larger secondary prevention trial similar in design to AIM-HIGH outside North America (the Second Heart Protection Study [HPS-2 THRIVE]) comparing simvastatin plus ERN/laropiprant versus simvastatin alone in 25 673 patients has recently concluded.¹³⁵ Study participants aged between 50 and 80 years with a history of MI, cerebrovascular atherosclerotic disease, PAD, or DM with other evidence of symptomatic CHD were enrolled from China, Scandinavia, and the United Kingdom. All patients received at baseline either simvastatin 40 mg daily (with a total cholesterol <3.5 mmol/L) or ezetimibe/simvastatin 10/40 mg daily. The proprietary ERN preparation used in HPS-2 THRIVE was fundamentally different from that used in AIM-HIGH in that the niacin was combined with laropiprant (LRPT), a prostaglandin D₂ (PGD₂) antagonist, in order to mitigate niacin-induced flushing. Unlike AIM-HIGH, participants were enrolled regardless of their baseline (entry) HDL-C levels. The primary outcome measure was major vascular events defined as the first occurrence of either:

major coronary event (nonfatal MI or coronary death); or

stroke (any nonfatal or fatal stroke, including subarachnoid hemorrhage); or

revascularization (coronary or noncoronary artery surgery or angioplasty [including amputation])

In HPS-2 THRIVE, 83% of enrolled patients were men, the mean age was 64.9 years, 78% had a history of prior CHD, and 32% had DM. The baseline lipid values showed a remarkably stable and exceedingly well treated population with a mean total cholesterol of 128 mg/dL, direct LDL-C of 63 mg/dL, HDL-C of 44 mg/dL, and triglycerides of 125 mg/dL. During an average 4-year follow-up, the ERN/LRPT patients receiving simvastatin compared to placebo showed an average 10 mg/dL further decrease in LDL-C, a 6 mg/dL increase in HDL-C, and a 33 mg/dL decrease in TG levels—directional changes that were virtually identical to those observed in AIM-HIGH. Among patients randomized to the ERN/LRPT combination, as compared to simvastatin plus placebo, the hazard ratio for major vascular events was 0.96 (95% CI, 0.90-1.03, P = .29). There were no differences in the components of the primary end point or in any of the secondary end points as a function of treatment assignment. Similarly, there were no treatment differences among enrolled patients who were less than 65 years, those between 65 and75 years of age, or those greater than 75 years by treatment assignment. There was a borderline interaction (P = .06) for the region from which patients were enrolled with a better response to ERN/LRPT among European study participants compared to those from China, while the mean changes in lipids over time (especially LDL-C) were notably less among Chinese (−7 mg/dL) compared to Europeans (−12 mg/dL).¹³⁵

Importantly, there were several serious adverse events (SAEs) noted among patients randomized to ERN/LRPT compared to those taking simvastatin plus placebo. In particular, there were significant excess rates of any diabetic complication (HR 1.55; 95% CI 1.34-1.78); serious bleeding (HR 1.38; 95%CI 1.17-1.62), and serious infection (HR 1.22; 95%CI 1.12-1.34).¹³⁵ The incidence of statin-related myopathy was significantly higher among Chinese enrollees compared to Europeans. The use of ERN/LRPT in combination with simvastatin increased the risk of definite myopathy (75 [0.16%/year] vs 17 [0.04%/year]: risk ratio 4.4; 95% CI 2.6-7.5; P < .0001). Definite or “incipient” myopathy occurred more frequently in Chinese participants (138 [0.66%/year] vs 27 [0.13%/year]) compared to those from Europe (17 [0.07%/year] vs 11 [0.04%/year]).¹³⁶

The reasons for the excess SAEs observed in HPS-2 THRIVE are not entirely clear. While the trial results are not yet published, the Oxford trialists who conducted the study indicated that niacin was the most likely cause for the observed findings. Yet, in AIM-HIGH, no such pattern of excess SAEs was observed for serious infections or bleeding. As expected, niacin worsens glycemic control in approximately 10% of patients and is associated with cutaneous side effects.

Nevertheless, given the fact that the ERN combination used in HPS-2 THRIVE included a prostaglandin inhibitor, it is certainly plausible that some (or most) of the off-target effects observed in this trial may be related to laropiprant as opposed to niacin. A critical issue is whether the PGD₂ receptor 1 antagonist laropiprant that was used in HPS-2 THRIVE to reduce niacin-induced flushing is really biologically inert with respect to atherosclerosis and thrombosis, as the Oxford trialists have maintained in their public commentary following the presentation of the trial preliminary results in March 2013. In particular, there is a paucity of scientific information relating to the known pathobiologic effects of PGD₂. Of note, experimental data suggest that PGD₂ receptor 1 deletion in mice augmented aneurysm formation and accelerated atherogenesis and thrombogenesis, implicating the possibility that niacin-induced PGD₂ release may function as a constraint on platelets during niacin therapy.^136,137 Landmesser suggested that the effects of inhibiting the PGD₂ receptor 1 by laropiprant on thrombosis and atherosclerosis in humans in vivo may be difficult to predict and complex, since it has been observed that, on one hand, laropiprant at low concentrations may prevent the inhibitory effects of PGD₂ on platelet function, including effects on platelet aggregation and thrombus formation, while, on the other hand, laropiprant at higher concentrations may attenuate platelet activation induced by thromboxane and inhibit thrombus formation.¹³⁷ These observations raise the very distinct possibility that the unexpected serious adverse effects observed in HPS-2 THRIVE may have, in part, been related to the use of this agent when combined with ERN. Certainly, inhibiting PGD₂ activity could have contributed to an increased frequency of infection.

Translating the Results of AIM-HIGH and HPS-2 THRIVE Into Clinical Practice

In the aftermath of the neutral findings of both AIM-HIGH and HPS-2 THRIVE, uncertainties abound in terms of how the trial results should be interpreted and incorporated into clinical practice. Accordingly, several questions have been posed:

Was the fundamental “HDL Hypothesis” as configured in AIM-HIGH wrong?

Was the therapeutic intervention wrong?

Did these trials randomize inappropriate patients (ie, their atherogenic lipoprotein burden was already meeting the most stringent criteria for adequate control)?

Were the expectations of clinical benefit for ERN and simvastatin wrong?

For more than 4 decades, there has accrued an abundance of robust epidemiological evidence that supports the observation that low levels of HDL-C and elevated levels of LDL-C are independently predictive of the risk of developing CHD in both men and women. As already noted, in the original placebo-controlled Coronary Drug Project, high-dose IR niacin (3000 mg/d) was associated with a significant 14% reduction in CHD death or MI, a 26% reduction in non-fatal MI alone, and a 21% reduction in stroke/transient ischemic attacks—event rate reductions that are comparable to those achieved in contemporary placebo-controlled statin trials. In addition, VA-HIT demonstrated a 22% reduction in CHD death or nonfatal MI during a 5.1-year mean follow-up, while the combined incidence of CHD death/MI/stroke was reduced significantly by 24%. Seemingly, these data confirmed the so-called “HDL hypothesis” that raising low levels of HDL-C (by 6%, or 2 mg/dL) from 32 mg/dL at baseline to 34 mg/dL at follow-up and lowering TG levels (by 31%) from 160 mg/dL at baseline to 115 mg/dL at follow-up was associated with significant clinical event rate reductions. Importantly, however, baseline LDL-C in VA-HIT, which predated widespread statin use, was 111 mg/dL, as compared with 71 mg/dL in the present study among those receiving a statin at trial entry. This 40 mg/dL between-trial difference in baseline LDL-C is consistent with the significant impact statins have made on both reducing elevated LDL-C levels and CV risk.

In addition to the anticipated effects of ERN on raising HDL-C and lowering both TG and LDL-C, AIM-HIGH was designed with an aggressive on-treatment LDL-C target of 40 to 80 mg/dL, in part because of the continued evolution in clinical practice that has supported lower levels of LDL-C in high-risk patients with metabolic syndrome and atherogenic dyslipidemia, as were targeted for enrollment in the trial. As noted previously, 94% of patients who were randomized to AIM-HIGH had a mean baseline LDL-C level of 71 mg/dL, in contrast to the 6% of statin-naive patients whose mean baseline LDL-C level was 125 mg/dL—an almost 45 mg/dL difference. Again, by comparison to VA-HIT, where the baseline LDL-C was 111 mg/dL and patients were not receiving a statin, the baseline LDL-C difference was 40 mg/dL. In addition to the very well-controlled LDL-C levels in AIM-HIGH patients at baseline, the levels of baseline non-HDL-C (mean: 108 mg/dL) and ApoB (mean: 81 mg/dL) were likewise very low at baseline.

Hence, the patients enrolled in AIM-HIGH exhibited excellent lipid control at baseline, which reflected the proficiency and dedication of the trial investigators in optimizing lipid treatment and secondary prevention. Similarly, in HPS-2 THRIVE, one might dispute the characterization that this was a high-risk study population, given the fact that these patients were so well treated and had a mean baseline LDL-C in the mid-60 mg/dL range with a mean baseline HDL-C in the mid-40 mg/dL range. Given such a baseline lipid profile that is well within the existing ATP-III clinical practice guidelines for the optional, “optimal” LDL-C target, why would one expect a dyslipidemic intervention such as niacin to provide incremental clinical benefit? In retrospect, it may well be that the inclusion of such very well-treated patients with such low levels of baseline LDL-C, non-HDL-C, and ApoB played an important role in mitigating much of the long-term residual risk we sought to demonstrate with ERN. Importantly, 75% of the statin-treated patients in AIM-HIGH at baseline had been taking a statin for at least 1 year, and 40% of patients had been taking a statin for 5 or more years. Because of the long-standing treatment with statins and the concomitant use of aggressive secondary prevention (or disease-modifying therapies), it may have been difficult to discern incremental clinical benefit with ERN. Multiple studies have shown that in patients with CHD, lipids are not, however, nearly as well controlled in real clinical practice as they were in these 2 trials.

Finally, what could explain the lack of clinical benefit viewed from the perspective of the practicing clinical cardiologist who is often faced with such patients who have low levels of HDL-C but varying levels of LDL-C? As hypothesized previously, it is possible that long-standing, aggressive LDL-C reduction therapy with statins may deplete the soluble constituents of the large eccentric lipid cores of vulnerable coronary plaques and, by so doing, may convert such vulnerable plaques destined for rupture (with associated sudden cardiac death, MI, or ACS) to stable, quiescent plaques, where the risk of such plaque ruptures is significantly reduced. This remains speculation at present but could provide a plausible explanation for the findings observed.

In summary, how should clinicians interpret the results of AIM-HIGH and HPS-2 THRIVE and, as a corollary, are there subsets of patients for whom niacin should (or should not) continue to be administered? Recognizing that the studies, by design, included only those patients with established, stable, nonacute atherosclerotic CV disease, the results of our trial only apply to the types of patients enrolled and should not be generalized to the broader subpopulations (such as those with acute MI, ACS, or those likely to require myocardial revascularization in the subsequent 4-8 weeks after trial enrollment). By contrast, for those stable, nonacute patients with CHD with residually low levels of HDL-C who are able to achieve and maintain very low levels of optimal LDL-C on a statin, the results of AIM-HIGH and THRIVE do not support the use of ERN to further reduce clinical risk and improve CV outcomes. Data derived from several, prospective, observational registries suggest that only about 15% to 20% of all-treated high-risk patients with CHD are able to achieve and maintain the kinds of very low LDL-C that were achieved in AIM-HIGH and HPS-2; as such, these trial results may directly apply only to this subset of more unselected patients with CHD with dyslipidemia.

Future Studies and Directions

Novel agents in development that affect HDL-C metabolism include the CETP inhibitors, Apo A-I mimetic peptides, and delipidated HDL.^138
–140 Another area of research involves the peroxisome proliferator-activated receptor α. Peroxisome proliferator-activated receptor α agonists (including fibrates) enhance the production and activity of HDL particles by increasing expression of their apoproteins and reducing their catabolism.¹⁴¹ These studies also highlight the growing recognition of HDL-C as a target of therapy. Torcetrapib raised HDL-C by more than 50% and further decreased LDL-C in humans, but because of increased mortality in phase III studies and unforeseen off target effects of increased aldosterone levels and blood pressure, this agent was withdrawn from further commercial development. Both dalcetrapib and anacetrapib increase HDL-C by 30% and 138%, respectively, while anacetrapib also decreases LDL-C by 40%—and is under active phase III clinical trial evaluation.¹⁴² Thus far, both drugs increase HDL-C without an apparent adverse effect on blood pressure. Both anacetrapib and dalcetrapib increase HDL particle size, and HDL particles isolated from anacetrapib-treated patient show improved anti-inflammatory and RCT.¹⁴³

Summary

Advances in the management of dyslipidemia are, in large part, responsible for the sustained decline in CHD mortality observed over the past 3 decades; however, despite these impressive gains, CHD remains the most frequent cause of death in the United States and the western world. Although large-scale clinical trials with statins have found that reducing LDL-C decreases mortality and CV events, these rates remain unacceptably high, in the range of 65% to 75% of the rates observed in placebo-treated patients. The majority of high and very-high-risk patients are not treated to their LDL-C and non-HDL-C targets, leaving them with residual risk for CV events.

Although the use of niacin–statin combination therapy has been shown to favorably influence surrogate outcome measures of coronary and vascular atherosclerosis, combination therapy using niacin and statin has not, to date, been demonstrated to reduce major adverse cardiac events despite its favorable effects on the serum lipid profile. Future studies are warranted to explore different trial designs in higher risk subsets of patients than have been studied to date. Until then, niacin should remain an important therapeutic approach to achieving optimal lipid targets in selected patients with CHD whose atherogenic lipoprotein burden is inadequately controlled with statin monotherapy.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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The Therapeutic Role of Niacin in Dyslipidemia Management

Abstract

Keywords

Introduction

Cardioprotective Role of HDL-C

Effects on Lipid Homeostasis

Population-Based Studies and the Importance of HDL-C

Clinical Effects of Raising HDL-C

Nicotinic Acid

Mechanism of Action

Effects on HDL metabolism

Effects on TG, LDL, and VLDL

Role of GRP-109A

Pleiotropic Effects of Niacin on Inflammation and Endothelial Function

Cardiovascular Outcome Studies With Niacin

Recent Clinical Trials Directed at Clinical Event Reduction

The AIM-HIGH Trial

Second Heart Protection Study

Translating the Results of AIM-HIGH and HPS-2 THRIVE Into Clinical Practice

Future Studies and Directions

Summary

Footnotes

Declaration of Conflicting Interests

Funding

References