HDL Hypothesis: Where Do We Stand Now?

  • Sayed M. Tariq
  • Mandeep S. Sidhu
  • Peter P. Toth
  • William E. Boden
Nonstatin Drugs (WB Borden, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Nonstatin Drugs


There is robust epidemiological evidence dating back to the original Framingham Heart Study from 1977 that indicates an important inverse relationship between high-density lipoprotein cholesterol (HDL-C) and risk of incident coronary artery disease (CAD). Despite this body of scientific information demonstrating that low levels of HDL-C are an independent predictor of subsequent CAD events, multiple therapeutic attempts to raise HDL-C levels have failed to demonstrate a consistent reduction in prognostically important endpoints such as death, myocardial infarction (MI), and stroke. Recently, several major randomized trials using different therapeutic interventions have raised appropriate concerns about our basic understanding of HDL-C and whether the “HDL hypothesis” of lowering cardiovascular events through therapeutic interventions directed at raising HDL-C is a scientifically viable one. While two recent randomized controlled trials (AIM-HIGH and HPS2-THRIVE) failed to show a reduction in cardiovascular events in patients treated to optimally low levels of low-density lipoprotein cholesterol (LDL-C) at baseline with extended-release niacin on a background of simvastatin, these clinical trials studied specific populations of stable ischemic heart disease patients. The data from these two contemporary trials cannot be extrapolated to all patient populations, such as those with acute coronary syndromes or myocardial infarction or those with significant residual mixed dyslipidemia not treated with optimal doses of intensive statin therapy, as these patients were excluded by trial design in both studies. Therefore, at the present time, there is insufficient evidence from clinical trials to recommend HDL-targeted therapy for additional event reduction in CAD patients. However, we will review the relevant data from recent major trials (AIM-HIGH, HPS2-THRIVE, ILLUMINATE, and dal-OUTCOMES) and highlight the potential clinical implications of these trials in modern pharmacotherapy as it relates to HDL-C raising and potential cardiovascular event reduction.


HDL Niacin Atherosclerosis Coronary artery disease AIM-HIGH HPS2-THRIVE 


The National Cholesterol Education Program recommended that optimal treatment for high-risk cardiac patients include both lowering LDL-C and non-HDL-C to risk-stratified levels and that raising HDL-C levels should be considered for HDL-C <40 mg/dL, but the Adult Treatment Panel (ATP) III committee did not specify a therapeutic target goal for HDL-C [1]. The controversial new 2013 AHA/ACC cholesterol treatment guidelines have eliminated LDL-C and non-HDL-C risk-stratified treatment thresholds and targets. These guidelines now define patient eligibility for treatment of dyslipidemia with a statin-based regimen solely on the projected risk for an atherosclerotic disease-related cardiovascular event [2•]. The new guideline is not endorsed by the EAS/ESC, IAS, or the NLA. The risk calculator based on the prospective pooled cohort has also been shown to be flawed [3]. Given these issues, we will contextualize the HDL hypothesis based on ATP III, which is also consistent with guidelines promulgated in Europe, Canada, and elsewhere.

Elevated LDL-C level is a well-established risk factor for CAD. As a major predictor of coronary heart disease (CHD) risk, optimizing LDL-C levels has been an area of focus over the past two decades with the advent and widespread use of the hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), which have demonstrated a significant reduction in vascular events [4, 5, 6, 7, 8, 9, 10, 11, 12, 13]. However, LDL-C reduction is not the only predictor of favorable cardiovascular outcomes, and there are substantial epidemiological data to suggest that low HDL-C levels are also associated with an increased CAD risk. It has been shown that even after treating patients to optimal goals of LDL-C, there is, at best, a 25–35 % relative risk reduction in subsequent CAD events [11, 12, 13, 14, 15] over 4–5 years of follow-up. This suggests that LDL-C and non-HDL-C are not the only lipoproteins to predict cardiovascular outcomes and that there must be other significant factors that explain the persistently high residual risk of CAD. Another fact to consider is that after intensive treatment with statins to achieve previously defined optimal target levels of LDL of <70 mg/dL, there continues to be an inverse relationship between HDL-C level and CAD events, even at these low levels of achieved LDL-C [14]. The previous ATP III had indicated that HDL-C levels of <40 mg/dL for men and <50 mg/dL for women were undesirable [1]. There are over three decades of epidemiological data supporting low levels of HDL-C level as a powerful independent predictor of poor cardiovascular outcomes. One of the earliest studies to provide evidence of this relationship was first described in 1977, when data derived from the Framingham Heart Study of men and women between the ages of 49 and 83 years showed an inverse relationship between HDL-C levels and incidence of CAD [4]. The study also showed strong evidence that in addition to high LDL-C and total cholesterol levels, low HDL-C levels remained an independent inverse risk factor for CAD. There are data to suggest that HDL-C levels <35 mg/dL in women may be an even more powerful predictor of CAD events than high levels of LDL-C [16].

In the decades since the original Framingham studies, multiple other studies have reinforced these findings by demonstrating that for every 1 mg/dL increase in HDL-C, there is a 2–3 % reduction in future coronary heart disease events [17]. The Veterans Affairs HDL Intervention Trial (VA-HIT) evaluated the impact of gemfibrozil therapy in men with known CAD who were followed for an average of 5.1 years. Approximately two-thirds of these patients had low HDL-C (<40 md/dL), with a mean baseline level of 32 mg/dL [18, 19]. VA-HIT randomized 2,531 male veterans to gemfibrozil 1200 mg daily vs. placebo that study demonstrated that after a mean follow up of 5.1 years, patients receiving gemfibrozil had 6 % higher HDL-C, with an average increase of 2 mg/dl rising to 34 mg/dl from a baseline level of 32 mg/dl. The Triglycerides levels were reduced by 31 % from a baseline of 160 mg/dL to 115 mg/dL. VA-HIT demonstrated a 22 % reduction in CHD death or non fatal MI during the 5.1 year mean follow up and 24 % combined incidence reduction of CHD death/MI/Stroke. Importantly, however, baseline LDL-C in the VA-HIT trial, which predated widespread statin use, was 111 mg/dL, as compared with more recent trials among those receiving a statin at trial entry where baseline LDL-C values ranged from the low- to mid-60s to low-70s prior to randomization [20••, 21••, 22]. This 40–50 mg/dL difference in baseline LDL-C between trials is consistent with the significant impact statins have had on both reducing elevated LDL-C levels and cardiovascular risk.

As noted above, VA-HIT was the first randomized controlled trial to demonstrate that raising low HDL-C levels was associated with significant reductions in CHD events, independent of LDL-C reduction [18, 19]. A more recent meta-analysis showed that statin therapy did not alter the association between low levels of HDL-C and increased cardiovascular risk. This study, which entailed 543,210 person-years of follow-up, showed that for every 10 mg/dL decrease in HDL-C level, there was an 8.3 % increase in MI per 1,000 person-years [14]. Even after aggressive statin treatment and significant lowering of LDL-C levels, patients still experienced a 7.1 % increase in MI per 1,000 person-years for every 10 mg/dL decrease in HDL. The inverse association between HDL-C levels and MI did not change for statin-treated patients vs. controls (p = 0.57) [14].

There is also evidence that patients who present with acute coronary syndrome (ACS) and are treated aggressively per guideline recommendations (such as percutaneous intervention with drug-eluting stents and optimal pharmacologic therapy, including intensive statin treatment) continue to have a higher incidence of death and adverse cardiac events if they have lower HDL-C levels at the time of ACS presentation [23]. Wolfram et al. demonstrated that a baseline HDL-C <40 mg/dL in patients who underwent stent deployment was an independent predictor of adverse coronary events and higher mortality due to CAD at 30 days and 1 year after revascularization [23]. This important point is reinforced by a recent retrospective review of data from the NCDR registry showing that low HDL-C levels are a strong predictor of increased mortality in patients with acute non-ST-segment elevation myocardial infarction (NSTEMI) [24]. Data also demonstrated that lower levels of HDL-C were associated with more diffuse and extensive angiographically apparent multivessel coronary disease. A hazard ratio of 1.28 was observed in patients with 3-vessel or left main equivalent CAD whose HDL-C levels were between 10 and 30 mg/dL (p-value of <0.0001) compared to quartiles of patients with higher HDL-C levels) [24]. In addition, a post hoc analysis of data from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial, in which 2,193 patients with stable ischemic heart disease, all on optimal medical therapy, were followed over a 4-year period, revealed that death and MI were 33 % lower (p = 0.02) in patients with HDL-C levels >48 mg/dL compared to patients with HDL-C levels <34.9 mg/dL [25, 26]. Even among patients with optimally controlled levels of LDL-C (<70 mg/dL), the highest quintile of HDL-C had a 65 % relative risk reduction in death and MI compared to the lowest quintile [26].

On the basis of such consistent scientific evidence marshaled from numerous epidemiological and observational sources, it is clear why there has been such intense interest in examining various therapeutic strategies to raise low levels of HDL-C in order to favorably impact clinical events in patients whose low baseline levels of HDL-C are felt to be a manifestation of residual CV risk. Unfortunately, several large clinical outcomes trials have failed to convincingly demonstrate cardiovascular event reduction through pharmacologically targeted HDL-raising interventions. In order to better understand this conundrum, it is important to first understand the structure, physiology, and metabolism of HDL particles.

HDL Metabolism

HDL particle biogenesis occurs on the surface of jejunal enterocytes, hepatocytes, adipocytes, and macrophages [27]. Unlike apoB-containing lipoproteins that deposit cholesterol and other lipids in arterial walls, HDL particles are able to interact with subendothelial macrophage foam cells and promote the mobilization and externalization of excess intracellular cholesterol [28]. During direct reverse cholesterol transport, HDL particles deliver cholesterol back to the liver for disposal (either as cholesterol or bile acids) after binding to scavenger receptor BI, which selectively delipidates HDLs and then releases the lipid-poor particle back into the circulation to start another round of the reverse cholesterol transport cycle. The reverse cholesterol transport cycle has been confirmed in humans, and cholesterol efflux capacity correlates significantly with risk for cardiovascular events. Nascent discoidal HDL is composed of cholesterol, apoA1, and phospholipids. Nascent discoidal HDL particles undergo lipidation and remodeling by a series of reactions mediated by ABCG1, ABCA1, hepatic lipase, endothelial lipase, cholesteryl ester transfer protein (CETP), and phospholipid transfer protein [29, 30, 31, 32].

Macrophages play a key role in the model of reverse cholesterol transport, as they are within the arterial wall and transform into foam cells, as they accumulate larger and larger amounts of cholesterol along with other lipids via ATP-binding membrane cassette transport proteins (ABCA1 and ABCG1). Macrophages also scavenge oxidized lipids in the subendothelial space, leading to the formation of foam cells. Both apoA1 and apoE can bind to ATP-binding membrane cassette transport proteins A1 and G1 (ABCA1 and ABCG1) [33]. As cholesterol is externalized, it is esterified with fatty acid by lecithin-cholesterol acyltransferase. This reaction establishes a concentration gradient for cholesterol esters to be sequestered into the core of an HDL particle, leading to the formation of small, dense spherical HDLs (HDL3). As the HDL3 undergoes further lipidation, it becomes larger and more buoyant, thereby forming HDL2. ABCA1 lipidates HDL1 and HDL3. ABCG1 lipidates HDL2 (Fig. 1) [33]. Through CETP, the cholesterol within HDLs can undergo a 1:1 stoichiometric exchange for triglycerides from triglyceride-rich lipoproteins. Phospholipid transfer protein transfers phospholipids between HDL-C and triglyceride-rich lipoproteins. Inhibition of CETP can lead to increased HDL-C levels and the increased formation of large HDL2 particles. From a biologic and mechanistic perspective, CETP inhibitors are promising drugs for modulating risk attributable to dyslipidemia. Hepatic lipase hydrolyzes triglycerides and can promote the catabolism of HDL particles. During indirect reverse cholesterol transport, HDL particles act as a shuttle by taking up cholesterol from the periphery and exchanging it for triglyceride from apoB-containing lipoproteins, which are then cleared by the LDL receptor and LDL receptor-related protein [27, 32, 33, 34].
Fig. 1

Model of reverse cholesterol transport

Genetic polymorphism studies suggest that lower CETP mass or activity leads to higher HDL-C levels and lower LDL-C levels [35]. This observation led to the development of CETP inhibitors, and the first study to evaluate such agents was 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 [36]. Torcetrapib in combination with atorvastatin increased HDL-C by 72 % and further lowered LDL-C by 25 %, but caused a significantly higher rate of cardiovascular events and mortality compared to atorvastatin monotherapy, and so the trial was terminated prematurely at one year. Torcetrapib raised HDL-C levels in phase III trials but increased cardiovascular events by 60 % compared to placebo, which was likely due to serious unanticipated off-target effects mediated by an enhancement of the renin-angiotensin-aldosterone system and manifested in an increase in blood pressure and multiple electrolyte disturbances [36]. As such, this trial did not demonstrate the expected benefits of raising HDL-C on clinical outcomes.

In the Effects of the Cholesteryl Ester Transfer Protein Inhibitor Dalcetrapib in Patients with Recent Acute Coronary Syndrome (dal-OUTCOMES) trial, a total of 15,871 patients with a recent ACS were randomly assigned to receive dalcetrapib 600 mg once daily or placebo. Importantly, like HPS2-THRIVE and ILLUMINATE, the dal-OUTCOMES trial was an all-comers design with no pre-selection for low baseline HDL-C levels, and so patients also began with a normal/high-normal HDL-C level. Dalcetrapib increased HDL-C levels significantly (by up to 40 %) but, like the ILLUMINATE trial with torcetrapib, failed to show any reduction in risk of secondary cardiovascular events. In dal-OUTCOMES, there was also a slightly higher incidence of elevated blood pressure and higher levels of C-reactive protein (CRP) in the treatment group [22]. There are even more potent CETP inhibitors such as anacetrapib and evacetrapib that are presently undergoing phase III clinical trials to assess efficacy on long-term clinical outcomes [37, 38].

In addition to driving reverse cholesterol transport, HDL particles are associated with multiple antiatherogenic functions (Table 1). The HDLs have other potentially antiatherogenic properties, including anti-inflammatory, antioxidant, antithrombotic, and profibrinolytic effects. They are important transport vehicles of sphingolipids, bioactive fatty acids, and microRNAs, and they can improve endothelial function and promote endothelial nitric oxide production (Table 1) [27, 32]. In particular, the HDL effect on nitric oxide production and improvement of endothelial vasorelaxation has been demonstrated in trials of peripheral vasomotor function, reaffirming the relationship between vasomotor function and HDL [39, 40].
Table 1

Antiatherogenic functions of HDL-C

HDL Property

Basic Mechanisms

Clinical Correlate

Reverse Cholesterol Transport

Cholesterol shuttled from peripheral tissue to liver for excretion

Decreased cholesterol in artery wall


Scavenges oxidative seeding molecules (apoA1)

Decreased oxidation of LDL

Breaks down oxidized phospholipids (Paraxonase)

Decreases lipid peroxide formation (Paraxonase)


Inactivates platelet activating factor (PAF)

Decreased recruitment of leukocytes

↓ Complement activation & LPS-derived TNF release

Decreased recruitment of leukocytes

↓ Endothelial adhesion molecules (VCAM, ICAM)

Decreased adherence/infiltration of leukocytes


↓ Platelet Activation (Inc NO, PGI2, Dec PAF, vWF)

Decreased acute thrombosis

↑ Anticoagulants (protein S and C) & fibrinolysis

↓ Procoagulants (TF, factor X activation)

Endothelial Stabilization

↑ Vasodilation (NO, PGI2), decreased vasoconstriction (endothelin-1)

Improved arterial vasodilation

Maintenance of endothelial integrity

↑ Endothelial cell proliferation and migration


↓ Endothelial apoptosis (Caspase 3 inhibition)


Additional Clinical Trials of HDL-Raising Therapies

The Coronary Drug Project in 1972 was one of the earliest NIH-funded trials, predating advances in both pharmacology with statins and revascularization with percutaneous coronary intervention [6, 7]. The study compared immediate-release (or crystalline) niacin (3 to 6 g daily) to placebo in patients with established CAD. Among patients treated with niacin, during an initial average 5-year follow-up there was a 27 % reduction in nonfatal MI, a 26 % reduction in transient ischemic attacks and strokes, and a 47 % reduction in need for coronary artery bypass grafting [7]. In a later post hoc analysis with a mean follow-up of 15 years, there was a significant 11 % risk reduction in all-cause mortality in the niacin-treated group [8].

The findings of the VA-HIT trial were not substantiated in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, in which the therapeutic efficacy of fenofibrate to reduce risk for cardiovascular events was evaluated in close to 10,000 patients with type 2 diabetes mellitus [41]. Although the primary composite endpoint was not significant, the trial demonstrated a 24 % reduction in nonfatal MI and a 21 % reduction in coronary revascularization, yet fenofibrate did not reduce mortality. There was a 5 % increase in HDL-C levels 4 months after starting fenofibrate therapy, but the increase in HDL-C was not sustained, and at the end of the study there was only a 2 % increase in HDL-C levels. In a post hoc analysis, fenofibrate significantly reduced risk for the primary composite endpoint among patients with baseline TG >200 mg/dL and HDL-C <40 mg/dL. The FIELD study was significantly confounded by statin drop-in therapy in both the placebo and fenofibrate groups [41].

The NIH-funded Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial was designed to evaluate whether the addition of fenofibrate to ongoing simvastatin therapy provided incremental risk reduction for diabetic patents [42]. Baseline LDL-C and HDL-C were 100 mg/dL and 39 mg/dL, respectively. Although there was no difference in primary endpoint between treatment groups for the trial as a whole, in a subgroup analysis there was a trend toward benefit (relative risk reduction of 34 %, p = 0.06) in patients with baseline HDL-C levels <34 mg/dL and TG levels >204 mg/dL. This subgroup with low baseline HDL-C levels had the most pronounced therapeutic response, with a 12.9 % rise in HDL-C levels as compared with a 7.3 % rise in other subgroups [42]. This beneficial trend was also seen in post hoc analyses of patients with high baseline TG and low HDL-C levels in multiple other trials, including the Bezafibrate Infarction Prevention (BIP) trial, the FIELD trial, and the Helsinki Heart Study [15, 41, 43].

The HDL-Atherosclerosis Treatment Study (HATS) demonstrated angiographic evidence of regression in coronary stenosis after treatment for 3 years with high-dose niacin (average dose 2.7 g/day) and modest-dose simvastatin (average dose 13 mg/day) [44]. The HATS trial demonstrated that treatment of dyslipidemia with a combination of simvastatin and niacin was associated with significant regression of coronary atherosclerosis and incremental reductions in clinical events (up to a 90 % relative risk reduction) in patients with a mean baseline lipid profile that included an LDL-C of 124 mg/dL, HDL-C of 34 mg/dL, and TG of 160 mg/dL. LDL-C levels were reduced by 42 % and HDL-C levels were increased by 26 %, resulting in an 89 % reduction in cardiovascular death, stroke, and revascularization events in patients treated with niacin plus simvastatin compared to placebo (p = 0.03). The addition of antioxidant therapy mitigated the clinical and angiographic efficacy of combination therapy, as it may have attenuated the ability of statin/niacin therapy to raise HDL-C [44].

The AIM-HIGH trial was a randomized placebo-controlled clinical study in patients with a history of CHD and dyslipidemia. The primary hypothesis tested in this NIH-funded trial was that treatment with high-dose extended-release niacin (ERN) in a daily dose of 1500–2000 mg would reduce the risk of cardiovascular events among patients who had achieved target levels of LDL-C (40–80 mg/dL) with intensive simvastatin +/- ezetimibe therapy, as needed, in either arm [20••]. The trial involved 3,414 patients with stable established CHD who had residually low levels of HDL-C at baseline (less than 40 mg/dL in men; less than 50 mg/dL in women). The AIM-HIGH investigators hypothesized that high-dose ERN plus intensive LDL-C-lowering therapy would be superior to LDL-C-lowering therapy alone in reducing a long-term composite clinical endpoint of CHD death, non-fatal MI, ischemic stroke, hospitalization for ACS, or symptom-driven coronary or cerebral revascularization [20••]. In this event-driven trial, it was projected that 800 adjudicated primary events during a follow-up of 2.5 to 7 years (mean 4.6 years) would provide 85 % power to detect a relative 25 % treatment difference between the ERN and placebo groups [20••]. Follow-up was projected to be a mean of 55 months, but due to a lack of clinical efficacy, the Data Safety Monitoring Board recommended to the NIH that the study be terminated for futility after 36-month follow-up. At entry, 3,196 patients (94 %) were taking a statin, with a mean baseline LDL-C of 71 mg/dL, non-HDL-C of 106 mg/dL, HDL-C of 35 mg/dL, and triglyceride (TG) level of 161 mg/dL; by contrast, only 218 patients (6 %) 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 [20••].

During the abbreviated 3-year follow-up period, compared to placebo, ERN raised mean HDL-C by 25 % (to 42 mg/dL) and lowered TG by 29 % (to 122 mg/dL), while LDL-C further declined 10.8 % from 74 mg/dL to 62 mg/dL. The primary endpoint (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 subjects (16.4 %) as compared to 274 placebo-treated patients (16.2 %) (HR 1.02, 95 % CI, 0.87–1.21 p = 0.80). Despite the impressive improvement in cholesterol profiles, there was no significant reduction in the primary composite endpoint of cardiovascular events over a mean follow-up period of 36 months [20••].

When interpreting the results from AIM-HIGH, one should consider the fact that 94 % of patients entering the trial were chronically treated with statins (75 % of whom had been receiving a statin for 1 year or longer), while 40 % had been on statins for more than 5 years before randomization. The baseline cholesterol profile of patients entering the trial was already at ATP III-recommended targets for “optimal management,” which may have further reduced the rate of incident cardiovascular events during follow-up period. Furthermore, as all of the patients in the study already had CAD or peripheral vascular disease, they were also receiving guideline-directed medical therapy and secondary prevention that included antiplatelet agents such as aspirin or clopidogrel, beta blockers, and inhibitors of the renin-angiotensin system, in addition to intensive statin therapy. This most certainly had an impact on the risk of cardiovascular events in both groups, thereby attenuating the likelihood of detecting a difference between treatment groups. Another important observation to consider is that there was an unexpected 9.8 % on-treatment increase in HDL-C levels in the placebo group as compared with baseline. In order to maintain blinding and mask the identity of treatment to study participants and investigators, each 500 mg placebo tablet contained 50 mg of immediate-release niacin (sufficient to impart a mild cutaneous flush), such that patients receiving 2,000 mg ERN-placebo were actually receiving 200 mg of niacin daily. This may have further reduced the relative benefits of niacin as compared with the high-dose ERN treatment group, as the 3-year on-treatment difference in HDL-C was only 4 mg/dL (42 mg/dL in ERN-treated patients vs. 38 mg/dL in placebo-treated patients) [45].

The much-awaited Second Heart Protection Study Treatment of HDL to Reduce Incidence of Vascular Events (HPS2-THRIVE) is a multicenter randomized placebo-controlled trial of extended-release niacin combined with laropiprant (LRPT), a prostaglandin D2 (PGD2) receptor antagonist to inhibit flushing, which was undertaken in 25,673 patients with pre-existing cardiovascular disease. These results have been presented only in abstract form, while the publication of primary study results appears imminent. Preliminary results presented at the American College of Cardiology Scientific Sessions in 2013 revealed no clinical benefit in the primary composite endpoint of major vascular events, including major coronary event (nonfatal MI or coronary death), stroke (any nonfatal or fatal, including subarachnoid hemorrhage), or revascularization (coronary or non-coronary artery surgery or angioplasty, including amputation) [21••]. The baseline lipid values showed a remarkably stable and exceedingly well-treated population with mean total cholesterol of 128 mg/dL, direct LDL-C of 63 mg/dL, HDL-C of 44 mg/dL, and TG of 125 mg/dL [21••]. 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 the AIM-HIGH trial. 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 = 0.29) [21••].

There were no differences in the components of the primary endpoint or in any of the secondary endpoints as a function of treatment assignment. Similarly, there were no treatment differences among enrolled subjects who were less than 65 years of age, those 65–75 years of age, or those greater than 75 years of age by treatment assignment. There was a borderline interaction (p = 0.06) for the region from which subjects 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) [60]. Furthermore, there were significant side effects of new-onset diabetes and increased bleeding in the treatment group. One of the concerns already raised about HPS2-THRIVE is the large number of patients recruited from China, who may have different metabolic profiles and may respond differently genetically to pharmacologic therapy [45, 46].

The recent large clinical outcomes trials (AIM-HIGH and HPS2-THRIVE) have both failed to show incremental benefit from addition of niacin to statin therapy during 3 to 5 years of follow-up. While both trials showed significant improvement in HDL-C levels and a decrease in TGs, this did not translate into clinically relevant endpoint reduction. Both trials randomized patients with exceptionally low atherogenic lipoprotein burdens in serum at baseline. Previous epidemiological studies have shown increased cardiovascular risks in patients with very low HDL-C levels (less than 30 mg/dL). The baseline HDL-C levels in both the AIM-HIGH and HPS2-THRIVE trials were higher, at 35 mg/dL and 44 mg/dL, respectively. It is conceivable that these trials did not study the large understudied subset of the population that would benefit most. Certainly, in HPS2-THRIVE, baseline HDL-C levels were well within the average but not ideal range for enrolled men and women such that it may have been difficult to ascertain the favorable impact of HDL-C raising in subjects whose HDL-C levels were not low at baseline. In addition, both trials included chronic stable ischemic heart disease patients who had been on chronic treatment at the ATP III target lipid profile and likely already had stable quiescent plaques. Further studies are needed to investigate patients with ACS who have more unstable plaques and frequently present with HDL-C <30 mg/dL, as these subsets were all excluded from both trials. In this context, the results of AIM-HIGH and HPS2-THRIVE should not be extrapolated to populations of CHD patients with ACS or acute MI, who were excluded from study in both trials [45].

Future studies should measure HDL-C particle size and function rather than HDL-C levels. The elevations of HDL-C observed in ILLUMINATE, dal-OUTCOMES, AIM-HIGH, and HPS2-THRIVE were significant but did not correlate with clinical benefit. It would be interesting to review HDL-C function and particle size data from these trials, keeping in mind that it has yet to be determined which types of assays are most appropriate and informative to measure HDL functionality.

An important consideration with regard to the inconsistency between earlier positive epidemiological studies and the recent negative intervention trials is the possibility that HDL-C levels are linked to environmental, genetic, and metabolic factors. Visseren et al. recently analyzed the data from the Second Manifestation of ARTerial disease (SMART) cohort [47], in which the authors examined new vascular events in statin-treated patients during a median follow-up of 5.4 years. Patients not treated with statins had a 5 % reduced risk of vascular events for every 1.8 mg/dL rise in HDL-C level, which correlates with historical data. The intriguing finding in this analysis was that the usual dose of statin therapy increased this risk reduction to 6 %, but in the intensive statin therapy-treated cohort, the relationship between HDL-C and vascular events was not noted. HDL-C levels were not associated with recurrent vascular events, irrespective of LDL-C levels. This finding is inconsistent with the recent post hoc analysis from the COURAGE trial, which found a significant risk reduction (up to 65 %) in death and MI in stable ischemic heart disease patients on optimal medical therapy who had LDL-C levels lower than 70 mg/dL and HDL-C levels in the highest quintile as compared to HDL-C levels in the lowest quintile [26]. One can debate whether this indicates that intensive statin therapy alters HDL particle function or that the anti-inflammatory effects of high-dose statins make HDL particles less important or effective.


There is substantial evidence from human population studies that low levels of HDL-C are associated with increased cardiovascular events. This is especially true in patients with HDL-C levels <30 mg/dL. The hypothesis that HDL-targeted therapies in humans will reduce clinical cardiovascular events has still not been conclusively established, and there is insufficient evidence from clinical trials at this time to recommend HDL-targeted therapy as part of standard secondary prevention. In patients with established CHD who are able to achieve and maintain optimal levels of LDL-C (and non-HDL-C) on statin therapy, there are no data to support incremental clinical benefit with additional lipid-altering agents to raise HDL. By contrast, patients who are unable to achieve their LDL-C (or non-HDL-C) goals on a statin should continue to be considered for combination therapy with fibrates, fish oil, and niacin. The results of published clinical trials to date should not be extended, or generalized, to patient populations (i.e., ACS or MI) not represented by the study populations tested in the trials. Although there are four recent human trials with HDL-targeted agents that did not show a significant reduction in cardiovascular events, all four trials have methodological flaws, and additional studies are needed to better understand the effects of pharmacologic agents on HDL-C levels as well as HDL particle size and function. There is also an urgent need to study higher-risk patient populations and those important patient populations who have not yet been subjected to careful prospective study.


Compliance with Ethics Guidelines

Conflict of Interest

Sayed M. Tariq, Mandeep S. Sidhu, and William E. Boden declare that they have no conflict of interest.

Peter P. Toth is a consultant to Amgen, Atherotech, Kowa, Liposcience, Merck, and Novartis; received payment for development of educational presentations from Amarin, Genzyme, GSK, Kowa, and Merck.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    National Cholesterol Education Program (NCEP) Expert Panel on Detection, 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. Circulation. 2002;106(25):3143–421.Google Scholar
  2. 2.•
    Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013. doi:10.1016/j.jacc.2013.11.002. The controversial new 2013 AHA/ACC cholesterol treatment guidelines released in November of 2013 have now eliminated LDL-C and non-HDL-C risk-stratified treatment thresholds and targets. These guidelines now define patient eligibility for treatment of dyslipidemia with a statin-based regimen solely on the projected risk for an atherosclerotic disease-related cardiovascular event.PubMedCentralGoogle Scholar
  3. 3.
    Ridker PM, Cook NR. Statins: new American guidelines for prevention of cardiovascular disease. Lancet. 2013;382(9906):1762–5.PubMedCrossRefGoogle Scholar
  4. 4.
    Kannel WB, Dawber TR, Friedman GD, et al. Risk factors in coronary heart disease. An evaluation of several serum lipids as predictors of coronary heart disease; The Framingham Study. Ann Intern Med. 1964;61:888–99.PubMedCrossRefGoogle Scholar
  5. 5.
    Castelli WP. Cholesterol and lipids in the risk of coronary artery disease–the Framingham Heart Study. Can J Cardiol. 1988;4(Suppl A):5A–10A.PubMedGoogle Scholar
  6. 6.
    The Coronary Drug Project Research Group. JAMA. 1972;221(8):918.CrossRefGoogle Scholar
  7. 7.
    The Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. JAMA. 1975;231(4):360–81.CrossRefGoogle Scholar
  8. 8.
    Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in coronary drug project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986;8(6):1245–55.PubMedCrossRefGoogle Scholar
  9. 9.
    Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto Jr AM, Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195–207.PubMedCrossRefGoogle Scholar
  10. 10.
    LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425–35.PubMedCrossRefGoogle Scholar
  11. 11.
    Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–9.Google Scholar
  12. 12.
    Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001–9.PubMedCrossRefGoogle Scholar
  13. 13.
    The Long-Term Intervention with Pravastatin in Ischemic 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. N Engl J Med. 1998;339:1349–57.CrossRefGoogle Scholar
  14. 14.
    Jafri H, Alsheikh-Ali AA, Karas RH. Meta-analysis: statin therapy does not alter the association between low levels of high-density lipoprotein cholesterol and increased cardiovascular risk. Ann Intern Med. 2010;153(12):800–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Bezafibrate Infarction Prevention (BIP) study. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study. Circulation. 2000;102(1):21–7.CrossRefGoogle Scholar
  16. 16.
    Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97(18):1837–47.PubMedCrossRefGoogle Scholar
  17. 17.
    Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med. 1977;62(5):707–14.PubMedCrossRefGoogle Scholar
  18. 18.
    Rubins HB, Robins SJ, Collins D, et al. Distribution of lipids in 8,500 men with coronary artery disease. Department of Veterans Affairs HDL Intervention Trial Study Group. Am J Cardiol. 1995;75(17):1196–201.PubMedCrossRefGoogle Scholar
  19. 19.
    Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. For the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med. 1999;341(6):410–8.PubMedCrossRefGoogle Scholar
  20. 20.••
    Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365(24):2255–67. The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH) was the first prospective randomized, placebo-controlled clinical trial in patients with a history of CHD and atherogenic dyslipidemia (low HDL-C and high triglycerides) with a hypothesis 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.PubMedCrossRefGoogle Scholar
  21. 21.••
    Armitage J et al. HPS2-THRIVE: randomized placebo controlled trial of ER Niacin and laropiprant in 25,673 patients with pre-existing cardiovascular disease. Eur Heart J. 2013;34(17):1279–91. The Second Heart Protection Study (HPS2-THRIVE) trial was the largest international prospective double-blind secondary prevention trial with niacin to date, undertaken in 25,673 participants from the UK, Scandinavia, and China who were randomized either to extended-release niacin (ERN) combined with laropiprant (LRPT) 2 grams daily, a prostaglandin inhibitor, or matching placebo on top of a background of intensive LDL-C reduction therapy with simvastatin 40 mg daily (with or without ezetimibe 10 mg/daily).PubMedCentralCrossRefGoogle Scholar
  22. 22.
    Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367(22):2089–99.PubMedCrossRefGoogle Scholar
  23. 23.
    Wolfram RM, Brewer HB, Xue Z, et al. Impact of low high-density lipoproteins on in-hospital events and one-year clinical outcomes in patients with non-ST-elevation myocardial infarction acute coronary syndrome treated with drug-eluting stent implantation. Am J Cardiol. 2006;98(6):711–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Acharjee S, Roe MT, Amsterdam EA, et al. Relation of admission high-density lipoprotein cholesterol level and in-hospital mortality in patients with acute non-ST segment elevation myocardial infarction (from the National Cardiovascular Data Registry). Am J Cardiol. 2013;112(8):1057–62.PubMedCrossRefGoogle Scholar
  25. 25.
    Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007;356(15):1503–16.PubMedCrossRefGoogle Scholar
  26. 26.
    Acharjee S, Boden WE, Hartigan PM, et al. Low levels of high-density lipoprotein cholesterol and increased risk of cardiovascular events in stable ischemic heart disease patients: a post-hoc analysis from the COURAGE Trial. J Am Coll Cardiol. 2013;62:1826–33. doi:10.1016/j.jacc.2013.07.051.PubMedCrossRefGoogle Scholar
  27. 27.
    Fisher EA, Feig JE, Hewing B, Hazen SL, Smith JD. High-density lipoprotein function, dysfunction, and reverse cholesterol transport. Arterioscler Thromb Vasc Biol. 2012;32(12):2813–20.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Cuchel M, Rader DJ. Macrophage reverse cholesterol transport: key to the regression of atherosclerosis? Circulation. 2006;113:2548–55.PubMedCrossRefGoogle Scholar
  29. 29.
    Brewer Jr HB, Remaley AT, Neufeld EB, Basso F, Joyce C. Regulation of plasma high-density lipoprotein levels by the ABCA1 transporter and the emerging role of high-density lipoprotein in the treatment of cardiovascular disease. Arterioscler Thromb Vasc Biol. 2004;24:1755–60.PubMedCrossRefGoogle Scholar
  30. 30.
    Rigotti A, Miettinen HE, Krieger M. The role of the high-density lipoprotein receptor SR-BI in the lipid metabolism of endocrine and other tissues. Endocr Rev. 2003;24:357–87.PubMedCrossRefGoogle Scholar
  31. 31.
    Khera AV, Cuchel M, de la Llera-Moya M, Rodrigues A, Burke MF, Jafri K, et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med. 2011;364:127–35.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Bonow, Mann, Zipes, Libby. Braunwald’s heart disease: A textbook of cardiovascular medicine, vol. 1. 9th ed. Philadelphia: Saunders Elsevier; 2012. p. 975–82.Google Scholar
  33. 33.
    Toth PP. Model of reverse cholesterol transport torcetrapib and atherosclerosis: what happened and where do we go from here? Futur Lipidol. 2007;2(3):277–84.CrossRefGoogle Scholar
  34. 34.
    Hovingh GK, de Groot E, van der Steeg W, et al. Inherited disorders of HDL metabolism and atherosclerosis. Curr Opin Lipidol. 2005;16(2):139–45.PubMedCrossRefGoogle Scholar
  35. 35.
    Sirtori CR, Calabresi L, Franceschini G, et al. Cardiovascular status of carriers of the apolipoprotein A-I (Milano) mutant: the Limone sul Garda study. Circulation. 2001;103(15):1949–54.PubMedCrossRefGoogle Scholar
  36. 36.
    Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357(21):2109–22.PubMedCrossRefGoogle Scholar
  37. 37.
    Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (REVEAL). ClinicalTrials.gov Identifier: NCT01252953.Google Scholar
  38. 38.
    A Study of Evacetrapib in High-Risk Vascular Disease (ACCELERATE). ClinicalTrials.gov Identifier:NCT01687998.Google Scholar
  39. 39.
    Wu BJ, Yan L, Charlton F, et al. Evidence that Niacin Inhibits acute vascular inflammation and improves endothelial dysfunction independent of changes in plasma lipids. Arterioscler Thromb Vasc Biol. 2010;30(5):968–75.PubMedCrossRefGoogle Scholar
  40. 40.
    Kuvin JT, Patel AR, Sidhu MS, et al. Relationship between high density lipoprotein (HDL) cholesterol and peripheral vasomotor function. Am J Cardiol. 2003;92(3):275–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366(9500):1849–61.PubMedCrossRefGoogle Scholar
  42. 42.
    The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563–74.PubMedCentralCrossRefGoogle Scholar
  43. 43.
    Manninen V, Elo MO, Frick MH, et al. Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study. JAMA. 1988;260(5):641–51.PubMedCrossRefGoogle Scholar
  44. 44.
    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(22):1583–92.PubMedCrossRefGoogle Scholar
  45. 45.
    Boden WE, Sidhu MS, Toth PP. The Therapeutic Role of Niacin in Dyslipidemia Management. J Cardiovasc Pharmacol Ther. 2014;19(2):141–58.Google Scholar
  46. 46.
    Landmesser U. The difficult search for a ‘partner’ of statins in lipid-targeted prevention of vascular events: the re-emergence and fall of niacin. Eur Heart J. 2013;34(17):1254–7. doi:10.1093/eurheartj/eht055.PubMedCrossRefGoogle Scholar
  47. 47.
    van de Woestijne AP, van der Graaf Y, Liem AH, Cramer MJM, Westerink J, Visseren FLJ, et al. Low high-density lipoprotein cholesterol is not a risk factor for recurrent vascular events in patients with vascular disease on intensive lipid-lowering medication. J Am Coll Cardiol. 2013;62(20):1834–41. doi:10.1016/j.jacc.2013.04.101.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York (outside the USA) 2014

Authors and Affiliations

  • Sayed M. Tariq
    • 1
  • Mandeep S. Sidhu
    • 2
  • Peter P. Toth
    • 3
  • William E. Boden
    • 2
  1. 1.Department of Medicine, Albany Medical CenterAlbany Medical CollegeAlbanyUSA
  2. 2.Department of Medicine, Albany Stratton VA Medical Center and Albany Medical CenterAlbany Medical CollegeAlbanyUSA
  3. 3.Department of Family and Community MedicineUniversity of Illinois School of Medicine, and CGH Medical CenterSterlingUSA

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