Although the current cornerstone of pharmacologic atherosclerotic cardiovascular disease (ASCVD) prevention is lifestyle intervention and the use of drug therapy [particularly 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors or statins] to reduce low density lipoprotein cholesterol (LDL-C) levels, there still remains additional residual risk of cardiovascular events and thus a need for additional therapies to further lower cardiovascular risk [1▪,2]. High density lipoprotein cholesterol (HDL-C) concentrations are strongly and inversely associated with cardiovascular risk; epidemiological studies over the past several decades have shown the inverse association between HDL-C levels and ASCVD risk [3–5]. HDL-C comes in different sizes, and while there has been disagreement over which HDL subfractions have the strongest association with cardiovascular risk, recent studies suggest that the smaller HDL3 may have a stronger inverse relationship with cardiovascular risk than total HDL-C [6▪,7]. Thus, HDL-C metabolism has been the focus of significant efforts in atherosclerosis research. The ‘HDL hypothesis’ holds that HDL-C is causally related to ASCVD, and that intervention to increase plasma levels of HDL-C will reduce risk of ASCVD. As a result, there has been tremendous interest in the biology of HDL and in novel therapeutic approaches to raising levels of HDL-C.
Evidence from animal studies supported the HDL hypothesis, with findings showing that HDL-based interventions that raised HDL-C levels resulted in inhibition or regression of atherosclerosis. Badimon et al.  showed that infusing HDL into rabbits led to regression of atherosclerosis. Rubin et al.  demonstrated that mice overexpressing apolipoprotein A-I (apoA-I) were relatively protected from atherosclerosis. Viral overexpression of apoA-I in mice led to regression of preexisting atherosclerotic lesions . These and many other studies were consistent with the concept that raising HDL-C had favorable effects on atherosclerosis and supported the HDL hypothesis.
Advances in our understanding of HDL-C metabolism, structure, and biology also supported the HDL hypothesis . HDL-C is a diverse and highly complex class of lipoprotein with multiple forms, components, and functions. HDL-C is produced by the liver and intestine through the secretion of a lipid-poor apoA-I, which then interacts with the ABCA1 transporter on hepatocytes and enterocytes to recruit lipid (phospholipids and cholesterol) to produce the nascent prebeta HDL particle. This particle circulates and is then enriched with additional lipids via cells and other lipoproteins. The free cholesterol undergoes esterification by the enzyme lecithin-cholesterol acyl transferase (LCAT) to form cholesteryl ester, which forms the core of the mature HDL-C particle. HDL-C particles interact with ATP binding cassette transporters (ABCA1 and ABCG1) on cells including macrophages to promote cholesterol efflux. Cholesterol ester transfer protein (CETP) transfers triglycerides from very-low density lipoprotein (VLDL) and LDL to HDL-C in exchange for cholesteryl esters, thus depleting HDL-C of cholesteryl ester and enriching it in triglycerides (TG). HDL-C is modified by lipases such as hepatic lipase and endothelial lipase, which hydrolyze TG and phospholipids in HDL and change its size and composition. HDL cholesteryl ester can be selectively taken up by liver cells expressing the scavenger receptor B-1 (SR-BI). Thus, multiple components of the ‘reverse cholesterol transport’ (RCT) pathway, from cholesterol efflux to cholesterol esterification to transport to the liver, were seen to be mediated by HDL, consistent with an atheroprotective effect. As a result, multiple components of the HDL metabolism cycle have been candidates for therapeutic development designed to increase HDL-C levels in the hope of reducing atherosclerosis and cardiovascular risk.
DOUBTS ABOUT THE HIGH DENSITY LIPOPROTEIN HYPOTHESIS
Within the last several years, major doubts have arisen regarding the conventional HDL hypothesis. The evidence has been from two major sources: randomized clinical trials of HDL-C-raising drugs and genetic studies of gene variants that influence HDL-C levels.
Niacin has long been the major HDL-C-raising drug available in clinical practice. A clinical trial of immediate-release niacin in the prestatin era, in which the major rationale for the study was cholesterol-lowering, showed cardiovascular benefit [12,13]. However, two clinical trials in the last several years in which extended-release niacin was added to a statin failed to show clinical benefit. The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) trial included 3414 patients on high-intensity statin therapy (baseline median LDL 71 mg/dl) randomized to receive either extended-release niacin or placebo . The niacin-treated group had a modest but significant increase in HDL-C, but the trial was terminated early for futility, showing no benefit with regard to the primary composite endpoint of death from coronary heart disease (CHD), nonfatal myocardial infarction (MI), ischemic stroke, hospitalization for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization. The Heart Protection Study 2 - Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) study included 25 673 patients with vascular disease on statin therapy randomized to receive either extended-release niacin (along with a second drug laropiprant intended to reduce the flushing side-effect of niacin) or placebo . At a median follow-up of 3.9 years, niacin-treated participants had a modest but significant 6 mg/dl increase in plasma HDL-C levels. However, there was no significant difference in incidence of major vascular events. Thus, two large trials with the major HDL-raising drug available failed to show clinical benefit. For many, this was seen as compelling evidence that raising HDL-C levels (at least with niacin) did not confer additional benefit to statin monotherapy.
CETP inhibitors were developed specifically as HDL-raising drugs, stimulated by the observation that genetic CETP deficiency causes markedly elevated HDL-C levels. The failure of two different CETP inhibitors has also contributed to doubts about the HDL hypothesis. The first CETP inhibitor to enter phase 3 development, torcetrapib, raised HDL-C levels by 72% (while reducing LDL-C levels by 25%), but not only failed to reduce cardiovascular risk but actually increased cardiovascular and total mortality, leading to early termination of the clinical outcomes trial . Further studies showed that torcetrapib had side-effects in the form of elevated blood pressure, increased aldosterone secretion, and endothelial dysfunction that was not related to its HDL-C-raising functions . More recently, the CETP inhibitor dalcetrapib failed to reduce cardiovascular events in a phase 3 ASCVD outcomes trial . The Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome (Dal-OUTCOMES) study was a phase 3 placebo-controlled randomized controlled trial in 15 871 patients with a history of acute coronary syndrome on statin therapy. This study was stopped early after no significant improvement in overall or ASCVD-related mortality and related events was found. The failure of these two CETP inhibitors, which raised HDL-C even more than niacin, contributed substantially to skepticism about the HDL hypothesis.
Recent meta-analyses have examined composite cardiovascular outcome and mortality in patients treated with HDL-C-modulating medications. A 2014 meta-analysis pooled clinical trials of niacin, fibrates, and CETP inhibitors involving a total of 117 411 patients and found no reduction in all-cause mortality, CHD, MI, or stroke [19▪▪]. A 2015 meta-analysis of trials of niacin or CETP inhibitors involving 69 515 patients did not find a decrease in overall cardiovascular mortality .
In addition to disappointing randomized clinical trials of HDL-raising drugs, human genetics studies have failed to support the conventional HDL-C hypothesis. Genetic variants are randomly inherited and can be viewed as a natural form of randomized clinical trial, a process known as ‘Mendelian randomization’. There has been substantial interest in the question of whether genetic variants that raise HDL-C reduce ASCVD risk or, conversely, those that reduce HDL-C increase ASCVD risk. A landmark study by Voight et al.  systematically studied the effects of genetic variants associated with HDL-C across the genome and found scant evidence that they were associated with risk of CHD. One variant in particular, the Asn396Ser variant in endothelial lipase (gene LIPG) that had been previously shown to significantly increase HDL-C levels, was found to have no association with CHD . This not only cast doubt upon the specific approach of inhibiting endothelial lipase for reducing ASCVD risk, but also cast additional doubt upon the HDL hypothesis.
Despite the incontrovertible epidemiologic evidence of the inverse association of HDL-C with ASCVD risk, the available data in humans were not consistent with this being a causal relationship and therefore do not support the conventional HDL hypothesis. However, recent studies have focused on the function of HDL and suggest a possible approach to reconciling the human and animal data and pointing to a potential path forward for targeting HDL therapeutically.
FROM HIGH DENSITY LIPOPROTEIN MASS TO HIGH DENSITY LIPOPROTEIN FUNCTION
Recent evidence has suggested that measures of HDL function, rather than simply HDL mass, may be more informative with regard to ASCVD risk. It has long been appreciated that HDL can promote efflux of cholesterol from cells, including macrophages, the key lipid-laden cell type in the atherosclerotic plaque. Indeed, at least two specific transporters, ABCA1 and ABCG1, have the capacity to mediate cholesterol efflux from macrophages to HDL, with ABCA1 using lipid-poor apoA-I as an acceptor, and ABCG1 using a mature HDL particle . Pioneering studies by Rothblat established the concept of HDL ‘cholesterol efflux capacity’, namely the ability of HDL from a given individual to promote cholesterol efflux from cells . Adaptation of this assay to a higher-throughput approach allowed larger studies of the relationship between HDL cholesterol efflux capacity (CEC) and ASCVD. HDL CEC was shown to be strongly and inversely associated with both prevalent carotid intimal medial thickness (IMT) and angiographic coronary artery disease (CAD) even after adjustment for HDL-C or apoA-I levels . Application of this concept using a newer assay that is more selective for ABCA1 to samples from the population-based Dallas Heart Study found that HDL CEC was significantly inversely associated with incident cardiovascular events after adjustment for HDL-C levels [26▪▪]. Another recent analysis of a nested case–control cohort in the prospective European Prospective Investigation of Cancer-Norfolk (EPIC-Norfolk) study involving 1745 incident CHD cases and 1749 disease-free controls found a highly significant inverse association of HDL CEC with incident CHD after adjustment for HDL-C levels [27▪▪]. Thus, the data indicate that HDL CEC is predictive of prevalent and incident CHD independent of HDL-C. Whether measurement of HDL CEC will allow clinicians to risk stratify patients more accurately, leading to earlier and more aggressive interventions in vulnerable populations, remains to be determined. However, this concept of HDL function may help us to understand better why the trials that showed no benefit of HDL-C-raising therapies may have failed, for example if they simply raise levels of HDL-C without improving its ability to promote cholesterol efflux. Indeed, it is insights such as these that have continued to spur important research to target HDL for therapeutic benefit. However, the observation that a measure of classic HDL function (HDL CEC) has an even stronger relationship to CHD than measures of HDL mass (such as HDL-C) opens the door to the possibility that new therapies targeting HDL function, for example enhancing cholesterol efflux, may be a successful approach.
HIGH DENSITY LIPOPROTEIN-TARGETED THERAPIES THAT MAY ENHANCE HIGH DENSITY LIPOPROTEIN CHOLESTEROL FUNCTION
Cholesterol ester transfer protein inhibitors
Despite the failure of two CETP inhibitors in phase 3, there are at least two CETP inhibitors that are still in active late-stage clinical development. Analyses of previous trials have led to some hope for the class. For example, an analysis of a torcetrapib coronary intravascular ultrasound (IVUS) trial revealed that the higher the HDL-C increased, the more likely the coronary plaque was to stabilize or regress . An analysis of HDL CEC showed that a higher dose of torcetrapib (one not used in the phase 3 development) was much more effective in promoting cholesterol efflux than a lower dose (which was used in the phase 3 ASCVD outcomes trial) . Interestingly, the dalcetrapib in Patients Hospitalized For An Acute Coronary Syndrome (Dal-ACUTE) analysis showed that while there was a 30% increase in HDL-C in the dalcetrapib group, there was a minimal increase in cholesterol efflux capacity at best .
Anacetrapib is a potent CETP inhibitor that is still in phase 3 clinical development. Interestingly, anacetrapib has been shown to increase HDL cholesterol efflux from macrophages . The Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib (DEFINE) trial randomized patients with or at high risk for CHD to anacetrapib or placebo. At 76 weeks, there was a 140% increase in HDL-C and 36% decrease in LDL-C levels in the anacetrapib group. The study was not powered for ASCVD events, but it did suggest that this agent was safe and well tolerated . These encouraging findings led to a current large phase 3 study [Randomized Evaluation of the Effects of Anacetrapib Through Lipid-modification (REVEAL)] that is enrolling 30 000 patients with known ASCVD for a randomized placebo-controlled trial, with results due in 2017 .
Another CETP inhibitor, evacetrapib, is also in phase 3 clinical development. In a phase 2 trial of 398 patients, evacetrapib produced dose-dependent increases in HDL-C and decreases in LDL-C with no significant adverse effects . Evacetrapib has been shown to significantly increase HDL CEC both as monotherapy and on top of statin therapy . The current phase 3 trial [The Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High-Risk for Vascular Outcomes (ACCELERATE)] is recruiting 11 000 patients at high risk for ASCVD who will be randomized to placebo or evacetrapib in addition to standard therapy including statins . These two trials, ACCELERATE and REVEAL, are greatly anticipated for their likely important final verdict on the use of CETP inhibitors for ASCVD and overall mortality benefit. As both drugs have been shown to promote cholesterol efflux capacity at the doses at which they are being studied in the phase 3 ASCVD outcomes trials, there is the possibility that they may produce different results than the first two CETP inhibitors.
Reconstituted apolipoprotein A-I/high density lipoprotein
One approach that has been of interest for decades is the concept of infusion of reconstituted apoA-I-containing HDL particles. In preclinical studies, most of the successful interventions involved increasing apoA-I through infusion or genetic overexpression. Theoretically, infusing apoA-I would lead to an increased reserve of lipid-deficient particles that would be able to extract more lipids from atherosclerotic plaques. Additional theoretical support for increasing apoA-I levels for cardiovascular benefit comes from a study of a family from Brazil with the rare familial deficiency of apoA-I that yielded additional knock-out information on the physiologic significance of this molecule. Heterozygotes and especially homozygotes with this deficiency were seen to have significant or complete lack of apoA-I, with multiple alterations in lipid composition of HDL as well as decreased cholesterol efflux . Not only does apoA-I overexpression regress atherosclerosis , but also it has been shown to accelerate macrophage RCT .
Nissen et al.  performed a small study that infused reconstituted apoA-I (the naturally occurring Milano variant) in patients with CHD. Atheroma volume by intravascular ultrasound was reduced; however, no significant change was seen in the study group compared with placebo. Similarly, infusion of reconstituted apoA-I (wild-type isolated from plasma) particles showed improvement in plaque characteristics; however, comparison with placebo failed to show a significant improvement . A larger randomized double-blinded placebo-controlled study called Can HDL Infusions Significantly Quicken Atherosclerosis Regression (CHI-SQUARE) infused CER-001 in patients after they suffered an acute coronary syndrome. The study showed suggestion of regression in plaque volume compared with baseline, but the apoA-I group did not have significant decrease when compared with the placebo group . In a study of seven patients with familial hypoalphalipoproteinemia (FHA), CER-001 infusion increased apoA-I and HDL-C levels, as well as RCT, while simultaneously decreasing carotid mean vessel wall area and inflammation . A more recent study investigated a new reconstituted formulation of apoA-I (CSL112) in a group of healthy volunteers. Results showed significant increases in apoA-I, HDL-C, and ABCA1-dependent efflux, all of which are thought to be a part of the atheroprotective pathway in HDL metabolism . This approach is conceptually very attractive, and at least three different reconstituted apoA-I/HDL infusion approaches are in active clinical development.
Apolipoprotein A-I induction
In keeping with the premise that the lipid-poor apoA-I component of nascent HDL-C may be effective in increasing RCT, the possibility of inducing apoA-I gene transcription leading to atheroprotection is interesting. The apoA-I transcriptional inducer RVX-208 was studied in the ApoA1 Synthesis Stimulation Evaluation in Patients Requiring Treatment for Coronary Artery Disease (ASSERT) trial . Although there were modest but significant increases in HDL-C compared with placebo, apoA-I levels were not significantly increased by RVX-208 treatment. In addition, a reversible transaminase elevation was also seen in the treatment group, raising safety concerns. A phase 2b trial studied 172 patients on statin therapy with low HDL-C levels who were given RVX-208 in comparison with placebo. Early results indicate that patients receiving the treatment achieved all prespecified endpoints with high statistical significance compared with the placebo group, an encouraging finding for future studies . Another phase 2 trial [ApoA1 Synthesis Stimulation and Intravascular Ultrasound for Coronary Atheroma Regression Evaluation (ASSURE), ClinTrials.gov identifier NCT01067820] evaluated regression of coronary atheroma by IVUS in 310 patients with CAD who were on statins and then treated with RVX-208 for 26 weeks . Recently revealed results showed that while HDL-C and apoA-I levels were modestly increased, the primary endpoint of 0.6% atheroma regression was not achieved .
Apolipoprotein A-I mimetics
Another strategy to capitalize on the potential benefits of apoA-I is to utilize peptides that can mimic apoA-I function. apoA-I mimetic peptides share common structure with apoA-I but are much shorter and therefore easier to produce, formulate, and administer . Several apoA-I mimetic peptides with lipid binding and functional properties similar to apoA-I have been reported and studied in preclinical models . In addition to the potential for inducing cholesterol efflux and mitigating cardiovascular risk, apoA-I mimetics have been shown to inhibit endotoxin activity, suppress neutrophil chemotaxis, and inhibit leukocyte and neutrophil activation in patients with ARDS [51,52]. The apoA-I mimetic D-4F was also shown to affect nitric oxide signaling in a mouse model of hyperglycemia and MI . apoA-I mimetic peptides are generally administered parenterally, but there has been interest in potential oral administration .
However, initial enthusiasm has been tempered by a potential narrow therapeutic window for apoA-I mimetic peptide . In addition, production of apoA-I mimetic peptides is not trivial. Interestingly, the novel apoA-I mimetic peptide 6F has amphipathic helical structure achieved without chemical modification. This peptide has been expressed in genetically engineered tomatoes and fed to LDL receptor-null mice. 6F was found to reduce the percentage of the aorta with atherosclerotic lesions, decrease total cholesterol, and increase HDL in this mouse model . Thus, there remains continued interest in this approach.
Lecithin-cholesterol acyl transferase infusion or activation
Lecithin-cholesterol acyl transferase (LCAT) is an HDL-associated enzyme that has a critical role in lipoprotein metabolism. LCAT esterifies free cholesterol to cholesteryl ester and therefore results in maturation of cholesterol-rich mature HDL particles. Through its action, LCAT is thought to stimulate RCT. Several studies have sought to elucidate the relationship between LCAT and ASCVD, which remains uncertain. Although LCAT deficiency does result in very low HDL-C levels and progressive kidney disease, it remains uncertain whether LCAT activity correlates with ASCVD risk.
Overexpression of LCAT in preclinical models increases HDL-C levels and in rabbits also reduces atherosclerosis. A small molecule activator of LCAT resulted in increased HDL-C and decreased triglycerides in mice and hamsters . Recombinant LCAT improves HDL-C levels in LCAT-deficient mice , and gene-transduced adipocytes were capable of raising HDL-C levels in LCAT deficiency . LCAT replacement therapy is a logical approach to reducing the risk of chronic kidney disease in LCAT deficiency. Whether infusing LCAT protein or increasing endogenous LCAT expression or activity will reduce cardiovascular risk remains an open question.
Liver X receptor agonists
Liver X receptors (LXRs) in macrophages function to coordinate gene expression in response to fluctuating sterol levels. When LXRs are activated by endogenous oxysterols reflecting cholesterol overload, they upregulate the cholesterol efflux pathways ABCA1 and ABCG1, thus promoting cholesterol efflux to HDL and apoA-I acceptors. Given the mechanistic evidence of LXR's effect on cholesterol flux, LXR agonists have been developed in the hope of reducing risk of atherosclerosis. A nonsteroid LXR agonist, GW3965, was shown to reduce atherosclerotic lesion area by approximately 50% in LDL receptor (LDLR) knockout mice . Similar findings were reported with a different LXR agonist, T-0901317, in a similar LDLR knockout murine model . However, despite these initially promising results, nonselective LXR agonists were found to promote hepatic lipogenesis and increase hepatic and plasma triglycerides, tempering initial enthusiasm for utilizing this approach to mitigate atherosclerotic risk . It was hypothesized that a more selective LXR agonist could capitalize on the antiatherogenic properties of the LXR pathway with decreased risk of hypertriglyceridemia and hepatic steatosis. Recently, the use of a PLGA-b-PEG based nanoparticle to encapsulate and deliver GW3965 was found to produce a similar reduction in atherosclerotic plaque but with a reduced effect on hepatic LXR. Total cholesterol and triglycerides were unaffected . These findings are enticing, but further investigation is warranted.
The inverse relationship of HDL-C levels to ASCVD risk is a robust one seen in numerous large studies. However, to date, no intervention specifically targeting HDL-C elevation has yielded benefit in ASCVD or overall mortality. This has cast a shadow of doubt over the HDL hypothesis and the entire field of HDL-based therapeutics. The development of the HDL flux hypothesis has renewed interest in HDL-C by focusing on the multiple unique functions of the HDL particle. Numerous new interventions that manipulate the various functions of HDL-C, particularly the cholesterol efflux pathways, hold some promise of reducing risk of ASCVD.
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Conflicts of interest
There are no conflicts of interest.
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