Cardiovascular disease (CVD) remains the number. High-Density Lipoprotein Targeted Therapies: Hope or Disappointment? HDL-targeted therapies

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1 High-Density Lipoprotein Targeted Therapies: Hope or Disappointment? Michael B. Rocco, MD Abstract Objective: To discuss therapies that have been used to target high-density lipoprotein cholesterol (HDL-C), studies that have examined their effects, and implications for practice. Methods: Review of the literature. Results: Observational studies and monotherapy studies with fibrates and niacin suggest a reduction in cardiovascular disease (CVD) events with interventions that modify HDL-C, particularly in patients with metabolic syndrome. Meta-analyses and trials utilizing surrogate markers of CVD risk further support benefits when these medications are added to statin therapy. However, larger controlled trials have not demonstrated reduction in CVD adverse events when therapies to modulate HDL-C such as fibrates, niacin, or investigational cholesteryl ester transfer protein inhibitors have been added to well-treated individuals on statin therapy. Problems with study design, relatively small HDL-C increases with current therapies, and the selected well-treated populations tested limit applying these results to all patients. Conclusion: Statin therapy remains the primary treatment choice to reduce CVD events and although the hunt for HDL-modulating therapies still goes on, there should be restraint in uniformly raising HDL-C with current therapies. In selected populations inadequately treated to recommend low-density lipoprotein cholesterol or non-hdl-c goals, addition of these therapies may offer further benefit. Cardiovascular disease (CVD) remains the number one cause of mortality in the United States and is quickly becoming the leading cause of morbidity and mortality in the world. The World Health Organization estimates that dyslipidemia accounts for one-third of the worldwide burden of ischemic heart disease and that inadequate control of dyslipidemia is responsible for 4 million yearly deaths worldwide and 350,000 in the United States. Management of dyslipidemia, particularly with statin therapy in individuals with moderate to high cardiovascular risk, has been shown to reduce cardiovascular adverse events in many placebo-controlled trials [1 6]. Recent meta-analyses confirm benefit in moderate- to high-risk individuals as well as in lower-risk individuals when treated with statins [7 9]. The Cholesterol Treatment Trialists (CTT) collaborators demonstrated a 20% to 25% reduction in cardiovascular events for each mmol/l (~40 mg/dl) reduction in low-density lipoprotein cholesterol (LDL-C). In addition, more aggressive LDL-C lowering, particularly with higher doses of or more potent statins, has been shown to offer incremental benefit and risk reduction [10 14]. Based on these observations, therapy has been primarily directed toward reducing LDL-C and preferably with statins. Consequently, most guidelines for managing dyslipidemias including NCEP ATP III [15,16], AHA/ ACC secondary prevention guidelines [17], European Society of Cardiology [18], the Canadian Cardiovascular Society [19] and the American Diabetes Association [20,21] recommend reducing LDL-C levels to at least < 100 mg/dl and preferably to < 70 mg/dl in highrisk groups as the primary goal of therapy. However, as we reach the maximum reductions in LDL-C achievable with current therapies, we may be approaching the limits of benefit when LDL-C management is the only target. Even on high-dose statins, risk is not eliminated. In the treatment arms of statin placebo-controlled studies and even when including those in which very low LDL-C levels are achieved, a significant residual CVD risk persists (Figure 1). In addition, data from National Health and Nutrition Examination Survey (NHANES) reports that of the 48% of U.S. adults with dyslipidemia, approximately a third have elevations in triglycerides and/or low high-density lipoprotein cholesterol (HDL-C) [22]. From the Cleveland Clinic, Cleveland, OH. 364 JCOM August 2013 Vol. 20, No. 8

2 Clinical Review A B Figure 1. Residual CVD risk in patients treated in statin trials. A. Placebo comparison. B. High-dose vs. standard-dose comparison. With the growing prevalence of obesity, diabetes, inactivity, and metabolic syndrome, more individuals are presenting with a combined dyslipidemia characterized by only moderate elevation of LDL-C but increased numbers of small dense LDL and other atherogenic apolipoprotein B (apo B) particles, elevated triglycerides, and low HDL-C. Particularly in these groups it is reasonable to hypothesize that therapies beyond LDL-C lowering may be beneficial. For this reason treatment guidelines have for years suggested that non-hdl-c should be a secondary target for therapy after achieving LDL-C goals. A number of reasons exist to consider looking beyond LDL-C lowering to further reduce cardiovascular adverse events. Cardiovascular events while reduced still occur in individuals with low LDL-C and even in groups after LDL lowering with potent statins When diabetics (a high-risk group often characterized by a mixed dyslipidemia) are treated with statins in clinical trials, CVD event rates, while reduced, remain higher than CVD event rates in patients without diabetes on placebo Vol. 20, No. 8 August 2013 JCOM 365

3 5-yr risk of major CV event in patients with LDL < 70 mg/dl, % Q1 < 37 Q2 37 to < 42 Q3 42 to < 47 HDL Quintiles Hazard Ratio vs. Q1 Q2: 0.85 ( ) Q3: 0.57 ( ) Q4: 0.55 ( ) Q5: 0.61 ( ) Q4 47 to < 55 Q5 > 55 Figure 2. Impact of low HDL-C even with aggressive treatment with statins, TNT Study. Epidemiologic and observational studies demonstrate an association of other atherogenic particles, including low or abnormally functioning HDL, VLDL remnants, elevated triglycerides and small dense LDL particles, with cardiovascular risk [23,24] Measures other than LDL-C, including non-hdl- C, apo B, LDL particle number and apo B/apolipoprotein A1 (apo A1) ratio, are better predictors of risk than LDL-C alone, particularly when on therapy [25 28] In coronary IVUS (intravascular ultrasound) studies, LDL-C lowering to < 70 to 80 mg/dl has been shown to be associated with plaque regression, but the 20% of patients in this group that continue to have progression often have associated diabetes mellitus, and less increase in HDL or decrease in apo B on therapy [29] IVUS studies suggest that the greatest degree of plaque regression is seen in individuals achieving the lowest LDL-C and the greatest increase in HDL-C [30] This article will discuss therapies that have been used to target HDL-C, available clinical trial evidence, observational research, and implications for practice. How important Is HDL Cholesterol? The large majority of observational studies support the relationship between HDL-C and CVD outcomes. In general, for every 1 mg/dl increase in HDL-C there is a 2% to 3% decrease in CVD risk. Decades ago, the Framingham Heart Study recognized this inverse relationship between HDL-C and adverse CVD events and showed that the lower the level of HDL-C, the greater the risk of a coronary event, regardless of LDL-C level [24]. In fact, a person with a desirable LDL-C of 100 mg/dl but a low HDL-C of 25 mg/dl has the same risk for a cardiac event as a person with an LDL-C of 220 mg/dl and an HDL-C of 45 mg/dl. Further strengthening the link between HDL-C and poor CVD outcomes is the observation that patients presenting with a new diagnosis of CHD have higher triglycerides and lower HDL-C then those without CHD and that more than 50% of patients hospitalized with CHD have low levels of HDL-C (~40 mg/dl) [31,32]. A 2010 meta-analysis of multiple statin trials reported that the inverse relationship of HDL-C to CVD events was not altered by statin therapy [33]. In fact, in the Treating to New Targets (TNT) trial, this relationship continued to exist even following aggressive statin therapy. Overall, this study demonstrated aggressive treatment with high-dose statins to an LDL-C of 73 mg/dl decreased coronary events in a CHD patient population to a greater extent than less aggressive treatment (to LDL-C of 99 mg/dl; OR = 1.22). When a subgroup of individuals all achieving LDL-C below 70 mg/dl was examined, CVD events increased significantly when HDL-C was below 42 mg/dl even in this group with very low LDL-C levels [34] (Figure 2). HDL Metabolism and Potential Targets for Therapeutic Interventions It is overly simplistic to assume that further management of lipids will eliminate all of this residual risk. However, in this landscape of strong observational and epidemiologic data supporting HDL-C s relationship to CVD risk, the limitations of current therapies, and the increase in incidence of diabetes/metabolic syndrome, there remains a strong interest in focusing on other therapeutic interventions in addition to LDL-C lowering. Consequently there has been a strong interest in developing HDL-targeted therapies to further reduce cardiovascular risk. There are many proposed mechanisms offered to explain the beneficial anti-atherosclerotic activity of HDL-C, including increase in nitric oxide production and enhanced endothelial function, inhibition of LDL-C oxidation, reduction of cytokine-induced endothelial vas- 366 JCOM August 2013 Vol. 20, No. 8

4 Clinical Review Figure 3. HDL-C metabolism and potential sites for new therapeutics. ABCA1 = ATP-binding cassette protein A1; CETP = cholesterol ester transfer protein; CE = cholesterol ester; FC = free cholesterol; LCAT = lecithin cholesterol acyltransferase; SR-A = scavenger receptor class A; SR-BI = scavenger receptor class B type I; TG = triglyceride. cular cell adhesion molecule induction and macrophage infiltration, as well as anti-inflammatory, antithrombotic (including reduction of platelet activation/aggregation, activation of protein C-mediated anticoagulant effects and stimulation of fibrinolysis) and antioxidant effects [35]. However, reverse cholesterol transport (RCT), the transfer of cholesterol from the peripheral tissues to the liver for excretion in the feces or bile, may offer the greatest cardioprotective role and therefore the greatest opportunities for therapeutic interventions. HDL is more than a simple carrier of cholesterol. A brief review of HDL metabolism highlights the complexity of the generation and conversion of HDL and the multiple possible targets for therapeutic interventions. The mature alpha HDL particles are generated from lipid-free apo A1 or lipid-poor pre-ß1-hdl as the precursors. These precursors are produced by the liver or intestine, released from lipolysed very-low-density lipoprotein (VLDL) and chylomicrons or released by interconversion of mature HDL particles. ATP-binding cassette transporter 1 (ABCA1) facilitates free cholesterol efflux from cells and initial lipidation of these precursors. Enzymatic modification with lecithin cholesterol acyltransferase (LCAT) enables esterification of cholesterol and generates spherical particles that continue to grow with ongoing cholesterol esterification and phospholipid transfer protein (PLTP)-mediated particle fusion. Lipid efflux to the more mature HDL particles can also occur via ABCG1 mediated transfer. The larger mature HDL particles are converted into smaller HDL particles via cholesteryl ester transfer protein (CETP) enabled exchange of cholesterol esters for triglycerides between HDL and apo B containing lipoproteins (LDL and VLDL), scavenger receptor class-b type I (SR-BI) selective uptake of cholesteryl esters into liver and steroidogenic organs, and lipase mediated hydrolysis of phospholipids. HDL can deliver cholesterol to the liver via the SR-B1 receptor or by holoparticle uptake (direct RCT). It may also dispose of HDL-donated cholesterol via CETPmediated transfer of cholesterol esters to LDL and VLDL and removal through normal clearance by hepatic LDL receptors (indirect RCT). The interconversion of mature HDL particles liberates lipid-free or poorly lipidated apo A1. A portion of lipid-free apo A1 undergoes glomerular filtration in the kidney and tubular reabsorption through cubilin (Figure 3). Considering this HDL metabolism scheme, it can be seen that there are a number of possible therapeutic inter- Vol. 20, No. 8 August 2013 JCOM 367

5 Table 1. Monotherapy and Combination Therapy Trials with Fibrates Trial (Drug) Primary Endpoint: Entire Cohort (p Value) Lipid Subgroup Criterion Primary Endpoint: Subgroup (p Value) HHS [40] (Gemfibrozil) 34% (0.02) TG > 200 mg/dl 71% (0.005) LDL-C/HDL-C > 5.0 BIP [41] (Bezafibrate) 7% (0.24) TG 200 mg/dl 40% (0.02) FIELD [42] (Fenofibrate) 11% (0.16) TG 204 mg/dl and 27% (0.005) HDL-C 42 mg/dl ACCORD [55] (Fenofibrate) 8% (0.32) TG 204 mg/dl and HDL-C 34 mg/dl 31% ventions that may increase or improve HDL-C levels and possibly HDL function. Currently available therapies, including statins, nicotinic acid, and fibrates, can raise HDL-C but the effects are modest, thereby encouraging the search for new treatment interventions. Studies in atherogenic animals show that raising HDL-C via genetic modification or infusion of HDL has favorable effects on experimental plaque size and structure [36,37]. In 2003, reports of the ability of apo A1 Milano infusion therapy to reduce IVUS-measured atherosclerotic plaque volume over a short period of 6 weeks in individuals following myocardial infarction rekindled the interest in newer HDL-directed therapies [38]. This raised hopes that synthetic forms of HDL, HDL mimetics, reconstituted HDL, reinfusion of delipidated HDL and other therapies designed to increase HDL-C would be potential therapeutic approaches to reduce CVD. Therapies to improve cholesterol efflux from the tissues have also been proposed. Up regulation of Liver X receptor (LXR), the nuclear receptor that protects cells from cholesterol toxicity, may be of benefit by resulting in the cellular transduction of the ATP-binding cassette sterol transporters that efflux free cholesterol into either nascent HDL or mature HDL. Enhancing lecithin cholesterol acyltransferase (LCAT) activity increases the esterification of cholesterol in HDL, resulting in HDL maturation. Modifying the holoparticle uptake of HDL (a possible mechanism of niacin) may delay catabolism by allowing the HDL particle to continue circulating and potentially increase RCT. Genetic and pharmacologic studies in mice for example suggest that overexpression of apo A1 and SR-B1 or LXR agonists may be beneficial. Unfortunately, methodology, delivery concerns, and offtarget adverse effects have so far limited the use of these therapeutic approaches in humans. Despite many new possible therapeutic strategies, only inhibiting CETP, which increases HDL particle size and delays catabolism of HDL, is currently under active clinical phase 3 trial investigation. HDL-directed therapeutics: Is There Proof of Benefit? Current therapies and nonpharmacologic lifestyle modifications have been shown to positively impact HDL-C levels. In general, dietary changes are associated with a 3% to 15% increase in HDL-C, with an average 0.35 mg/dl increase in HDL for each 1 kg of weight loss. Further, 120 to 180 minutes of aerobic exercise a week and discontinuation of smoking can each raise HDL-C by 5% to 10%. Available drug therapies also have been shown to have a positive effect on HDL-C. Statins increase HDL by 5% to 10%, thiozolidinediones by 5% to 10%, fibrates by 10% to 20%, and niacin by 20% to 30%. Since the effects of these interventions are not limited to HDL-C alone and the relative change in HDL-C is at best modest, testing the impact of these therapies and in particular sorting out the independent effects of HDL modulation by these interventions has been a challenge. Results from small studies and trials utilizing surrogate marker endpoints such as carotid intima media thickness (CIMT) have suggested a benefit of such therapies. Monotherapy outcome trials support a role for treatment with fibrates or niacin as a means to reduce CVD events, particularly in subgroups with metabolic syndrome and diabetes. However, long-term outcome trials examining adding these therapies to a background of statin therapy are few, only recently completed, or still forthcoming. 368 JCOM August 2013 Vol. 20, No. 8

6 Clinical Review Table 2. Clinical Outcomes: Selected Combination Therapy Niacin Trials and Meta-analysis Trial (treatment) Primary Endpoint niacin/control Patients, n Odds ratio for CHD events (CI) HATS [50] Angiographic regression 38/ ( ) (niacin + statin vs. placebo) CLAS [49] Angiographic regression 94/ ( ) (niacin/colestipol vs. placebo) ARBITER-6 [53] Carotid intima media thickness 187/ ( ) (statin + niacin vs. statin + estimibe) STOCKHOLM [48] Clinical outcomes 279/ ( ) (niacin + clofibrate vs. ususal care) CDP [45] Clinical outcomes 1119/ ( ) (niacin vs. placebo) Meta-analysis [54] Myocardial infarction 2682/ ( ) Monotherapy Trials with Fibrates and Niacin Not all therapies that raise HDL-C improve outcomes. Estrogen replacement, for example, which increases HDL-C 10% to 15%, failed to reduce CVD events although it raised HDL-C in postmenopausal women in the Women s Health Initiative [39]. However, a number of monotherapy trials with fibrates including the Helsinki Heart Study, Bezafibrate Infarction Prevention Trial (BIP), Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and the Veterans Affairs High-Density Lipoprotein Cholesterol Trial (VA-HIT) [40 43] have shown reduction in CVD events. The extent of benefit has been inconsistent and not uniformly of statistical significance across all these studies. However, in subgroup analysis of those individuals with parameters consistent with metabolic syndrome or a metabolic pattern on the lipid profile, benefits of treatment are uniformly better (Table 1). These studies collectively suggest that while monotherapy with fibrates may not benefit all individuals with dyslipidemia, subgroups with a metabolic pattern of elevated TG and low HDL-C may benefit. In a VA-HIT trial post-hoc investigation, multivariate analysis demonstrated that only the increase in HDL-C and not changes in triglycerides or LDL-C achieved with gemfibrozil predicted the reduction in CHD [44]. The Coronary Drug Project (CDP), initiated in the late 1960s, was a large secondary prevention study among men with several treatment arms, one of which utilized up to 3 g/day of niacin. Compared with placebo, niacin (which has been shown to raise HDL-C 20% to 25%, although HDL-C data not available) lowered total cholesterol by 10% and TG by 26%, and after 6 years significantly reduced nonfatal myocardial infarction (MI) by 27% [45]. A 15-year follow-up analysis (9 years after the interventions had ended) revealed a significant 11% decrease (p < 0.004) in total mortality. Further analysis has demonstrated equivalent reductions in CVD risk regardless of entry fasting glucose level, presence or absence of diabetes at entry, or change in fasting glucose while on therapy [46]. Combination Trials with Statins Since statin therapy remains the primary pharmacologic treatment, the relevant clinical question is whether the addition of HDL-modulating therapies after maximal LDL-C lowering with statins would result in incremental reduction in cardiovascular events. Unfortunately, outcome trials using combination therapy are limited. A number of studies have examined niacin in combination with other lipid-lowering drugs [47 54] (Table 2). The Familial Atherosclerosis Treatment Study (FATS) was an angiographic regression trial comparing treatment with lovastatin/colestipol or niacin/colestipol with conventional therapy [48]. After 2.5 years, the niacin group as well as the statin group had a similar number of patients with regression of atherosclerosis (39% and 32%) compared with 11% in the conventional group. The Cholesterol-Lowering Atherosclerosis Study (CLAS) compared niacin/colestipol combination with placebo and demonstrated significant regression in 16% of patients on combination therapy vs. 2.4% in the placebo group [49]. The HDL-Atherosclerosis Treatment Study (HATS) was a 3-year, double-blind, placebo-controlled, study that evaluated slow-release niacin therapy in 160 patients with CHD who had low HDL-C ( 35 mg/dl in men or 40 mg/dl in women). It demonstrated significant ben- Vol. 20, No. 8 August 2013 JCOM 369

7 Table 3. Completed and Ongoing Combination Trials with Statins Study Rx vs. Control Patient Total Median Follow-up/Results ACCORD [55] Fenofibrate + statin vs. statin yr; No difference in primary endpoint AIM-HIGH [57] Niacin + simvastatin vs. simvastatin 3414 Stopped early Futility HPS2-THRIVE [58] Niacin + simvastatin vs. simvastatin 25, yr; No difference in primary endpoint CETP Trials: Illuminate Torcetrapib + atorvastastin vs. atorvastatin ~16,000 Stopped early Adverse events dal-outcomes 1 Dalcetrapib + statin vs. statin ~16,000 Stopped early Futility Reveal Anacetrapib ~30,000 Ongoing Accelerate Evacetrapib ~11,000 Ongoing efits of combined simvastatin/niacin vs. placebo for the angiographic endpoint of a change in coronary stenosis ( 0.4% vs. 3.9%, P < 0.001) and the occurrence of a first cardiovascular event (reduction of 90%, p = 0.03) [50]. However, none of these studies compared a strategy of aggressive statin alone to statin plus niacin. Studies examining surrogate markers for CVD outcomes offer some encouragement. The Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER)-2 study was a small trial of 167 persons with known CHD and low HDL-C using the surrogate endpoint of CIMT as the primary outcome [51]. Extended-release niacin (1000 mg) or placebo was added to a background of statin treatment with a prerandomization LDL-C of 87 mg/dl and HDL-C of 39 mg/dl. At 1 year, HDL-C increased an average of 21% in the niacin group. Mean CIMT increased significantly in the placebo group but was not significantly changed in the niacin group. In addition, niacin significantly reduced the CIMT progression rate in subjects with insulin resistance (p = 0.026). ARBITER-3, a 1-year open-label extension of ARBITER-2 with all subjects on niacin and statin demonstrated regression in CIMT that was even more prominent in subjects with diabetes or metabolic syndrome [52]. ARBITER-6-HALTS compared the effects of niacin vs. ezetimibe when added to background statin therapy and demonstrated regression in CIMT over 14 months when niacin but not when ezetimibe was added [53]. Although these studies were not designed or powered to examine differences in clinical events, niacin treatment when added to statin therapy appeared to slow the rate of atherosclerotic progression in persons with CHD and low HDL-C. Furthermore ARBITER-6 suggested that adding a drug with HDL-Craising effects (niacin) in a low HDL-C population may more favorably slow the atherosclerotic process than further LDL-C lowering with other LDL-C-lowering therapies (ezetimibe). A meta-analysis combining both niacin monotherapy and combination therapy trials identified 10 trials with reported clinical outcomes in 6545 individuals. The authors reported a 26% reduction in coronary events, 26% reduction in stroke, and 27% reduction in any cardiovascular event associated with a 15.7% increase in HDL-C during treatment with niacin [54]. Combination Therapy Trials with Available Therapies Few large placebo-controlled trials address the question of combination therapy with statins and the effect on CVD events. The lipid arm of the ACCORD trial examined fenofibrate versus placebo added to a background of simvastatin therapy in 5518 individuals with diabetes [55]. The annual rate of the primary composite CVD outcome was not significantly different (2.2% in fenofibrate group vs. 2.4 in placebo group) and mortality was similar (1.5% vs 1.6% in the 2 treatment groups). However, in a pre-specified subgroup analysis of subjects with TG > 204 mg/dl and HDL-C < 34 mg/dl, the primary outcome was reduced 31% (12.4% in the fenofibrate group vs.17.3% in the placebo group, p = ) compared with 10.1% in both groups in the entire cohort (Table 3). A recent meta-analysis of the previously discussed monotherapy fibrate trials and ACCORD reported a 30% CVD reduction in subgroups with a similar type of metabolic pattern vs. only a 6% reduction in the non-metabolic pattern group [56]. 370 JCOM August 2013 Vol. 20, No. 8

8 Clinical Review Two placebo-controlled outcome studies were initiated to investigate the effects of adding niacin to a background of aggressive LDL-C treatment with statins. The AIM-HIGH trial of 3414 subjects with stable CVD was designed to test whether the addition of extended release niacin after lowering LDL-C with simvastatin (+ ezetimibe) to between 40 and 80 mg/dl would result in an additional 25% reduction in CVD events [57]. The Data Safety Monitoring Board ended this NIH-supported study early, in May of 2011, due to futility or inability to demonstrate a significant difference between the study arms. Despite discouraging results, there were a number of issues with the trial that will be addressed later. The larger Heart Protection Study 2 (HPS2)-THRIVE examined whether niacin (in a preparation combined with laropiprant, a prostaglandin receptor blocker to reduce flushing) when added to statin therapy in a broader population would reduce CVD events in 25,673 subjects followed for approximately 4 years [58]. There was no significant difference in the primary endpoint of coronary death, nonfatal MI, stroke and cardiovascular revascularization (15.0% in the control group vs. 14.5% in the niacin group). Adverse events were also higher in the niacin-treated subjects, with significant absolute excess of diabetic complications (3.7%), new-onset diabetes (1.8%), infection (1.4%), and bleeding (0.7%). Some of these were expected effects of niacin but it is unclear if others, such as infection and bleeding, could have been related to the laropiprant component. Clinical Trials with Investigative Therapies Of the newer potential treatment options for HDL-C modulation, CETP inhibitors are the furthest along in clinical trials. As already noted, CETP is a plasma protein that promotes exchange of cholesterol esters and triglycerides between apo B containing particles and HDL. Many observations suggest that inhibition of CETP might reduce CVD events. CETP activity is inversely correlated with HDL-C. Deficiencies in CETP have been shown to be associated with increases in HDL and low prevalence of CVD. In rabbit models, pharmacologic inhibition of CETP reduced atherogenesis [59]. However, whether the large cholesterol-laden HDL particles produced with these drugs will effectively alter the atherosclerotic process and reduce CVD events is unknown. Four compounds in this class either were or are still undergoing human trials. The first studied drug, torcetrapib, raised HDL-C by up to 60% to 72% and lowered LDL-C by 20% to 30%. Phase 3 clinical trials with torcetrapib, however, were stopped early due to higher overall mortality in the treatment group despite significant increases in HDL-C. This has been potentially attributed to off-target effects of the drug due to activation of the renin-angiotenson system, reduction in potassium, and elevation in blood pressure. Interestingly, in post-hoc analysis of the data, Barter reported on patients with known HDL-C levels at 1 month on therapy and found that the risk of MI was reduced proportionately to the amount of increase in HDL-C [60]. In addition, IVUS analysis from torcetrapib trials demonstrated that those individuals who had significant elevations in HDL-C on therapy had regression of atherosclerosis [61]. This offered hope that trials with next generation CETP inhibitors without these off-target effects might demonstrate cardiovascular benefit. Three later-generation CETP inhibitors have been shown to significantly increase HDL-C, have a favorable safety and tolerability profile, and not have the off-target effects seen with torcetrapib. Dalcetrapib, a partial inhibitor of CETP, raised HDL-C by 30% to 34% with little effect on LDL-C and triglycerides but has the added effect of modulating HDL particle type. This offered an opportunity to study a drug added to statin therapy that had the predominant lipid effect of raising HDL-C. Two large phase 3 outcome trials in patients with acute coronary syndrome (dal-outcomes 1: fully enrolled with > 15,000 patients) and stable CVD (dal-outcomes 2: in enrollment phase) were underway. Although dalcetrapib was shown to be effective in raising HDL-C and well-tolerated in phase 2 trials, in May of 2012 all ongoing outcome trials in the entire dal-heart program were discontinued by the developing company due to futility to meet specified objectives during an interim analysis of dal-outcomes 1. Analysis of the data after the closure of the trial database in August of 2012 was reported at the AHA in November 2012 [62]. In the setting of baseline HDL-C and LDL-C of 42 and 76 mg/dl, respectively, and a 31% to 40% increase in HDL-C, there was no difference in the placebo vs. dalcetrapib primary cardiovascular endpoints (8.0% vs 8.3%, p = 0.52). Two other CETP inhibitors, anacetrapib and evacetrapib, which more completely inhibit the enzyme, have been shown to increase HDL-C by up to 138% and 129%, respectively, and reduce LDL-C by up to 40% and 36%, respectively. Ongoing outcome trials are in progress with both of Vol. 20, No. 8 August 2013 JCOM 371

9 these compounds (REVEAL with anacetrapib and AC- CELERATE with evacetrapib). At this time, questions still remain whether the increase in cholesterol-laden mature HDL produced by CETP inhibition will be functional HDL associated with reduced CVD events and if the benefits will outweigh long-term safety concerns. And since the drugs still undergoing investigation have substantial LDL-C lowering effects as well, the benefits of HDL-C increases may be difficult to differentiate from the additional LDL-C lowering. Genetic Study Raises Concern Regarding HDL Treatment Not only have clinical trials to date been disheartening but also a recent study published in Lancet in 2012 raised doubt about the benefits HDL-C raising therapies [63]. Mandelian randomization analysis was used to test whether a genetic mechanism associated with increased HDL was associated with reduced MI risk and therefore a causal relationship. In this analysis, carriers of the LIPG 396 Ser allele (with a low 2.6% frequency) were found to have a consistent association with high HDL-C, similar levels of other lipid and non-lipid risk factors but without an associated lower risk of myocardial infarction. Based on epidemiological observations this degree of increase in HDL-C would have been expected to be associated with a 13% reduction in CHD. However in pooled data from a case-control analysis there was no benefit with an odds ratio (OR) of In addition, a genetic risk score combining 14 common variants associated with exclusive although small effects on HDL-C was examined. Although the reduction in risk of MI associated with a 1 standard deviation (SD) decrease in LDL-C was concordant with that estimated from the genetic score, this was not the case when comparing the observational risk reduction and genetic score estimate for each 1 SD increase in HDL-C (OR of 0.62 vs. OR of 0.93). Based on these observations, at least some forms of genetically elevated HDL-C did not seem to reduce CVD risk and raised the concern that not all interventions that simply raise HDL-C will uniformly reduce CVD events. This also emphasizes the potential limitations of using plasma HDL-C concentration alone as a surrogate measure of HDL function or of CVD risk assessment in intervention trials and supports the notion that biomarkers that are better surrogates for or direct assays of HDL function may be superior measures and need to be developed. Why Are Studies to Date Negative or Inconclusive? The results of these studies, while sobering, may not be a reason to give up hope on an HDL-directed approach. Perhaps we have not yet found the right compounds. Off-target adverse effects such as in the estrogen and the torcetrapib trials may have attenuated the potential benefits. While it remains possible that CETP inhibition adversely affects HDL functionality, the increase in blood pressure and production of aldosterone and cortisol remain likely explanations for the torcetrapib trial results. Whether or not the addition of laropiprant and inhibition of prostaglandin receptor activity in HPS2-THRIVE had untold off-target effects resulting in lack of difference in the primary endpoint and the increase in at least some of the adverse events reported is difficult to assess since there was no niacin-only comparison arm. The trials may not have been designed or powered to adequately test the HDL-C hypothesis. The AIM-HIGH trial was disappointing but there are a number of issues with the design and results. This 3414-individual study may not have been adequately powered to demonstrate the proposed 25% reduction in risk. Niacin up to 200 mg was allowed in the placebo group, potentially attenuating the differences in HDL-C between groups. Permitted open-label change in LDL-C drugs resulted in greater use of higher-dose statins and ezitimibe in the control group. In the end there was only a 4-mg/dL difference (42 vs. 38 mg/dl) in the HDL-C levels in the niacin vs. the placebo group, which may not have been sufficient to demonstrate a benefit in this group of patients who were already well-treated with statins (LDL-C was aggressively lowered to 66 mg/dl in the niacin group and 70 mg/ dl in the placebo group). The HPS2-THRIVE trial also demonstrated no significant differences between the treatment groups. This also was a very well-treated group of subjects with a median LDL-C level of 63 mg/dl before randomization. The trial did not have an HDL-C threshold for entry into the study, with a baseline HDL-C of 44 mg/dl and an increase on niacin of only 6 mg/dl (14% increase). As in AIM-HIGH, this difference may not have been sufficient to demonstrate benefit in such a well-treated population. Although subanalyses should be interpreted with caution, it is interesting that in an analysis examining baseline LDL-C groups below 58 mg/dl, between 58 mg/dl and 77 mg/dl, and above 77 mg/dl there was a significant trend toward benefit as the LDL-C levels increased. Subgroup analysis 372 JCOM August 2013 Vol. 20, No. 8

10 Clinical Review across the spectrum of HDL-C at entry or in metabolic pattern subgroups may yield important information. Even in well-designed trials, the magnitude of change in HDL-C achievable with current medications (10% 30% increase) may not be sufficient to demonstrate differences when added to aggressively statin-treated patients such as in the completed niacin and dalcetrapib trials. Additional CVD risk reduction may be demonstrated in the ongoing trials with more potent CETP inhibitors, which are associated with greater HDL-C increases. Perhaps the benefit of HDL modulation may not be applicable to all populations. Individuals with metabolic syndrome or insulin resistance may have a greater response to therapies that improve HDL availability and function, and a more targeted treatment approach in this population may yield better outcomes. At least this seems to be suggested in subset analysis of fibrate trials and CIMT data from the ARBITER trials with niacin. The ACCORD trial did demonstrate a strong trend toward benefit in the subgroup with elevated TGs and low HDL-C, also suggesting that a more populationtargeted approach may be beneficial. Conversely, CVD events in the low HDL-C patient may be confounded by other associated derangements, such as increased small LDL particle concentrations, insulin resistance, elevated triglycerides and increase in other atherogenic particles. The benefits of fibrates and niacin reported in subgroups with high triglycerides and low HDL-C may be due to effects on this excess in apo B particles and not on HDL-C alone. We may not be looking at the most accurate measure of HDL availability and function. Current available laboratory evaluation of HDL, which provides HDL cholesterol concentration only, offers little direct information about quality and function of HDL. Since only a portion of cholesterol carried in HDL at any time is transferred from peripheral arterial pools, changes in HDL-C concentration may not be a reliable measure of arterial cholesterol efflux and efficiency of RTC. HDL-C is a surrogate for the number of circulating HDL particles and it is the particle and not the cholesterol it carries that has the beneficial biological effect. HDL particles are constantly changing and are heterogeneous. While HDL-C may be a reasonable surrogate for HDL activity in some populations, this may not be the case in others. Individuals with diabetes, CHD, and other inflammatory diseases, for example, have been shown to have dysfunctional HDL. As suggested by the genetic analysis previously discussed, increases in HDL-C alone may not necessarily reflect improved HDL function. Assessment is further complicated by the fact that many therapies have multiple effects on the lipid profile. Even if a therapy raises HDL-C and reduces risk, it may be difficult to prove that the increase in HDL-C alone was responsible for the effect. Measures that better reflect HDL composition, particle number and functionality rather than HDL cholesterol content may turn out to be superior measures of treatment. Utilizing these measures in studies with newer compounds in development that target not just an increase in HDL-C but also improved cholesterol efflux from the tissues, increase in apo A1 production, or reduced HDL clearance may yield more favorable results. What Should We Do for Now? There clearly is an association between HDL-C and cardiovascular adverse events. This remains even after aggressive treatment with currently effective therapies such as statins. This is particularly true in populations with diabetes and metabolic syndrome, where LDL-C content alone may not accurately reflect CVD risk. These individuals need to be recognized as high risk for CVD events and aggressively treated to reduce risk. Although still a promising strategy, increasing HDL-C with current therapies cannot be assumed to uniformly reduce CVD events. Whether HDL-C is a marker for risk rather than a treatable risk factor that when modified can alter CVD outcomes continues to be debated. One thing, however, is certain. Since individuals with low HDL-C remain at high risk and statin trials consistently show a doseresponse reduction in adverse outcomes, treatment with statins to achieve aggressive LDL-C lowering should remain the cornerstone of therapy for high-risk individuals with low HDL-C. Controlled clinical trial data demonstrating an additional benefit of adding HDL-directed therapy to aggressive LDL-C lowering with statins is currently lacking. The ACCORD, AIM-HIGH, and HPS2-THRIVE results do not necessarily refute the HDL hypothesis nor do they offer justification to universally stop using fibrates or niacin in patient management. Rather, they suggest we should focus current available therapies on the populations most likely to benefit. The enthusiasm for use of these drugs in combination with statins has been reduced somewhat by lack of strong outcome data. However, since low HDL-C is often associated with excess of atherogenic apo B particles and these therapies may further modify these particles, their addition to statins may play a role in further reduction Vol. 20, No. 8 August 2013 JCOM 373

11 of CVD risk in certain patients. Until further trial data is available, it remains reasonable to consider combinations of these therapies in individuals intolerant to statins or statin dose titration, those with elevated non-hdl-c or apo B on maximally tolerated statins, and those not at LDL-C treatment goals on maximal statin therapy. The LDL-C subanalysis in HPS2-THRIVE suggests that there may be benefit of adding niacin in this latter group. However, the increase in adverse events would support restraint in the widespread addition of currently available HDL-C modifying drugs to statins with restriction to certain populations and careful follow-up for side effects. Non-HDL-C and apo B have already been proposed as secondary targets for this purpose. In the absence of clinical trial data, current NCEP ATP guidelines have not set a specific goal for HDL-C but emphasize the need to treat elevated LDL-C and non- HDL-C in this high-risk population [16,17,20]. The HDL story is far from over. Although the view that simply raising HDL-C will reduce CVD events is overly simplistic, it is far too early to abandon efforts to find new approaches to reduce risk. Development of newer more tolerable drugs with more potent effects on HDL-C as well as therapies targeted toward improving HDL availability and function is ongoing and may offer additional benefits not seen with current therapies. Therapies to increase apo A1, dual PPAR agents and LXR modulators, to name a few, may offer benefit. Data on a number of such compounds were recently presented at the 2012 American Heart Association meeting. Infusion of CSL112, a human apolipoprotein A-1 formulation, rapidly increased serum cholesterol efflux capacity as well as pre-beta HDL. ARI-3037MO, a niacin-like compound, has been shown to have favorable lipid changes without dose-limiting flushing, even at high doses. 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