Review
Ongoing challenges for pharmacotherapy for dyslipidemia Anthony D Pisaniello, Daniel J Scherer, Yu Kataoka & Stephen J Nicholls† †
1.
Introduction
2.
Contemporary lipid targets
3.
Unresolved issues with statin
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Laurentian University on 12/06/14 For personal use only.
therapy 4.
Finding a role for fibrates
5.
Implications of recent trials of niacin
6.
Is there a benefit of omega-3 fatty acids?
7.
Cholesteryl ester transfer protein inhibitors
8.
Proprotein convertase subtilisin kexin-type 9 inhibitors
9.
University of Adelaide, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
Introduction: While increasing evidence has led to lipid-modifying therapy achieving an important role in the treatment guidelines for the prevention of cardiovascular disease, these agents are suboptimally used and there remains a considerable risk of clinical events. Accordingly, there is a need to develop more effective lipid-modifying approaches in many patients. Areas covered: A literature search was performed of topical manuscripts focusing on factors influencing use of established therapies and new agents in development that target a range of lipid factors. Expert opinion: More intensive efforts are required to ensure that statin use is maximized in higher risk patients. A range of novel therapies, including proprotein convertase subtilisin kexin-type 9 and cholesteryl ester transfer protein inhibitors, may provide additional protection, although this remains to be established by clinical trials.
Other options for dyslipidemia
10.
Summary
11.
Expert opinion
Keywords: atherosclerosis, cardiovascular risk, lipid-modifying therapy, lipids Expert Opin. Pharmacother. [Early Online]
1.
Introduction
In the 20 years following the first report of clinical benefits of statins [1] these agents have been increasingly used in clinical practice [2] and have had a profound impact in the prevention of cardiovascular events. Despite these benefits, there remains uncertainty with regard to their optimal approach in all patients, challenges in maximizing tolerated doses [3] and a considerable residual risk of clinical events [4,5]. Accordingly, there is an ongoing need to formulate more effective approaches to promote optimal use of established lipid-modifying therapies. In parallel, there is considerable interest in the development of novel agents in order to achieve more effective reductions in cardiovascular risk (Table 1). 2.
Contemporary lipid targets
Accumulating evidence from clinical trials and meta-analyses has reinforced the concept that intensively lowering levels of low-density lipoprotein cholesterol (LDL-C) plays an important role in reducing cardiovascular risk [6-9]. This has supported the concept of proposing increasingly aggressive treatment targets for LDL-C in clinical practice. While most physicians support this concept of intensive lipid lowering, many patients fail to meet prescribed targets. This is likely to reflect some degree of clinical inertia with regard to statin dose escalation and the emergence of statin intolerance [10,11]. Despite this, the most recent updates to treatment guidelines have recommended more widespread use of high-intensity statin therapy, potentially requiring less reliance on treatment targets [12,13]. It is likely that demonstrating clinical benefit with new agents that more aggressively lower LDL-C will lead to further updates of guidelines that endorse lower treatment targets. In parallel, there is increasing interest in the clinical use of lipid biomarkers beyond LDL-C. Novel indices that characterize LDL particle concentration and size including apolipoprotein B (apoB) and nuclear magnetic resonance 10.1517/14656566.2014.986094 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
1
A. D. Pisaniello et al.
Article highlights. .
.
.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Laurentian University on 12/06/14 For personal use only.
.
Current lipid-modifying agents can have a profound impact on cardiovascular outcomes, although they are not optimally used. A range of novel lipid biomarkers beyond low-density lipoprotein cholesterol (LDL-C) may be of use in clinical practice and to guide development of new agents. Despite early failures there remains considerable optimism that cholesteryl ester transfer protein inhibitors that raise high-density lipoprotein cholesterol and lower LDL-C will reduce clinical events. Proprotein convertase subtilisin kexin-type 9 inhibitors produce profound LDL-C lowering in a range of disorders, and their clinical benefit is currently undergoing evaluation in clinical trials.
This box summarizes key points contained in the article.
muscle or other organ injury is low [33,35]. More effective approaches are required to manage the patient with some degree of intolerance to statin therapy [36]. This is demonstrated not only by reports of a high rate of discontinuation of statin therapy in clinical practice [37,38], but also by the fact that this can be significantly mitigated by a comprehensive approach to try and reinstate therapy in many patients. Furthermore, while the data have consistently demonstrated a greater signal of new diagnosis of type 2 diabetes with more potent statin therapy [39,40], their cardiovascular benefits in the appropriate high risk patients would seem to outweigh any adverse effect on glycemic control. Nevertheless, statin therapy will be the standard of care background therapy on top of which all new lipid-modifying therapies are evaluated. 4.
spectroscopy have been reported to provide incremental risk prediction beyond traditional measures of their cholesterol content [14-16]. Similarly, increasing reports have highlighted the potential importance of other atherogenic lipid parameters including triglycerides [17,18], lipoprotein (a) [Lp(a)] [19] and remnant cholesterol [20]. Ultimately, the measurement of non-high-density lipoprotein cholesterol may provide the best utility in clinical practice, given its ability to quantify the full extent of atherogenic lipoproteins. Measures of high-density lipoprotein cholesterol (HDL-C) provide a characterization of protective lipids with consistent reports of an inverse relationship between systemic levels and cardiovascular risk [21-24]. Given the lack of data demonstrating that novel HDL targeted therapies reduce cardiovascular events [25-28], it remains to be determined whether there will ever be a treatment target for HDL-C. To what degree measures of HDL particles or its functional quality will be integrated into clinical practice remains to be determined.
For > 50 years, various fibric acid derivatives have been used to prevent cardiovascular events with variable efficacy [41]. The most efficacious of these agents in clinical trials, gemfibrozil [42,43], proves difficult to administer in addition to statin therapy [44]. While more recent studies of fenofibrate have not positively influenced the primary endpoint in large trials [45,46], there has been some suggestion of benefit on hard clinical endpoints (death, myocardial infarction, stroke) in patients with prior cardiovascular events [45] and on microvascular endpoints in diabetic patients [47,48]. Large metaanalyses of fibrate studies suggest a marginal cardiovascular benefit, which is much greater in patients with baseline hypertriglyceridemia and low HDL-C levels, reflecting the patient in whom these agents are primarily used in clinical practice [49,50]. Additional efforts to develop more potent pharmacological agonists of PPAR-a or dual PPAR-a/g agonists have not proven to be efficacious in clinical trials and have demonstrated considerable safety issues [51,52]. It remains to be determined whether a novel agent from this class will be successful. 5.
3.
Implications of recent trials of niacin
Unresolved issues with statin therapy
As the evidence supporting the use of statins has accumulated, it has become increasingly apparent that a greater benefit is observed with the use of high-intensity statin therapy [29-33]. To what degree this is driven by more aggressive LDL-C lowering or the relative contribution by reported pleiotropic effects of statins remains uncertain. The finding that lowering C-reactive protein independently associates with the benefit of statins on clinical events and plaque progression suggests that anti-inflammatory properties of statins may contribute to their clinical benefit [34]. As the cost of statins has declined, accessibility should increase, enabling recommendations for their increasing use. There needs to be greater emphasis on the safety and efficacy of use of high-intensity statin therapy. Better understanding of the safety of these agents is required. While myalgia is commonly encountered, the incidence of 2
Finding a role for fibrates
Niacin has been widely used to manage a range of forms of dyslipidemia, given its ability to effectively raise HDL-C in addition to lowering triglycerides, LDL-C and Lp(a) [53]. Early studies prior to the development of statins suggested that immediate release formulations of niacin reduce cardiovascular events [54-57], with subsequent reports of a favorable effect on disease progression in the artery wall [58,59]. However, near ubiquitous experience of flushing with niacin has limited its use in many patients resulting in exploration of mechanisms to improve its tolerance [53]. Despite efforts to prolong its pharmacological release or co-administration with a chemical inhibitor of the interaction of niacin with epidermal prostanoid receptors, the presumed mechanism underlying flushing, this has not reduced cardiovascular morbidity and mortality in large trials of statin-treated patients [27,28]. When combined with a number of safety
Expert Opin. Pharmacother. (2014) 16(3)
Ongoing challenges for pharmacotherapy for dyslipidemia
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Laurentian University on 12/06/14 For personal use only.
Table 1. Current and emerging lipid-modifying agents. Therapeutic class
Target
Lipid effects
Clinical notes
Statins
HMGCoA reductase inhibitor
Fibrates
PPAR-a agonist
Lower LDL-C Variable HDL-C raising Lower triglyceride Raise HDL-C
Niacin
G protein receptor agonist
Guidelines promote increasing use of statins and more potent therapy Early benefit with gemfibrozil which is difficult to administer with statins Consistent benefit in patients with baseline hypertriglyceridemia and low HDL-C Early benefit prior to statin use Anti-atherosclerotic properties No convincing benefit in recent large trials
PCSK9 inhibitors
PCSK9 inhibition
Omega-3 fatty acids CETP inhibitors
Variable effects on lipolytic enzymes in blood and factors involved in hepatic lipoprotein synthesis CETP inhibition
Mipomersin
Antisense apoB therapy
Lomitapide
Microsomal transfer protein inhibitor
Anti-apoCIII therapy
Antisense apoCIII therapy
Raising HDL-C Lowering triglyceride Lowering LDL-C Lowering Lp(a) Lower LDL-C Lower Lp(a) Lower triglyceride
Raising HDL-C Lowering LDL-C Lowering Lp(a) Lowering triglyceride Lowering LDL-C Lowering triglyceride Lowering LDL-C Lowering triglyceride Lowering triglyceride Lowering LDL-C
Subcutaneous administration 2 -- 4 weekly Clinical trials in progress Clinical trials in progress
Mortality signal with torcetrapib Clinical futility with dalcetrapib Potent CETP inhibitors without off target toxicity currently in clinical trials Injection site reactions Some hepatic steatosis Clinical trials in progress
Apo: Apolipoprotein; apoC-III: Apolipoprotein C-III; CETP: Cholesteryl ester transfer protein; HDL-C: High-density lipoprotein cholesterol; HMGCoA: 3-hydroxy3-methylglutaryl; LDL-C: Low-density lipoprotein cholesterol; Lp(a): Lipoprotein (a); PCSK9: Proprotein convertase subtilisin kexin 9.
concerns that have emerged in these trials, it would appear that niacin will remain a niche agent for the management of refractory dyslipidemia and not be widely used. 6.
Is there a benefit of omega-3 fatty acids?
Observational studies have demonstrated an inverse relationship between both consumption and systemic levels of omega-3 fatty acids and cardiovascular risk [60,61]. These data have been embraced by treatment guidelines that recommend minimum dietary consumption of omega-3 fatty acids for prevention of cardiovascular disease [62,63]. Their benefit is likely to be multifactorial related to their ability to lower triglycerides and levels of atherogenic lipoproteins, antithrombotic and anti-arrhythmic effects [64-67]. To what degree pharmacological administration of omega-3 fatty acids results in cardiovascular benefit is unknown. While early reports prior to the use of statin therapy suggested some potential benefit [60,68], this has been difficult to confirm in more recent trials. A consistent criticism of failed clinical trials has reflected concerns with regard to use of relatively small doses and evaluation in broader populations, where a more targeted approach may have been more likely to be effective. This is supported by Japanese data demonstrating that larger doses of omega-3 fatty acids reduce cardiovascular events in statintreated patients [69]. Such findings have supported the
development of large programs that are currently evaluating the clinical effects of eicasopentanoic acid either as monotherapy or in combination with docasohexanoic acid in large quantities in statin-treated patients with elevated triglyceride levels. The results of these trials will definitively provide the answer to the question of whether omega-3 supplementation is of clinical benefit. 7.
Cholesteryl ester transfer protein inhibitors
Cholesteryl ester transfer protein (CETP) facilitates the transfer of esterified cholesterol from HDL to very low-density lipoproteins and LDL particles, in exchange for triglyceride [70]. Numerous lines of evidence suggest that CETP may be a promising target for cardiovascular prevention. Populations with low CETP activity and associated higher HDL-C levels appear to be protected from cardiovascular disease [71,72]. This is supported by genetic studies that demonstrate associations between polymorphisms resulting in low CETP activity with high HDL-C levels and less cardiovascular events [73,74], suggesting that CETP may play a causal role in the disease. Attempts to reduce CETP activity in animals that endogenously express CETP have a favorable effect on atherosclerotic plaque [75]. The clinical development of CETP inhibitors has proven challenging. The first agent to reach an advanced stage of
Expert Opin. Pharmacother. (2014) 16(3)
3
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Laurentian University on 12/06/14 For personal use only.
A. D. Pisaniello et al.
clinical development, torcetrapib, had no effect on plaque progression and was demonstrated to have an adverse effect on cardiovascular events and mortality [25,76]. These findings promoted considerable debate whether the problem reflected the generation of dysfunctional HDL with CETP inhibition or a molecule specific problem. Subsequent reports of intact cholesterol efflux to HDL from CETP deficient and torcetrapib-treated patients, plaque regression at the highest HDL-C levels with torcetrapib [77] and the demonstration that torcetrapib has a range of non-CETP mediated adverse effects on blood pressure, adrenal hormone synthesis and endothelin expression within the artery wall supported the concept that the adverse effects were more likely to reflect off-target toxicities [78]. Accordingly, the ability to develop other CETP inhibitors without such toxicity might still prove to be of clinical utility. Dalcetrapib [79], a modest CETP inhibitor in terms of HDL-C raising and no LDL-C lowering, had no clinical impact in a large trial [26]. Two ongoing trials are evaluating the effects of the potent CETP inhibitors, anacetrapib [80] and evacetrapib [81]. These agents raise HDL-C by > 120% and lower LDL-C by at least 25% in statin-treated patients and appear to lack the adverse effects of torcetrapib [82,83]. Whether potential benefit of these agents is due to their profound effects on HDL-C levels or simply due to incremental LDL-C lowering remains unknown. Ultimately, the impact of these agents on cardiovascular outcomes will determine whether they become available in clinical practice.
Proprotein convertase subtilisin kexin-type 9 inhibitors 8.
Proprotein convertase subtilisin kexin-type 9 (PCSK9) plays an important role in lipid homeostasis [84]. Molecular studies have elucidated that following interaction between circulating LDL particles and the LDL receptor on the liver surface, this complex is internalized, the LDL particle removed enabling for shuttling of the receptor back to the liver surface [85]. This provides an elegant mechanism facilitating removal of excess lipid from the circulation. PCSK9 has been identified to inhibit LDL receptor recycling to the liver surface [86] and as result represents an autosomal dominant form of hypercholesterolemia [87]. Further genetic studies have demonstrated that polymorphisms resulting in low PCSK9 activity associate with lower LDL-C levels and considerably lower cardiovascular event rates, reflecting the importance of lifelong exposure to low LDL-C levels [88-90]. Early studies with subcutaneous administration of human monoclonal antibodies against PCSK9 2 -- 4 weekly result in profound dose dependent reductions in LDL-C up to 70% in a broad range of patients [91-95]. Of particular interest is their ability to effectively lower LDL-C in patients with familial hypercholesterolemia or statin intolerance [96,97], both conditions presenting a challenge for strategies to reduce cardiovascular risk. The impact of these agents on cardiovascular events is currently undergoing evaluation in large clinical trials. The extent of 4
LDL-C lowering would suggest that these agents are likely to be clinically efficacious. The degree of benefit, safety, ease of use and cost will ultimately determine to what extent these agents are used in clinical practice. Their use in familial hypercholesterolemia would seem to be most likely. The degree of benefit in broader populations and their cost effectiveness will influence how widely they will be used. 9.
Other options for dyslipidemia
While most focus in the lipid field has concentrated on the development of CETP and PCSK9 inhibitors, there has been considerable activity in other classes as well. Mipomersin is an antisense oligonucleotide based therapy that inhibits apoB expression with evidence of LDL-C lowering up to 50% and is well tolerated apart from injection site reactions [98]. Microsomal transfer protein (MTP) packages neutral lipids into nascent atherogenic lipoproteins within the liver [98]. MTP inhibition with lomitapide lowers LDL-C by up to 50%, although with evidence of hepatic steatosis, the clinical implications of which are unknown. Both of these agents have been approved for use in patients with familial hypercholesterolemia. Apolipoprotein C-III (apoC-III) plays a pivotal role in the metabolism of triglyceride rich lipoproteins and has direct proatherogenic effects at the level of the artery wall [99]. Early experience with antisense therapy directed against apoC-III has demonstrated triglyceride lowering by up to 70% [100]. These encouraging early findings require further exploration in larger trials. While there is considerable interest in Lp(a) as an important factor driving atherosclerosis [19], agents that lower Lp(a) have not been demonstrated to reduce clinical events (niacin, oestrogen) [27,28,101]. While CETP and PCSK9 inhibitors reduce Lp(a) levels [102,103], there remains a need to develop more targeted Lp(a) therapies. From the HDL perspective, there continues to be interest in the concept of infusing lipid-deplete forms of HDL [104], with early evidence of regression in imaging studies [105-108]. Their effect on clinical outcomes is currently not known. 10.
Summary
While statins have been clinically available for two decades, there continues to be activity to achieve more effective lipid management to reduce cardiovascular risk. To what degree this will reflect more optimal use of existing therapies or taking advantage of clinical benefits of emerging therapies will remain to be determined by clinical trials. 11.
Expert opinion
Since the first reports of the clinical efficacy of statins, there has been considerable activity to understand how these agents can be most optimally used. The data supporting a lower-isbetter concept is irrefutable and supports the calls for greater
Expert Opin. Pharmacother. (2014) 16(3)
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Laurentian University on 12/06/14 For personal use only.
Ongoing challenges for pharmacotherapy for dyslipidemia
use of high-intensity statin therapy in patients at a high risk of a cardiovascular event. The degree to which non-lipid lowering effects of statins contribute to their benefits is uncertain. There needs to be increasing efforts to maximize the number of patients who should be treated with a statin. A greater understanding of the safety of these compounds, which, reassuringly, appears to be encouraging from large analyses, will be important in achieving more widespread use of these agents. There is currently no evidence to support the concept of treating everyone with a statin; this decision continues to be driven by the overall cardiovascular risk of the patient. The failure to demonstrate benefit of fibrates and niacin in widespread use in statin-treated patients suggests that their use will remain in a targeted approach for patients with refractory dyslipidemia. As the findings of these trials have influenced clinical guidelines, the emergence of a range of additional lipid based biomarkers beyond LDL-C provide the opportunity for more targeted management of patients and development of novel lipid-modifying agents. CETP inhibitors continue to be of interest, by virtue of their ability to substantially raise HDL-C to a greater extent than previously observed and to incrementally lower LDL-C on top of a statin. Despite the early concerns with torcetrapib, there remains optimism that a potent CETP inhibitor without off-target toxicity will be of clinical benefit. Large outcome trials are currently under way, which will determine their fate. While originally developed on the basis of their ability to raise HDL-C, these agents may ultimately work simply by their lowering of atherogenic lipoprotein levels. PCSK9 inhibitors have been demonstrated to profoundly lower LDL-C levels in a range of settings. Given the Bibliography
2.
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-9 Cohen JD, Cziraky MJ, Cai Q, et al. 30-year trends in serum lipids among United States adults: results from the National Health and Nutrition Examination Surveys II, III, and 1999-2006. Am J Cardiol 2010;106:969-75
3.
Mampuya WM, Frid D, Rocco M, et al. Treatment strategies in patients with statin intolerance: the Cleveland Clinic experience. Am Heart J 2013;166:597-603
4.
Pedersen TR, Faergeman O, Kastelein JJ, et al. Incremental Decrease in End Points
Declaration of interest S Nicholls has received research support from AstraZeneca, Eli Lilly, Amgen, Novartis, Resverlogix, Cerenis and Infraredx and consulting fees from AstraZeneca, Amgen, Eli Lilly, CSL Behring, Boehringer Ingelheim, Merk, Takeda, Roche and Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Through Aggressive Lipid Lowering Study Group. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA 2005;294:2437-45
Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
magnitude of reduction of atherogenic lipoproteins, it would seem likely that this would translate to clinical benefit. The degree to which there is additional benefit in driving LDL-C to very low levels is unknown. Where they may be of much greater clinical utility will be in the patient with either familial hypercholesterolemia or statin intolerance, in whom baseline LDL-C levels are higher and will drive higher cardiovascular event rates. The relative safety of this approach and its ease and cost effectiveness will ultimately determine the extent to which we use these agents. Additional approaches are currently under investigation for their ability to favorably lower levels of atherogenic lipoproteins or to promote the protective functions of HDL. Clinical outcome trials will be required to determine the clinical utility of novel agents. It is likely that moving forward with multiple agents coming to clinical practice we will require implementation studies to determine what is the most effective option in a given patient in addition to statin therapy.
coronary heart disease and a broad range of initial cholesterol levels. The LongTerm Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group. N Engl J Med 1998;339:1349-57 8.
Shepherd J, Blauw GJ, Murphy MB, et al. PROSPER study group. PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360:1623-30
5.
LaRosa JC, Grundy SM, Waters DD, et al. Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425-35
9.
6.
Colhoun HM, Betteridge DJ, Durrington PN, et al. CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebocontrolled trial. Lancet 2004;364:685-96
Cannon CP, Braunwald E, McCabe CH, et al. Pravastatin or Atorvastatin Evaluation and Infection TherapyThrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;35:1495-504
10.
7.
Prevention of cardiovascular events and death with pravastatin in patients with
Austin PC, Mamdani MM. Impact of the pravastatin or atorvastatin evaluation and infection therapy-thrombolysis in
Expert Opin. Pharmacother. (2014) 16(3)
5
A. D. Pisaniello et al.
myocardial infarction 22/Reversal of Atherosclerosis with Aggressive Lipid Lowering trials on trends in intensive versus moderate statin therapy in Ontario, Canada. Circulation 2005;112:1296-300 11.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Laurentian University on 12/06/14 For personal use only.
12.
.
13.
.
14.
.
15.
.
16.
6
Carroll MD, Lacher DA, Sorlie PD, et al. Trends in serum lipids and lipoproteins of adults, 1960-2002. JAMA 2005;294:1773-81 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 2014;63:2889-934 Summarizes the current treatment guideline for dyslipidemia. European Association for Cardiovascular Prevention & Rehabilitation. Reiner Z, Catapano AL, De Backer G, et al. ESC Committee for Practice Guidelines (CPG) 2008-2010 and 2010-2012 Committees. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32:1769-818 Summarizes the current treatment guideline for dyslipidemia. Mora S, Otvos JD, Rifai N, et al. Lipoprotein particle profiles by nuclear magnetic resonance compared with standard lipids and apolipoproteins in predicting incident cardiovascular disease in women. Circulation 2009;119:931-9 Describes the importance of lipoprotein particle size in evaluating cardiovascular risks. El Harchaoui K, van der Steeg WA, Stroes ES, et al. Value of low-density lipoprotein particle number and size as predictors of coronary artery disease in apparently healthy men and women: the EPIC-Norfolk Prospective Population Study. J Am Coll Cardiol 2007;49:547-53 Describes the importance of lipoprotein particle size in evaluating cardiovascular risks. Otvos JD, Collins D, Freedman DS, et al. Low-density lipoprotein and highdensity lipoprotein particle subclasses
.
17.
.
18.
.
19.
.
20.
.
predict coronary events and are favorably changed by gemfibrozil therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial. Circulation 2006;113:1556-63 Describes the importance of lipoprotein particle size in evaluating cardiovascular risks. Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation 2007;115:450-8 Indicates the importance of other biomarkers to identify highrisk subjects. Miller M, Cannon CP, Murphy SA, et al. PROVE IT-TIMI 22 Investigators. Impact of triglyceride levels beyond lowdensity lipoprotein cholesterol after acute coronary syndrome in the PROVE ITTIMI 22 trial. J Am Coll Cardiol 2008;51:724-30 Indicates the importance of other biomarkers to identify highrisk subjects. Emerging Risk Factors Collaboration. Erqou S, Kaptoge S, Perry PL, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 2009;302:412-23 Indicates the importance of other biomarkers to identify highrisk subjects. Kugiyama K, Doi H, Takazoe K, et al. Remnant lipoprotein levels in fasting serum predict coronary events in patients with coronary artery disease. Circulation 1999;99:2858-60 Indicates the importance of other biomarkers to identify highrisk subjects.
21.
Gordon DJ, Probstfield JL, Garrison RJ, et al. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation 1989;79:8-15
22.
Gordon DJ, Rifkind BM. High-density lipoprotein - the clinical implications of recent studies. N Engl J Med 1989;321:1311-16
23.
Gordon T, Castelli WP, Hjortland MC, et al. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med 1977;62:707-14
Expert Opin. Pharmacother. (2014) 16(3)
24.
Barter P, Gotto AM, LaRosa JC, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007;357:1301-10
25.
Barter PJ, Caulfield M, Eriksson M, et al. ILLUMINATE Investigators. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109-22
26.
Schwartz GG, Olsson AG, Abt M, et al. dal-OUTCOMES Investigators. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012;367:2089-99
27.
AIM-HIGH Investigators. 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;365:2255-67 Reports the absence of benefit to use niacin for further reduction of cardiovascular events.
.
28.
.
29.
..
30.
..
31.
HPS2-THRIVE Collaborative Group. Landray MJ, Haynes R, Hopewell JC, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014;371:203-12 Reports the absence of benefit to use niacin for further reduction of cardiovascular events. Cannon CP, Braunwald E, McCabe CH, et al. Pravastatin or Atorvastatin Evaluation and Infection TherapyThrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;35:1495-504 Demonstrates more beneficial effect of potent statin on cardiovascular events and plaque progression. Pedersen TR, Faergeman O, Kastelein JJ, et al. Incremental Decrease in End Points Through Aggressive Lipid Lowering Study Group. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA 2005;294:2437-45 Demonstrates more beneficial effect of potent statin on cardiovascular events and plaque progression. LaRosa JC, Grundy SM, Waters DD, et al. Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable
Ongoing challenges for pharmacotherapy for dyslipidemia
..
32.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Laurentian University on 12/06/14 For personal use only.
..
33.
..
34.
..
35.
coronary disease. N Engl J Med 2005;352:1425-35 Demonstrates more beneficial effect of potent statin on cardiovascular events and plaque progression. Nissen SE, Nicholls SJ, Sipahi I, et al. ASTEROID Investigators. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006;295:1556-65 Demonstrates more beneficial effect of potent statin on cardiovascular events and plaque progression. Nicholls SJ, Ballantyne CM, Barter PJ, et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med 2011;365:2078-87 Demonstrates more beneficial effect of potent statin on cardiovascular events and plaque progression. Puri R, Nissen SE, Libby P, et al. C-reactive protein, but not low-density lipoprotein cholesterol levels, associate with coronary atheroma regression and cardiovascular events after maximally intensive statin therapy. Circulation 2013;128:2395-403 Highlights a key role of inflammation in plaque progression and cardiovascular event even in patients who achieved low low-density lipoprotein cholesterol level under potent statin therapy. Newman C, Tsai J, Szarek M, et al. Comparative safety of atorvastatin 80 mg versus 10 mg derived from analysis of 49 completed trials in 14,236 patients. Am J Cardiol 2006;97:61-7
36.
Bitzur R, Cohen H, Kamari Y, et al. Intolerance to statins: mechanisms and management. Diabetes Care 2013;36(Suppl 2):S325-30
37.
Grundy SM. Statin discontinuation and intolerance: the challenge of lifelong therapy. Ann Intern Med 2013;158:562-3
38.
Phan K, Gomez YH, Elbaz L, et al. Statin treatment non-adherence and discontinuation: clinical implications and potential solutions. Curr Pharm Des 2014;20(40):6314-24
39.
Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensivedose compared with moderate-dose statin therapy: a meta-analysis. JAMA 2011;305:2556-64
40.
Dormuth CR, Filion KB, Paterson JM, et al. Canadian Network for Observational Drug Effect Studies Investigators. Higher potency statins and the risk of new diabetes: multicentre, observational study of administrative databases. BMJ 2014;348:g3244
41.
Maki KC, Bays HE, Dicklin MR. Treatment options for the management of hypertriglyceridemia: strategies based on the best-available evidence. J Clin Lipidol 2012;6:413-26
42.
Koskinen P, Ma¨ntta¨ri M, Manninen V, et al. Coronary heart disease incidence in NIDDM patients in the Helsinki Heart Study. Diabetes Care 1992;15:820-5
43.
Rubins HB, Robins SJ, Collins D, et al. Diabetes, plasma insulin and cardiovascular disease. Subgroup analysis from the Department of Veterans Affairs high-density lipoprotein intervention trial (VA-HIT). Arch Intern Med 2002;162:2597-604
44.
Jacobson TA. Myopathy with statinfibrate combination therapy: clinical considerations. Nat Rev Endocrinol 2009;5:507-18
45.
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;366:1849-61
46.
ACCORD Study Group. Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-74
47.
Keech AC, Mitchell P, Summanen PA, et al. FIELD study investigators. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 2007;370:1687-97
48.
Rajamani K, Colman PG, Li LP, et al. FIELD study investigators. Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial. Lancet 2009;373:1780-8
49.
.
Lee M, Saver JL, Towfighi A, et al. Efficacy of fibrates for cardiovascular risk reduction in persons with atherogenic dyslipidemia: a meta-analysis. Atherosclerosis 2011;217:492-8 Indicates the benefit of fibrates to cardiovascular events. Expert Opin. Pharmacother. (2014) 16(3)
50.
.
Jun M, Foote C, Lv J, et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet 2010;375:1875-84 Indicates the benefit of fibrates to cardiovascular events.
51.
Nissen SE, Nicholls SJ, Wolski K, et al. Effects of a potent and selective PPARalpha agonist in patients with atherogenic dyslipidemia or hypercholesterolemia: two randomized controlled trials. JAMA 2007;297:1362-73
52.
Lincoff AM, Tardif JC, Schwartz GG, et al. AleCardio Investigators. Effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome in patients with type 2 diabetes mellitus: the AleCardio randomized clinical trial. JAMA 2014;311:1515-25
53.
Kamanna VS, Ganji SH, Kashyap ML. Recent advances in niacin and lipid metabolism. Curr Opin Lipidol 2013;24:239-45
54.
Bruckert E, Labreuche J, Amarenco P. Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis. Atherosclerosis 2010;210:353-61
55.
Lee JM, Robson MD, Yu LM, et al. Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function: a randomized, placebocontrolled, magnetic resonance imaging study. J Am Coll Cardiol 2009;54:1787-94
56.
Taylor AJ, Sullenberger LE, Lee HJ, et al. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo- controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 2004;110:3512-7
57.
Taylor AJ, Lee HJ, Sullenberger LE. The effect of 24 months of combination statin and extended-release niacin on carotid intima-media thickness: ARBITER 3. Curr Med Res Opin 2006;22:2243-50
58.
Cashin-Hemphill L, Mack WJ, Pogoda JM, et al. Beneficial effects of colestipol-niacin on coronary atherosclerosis. A 4-year follow-up. JAMA 1990;264:3013-17
59.
Taylor AJ, Sullenberger LE, Lee HJ, et al. Arterial Biology for the Investigation of the Treatment Effects of
7
A. D. Pisaniello et al.
Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 2004;110:3512-17 60.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Laurentian University on 12/06/14 For personal use only.
61.
62.
63.
64.
65.
66.
67.
68.
8
Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet 1989;2:757-61
69.
..
Harris WS, Poston WC, Haddock CK. Tissue n-3 and n-6 fatty acids and risk for coronary heart disease events. Atherosclerosis 2007;193:1-10
70.
Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation 2011;123:2292-333
71.
Berglund L, Brunzell JD, Goldberg AC, et al. Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012;97:2969-89
72.
Saravanan P, Davidson NC, Schmidt EB, et al. Cardiovascular effects of marine omega-3 fatty acids. Lancet 2010;376:540-50 Moertl D, Hammer A, Steiner S, et al. Dose-dependent effects of omega-3-polyunsaturated fatty acids on systolic left ventricular function, endothelial function, and markers of inflammation in chronic heart failure of nonischemic origin: a double-blind, placebo-controlled, 3-arm study. Am Heart J 2011;161:e1-9 Nomura S, Inami N, Shouzu A, et al. The effects of pitavastatin, eicosapentaenoic acid and combined therapy on platelet-derived microparticles and adiponectin in hyperlipidemic, diabetic patients. Platelets 2009;20:16-22 Calo` L, Bianconi L, Colivicchi F, et al. N-3 Fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: a randomized, controlled trial. J Am Coll Cardiol 2005;45:1723-8 Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI--Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet 1999;354:447-55
73.
74.
75.
76.
..
77.
Yokoyama M, Origasa H, Matsuzaki M, et al. Japan EPA lipid intervention study (JELIS) Investigators. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007;369:1090-8 Demonstrates the favorable effect of eicosapentaenoic acid on cardiovascular events. Barter PJ, Rye KA. Cholesteryl ester transfer protein inhibition as a strategy to reduce cardiovascular risk. J Lipid Res 2012;53:1755-66 Boekholdt SM, Kuivenhoven JA, Wareham NJ, et al. Plasma levels of cholesteryl ester transfer protein and the risk of future coronary artery disease in apparently healthy men and women: the prospective EPIC (European Prospective Investigation into Cancer and nutrition)Norfolk population study. Circulation 2004;110:1418-23 Kappelle PJ, Perton F, Hillege HL, et al. High plasma cholesteryl ester transfer but not CETP mass predicts incident cardiovascular disease: a nested casecontrol study. Atherosclerosis 2011;217:249-52 Koizumi J, Mabuchi H, Yoshimura A, et al. Deficiency of serum cholesterylester transfer activity in patients with familial hyperalphalipoproteinaemia. Atherosclerosis 1985;58:175-86 Inazu A, Brown ML, Hesler CB, et al. Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation. N Engl J Med 1990;323:1234-8 Harder C, Lau P, Meng A, et al. Cholesteryl ester transfer protein (CETP) expression protects against diet induced atherosclerosis in SR-BI deficient mice. Arterioscler Thromb Vasc Biol 2007;27:858-64 Nissen SE, Tardif JC, Nicholls SJ, et al. ILLUSTRATE Investigators. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 2007;356:1304-16 Evaluates the effect of torcetrapib on coronary atherosclerosis. Nicholls SJ, Tuzcu EM, Brennan DM, et al. Cholesteryl ester transfer protein inhibition, high-density lipoprotein raising, and progression of coronary atherosclerosis: insights from
Expert Opin. Pharmacother. (2014) 16(3)
..
ILLUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation). Circulation 2008;118:2506-14 Demonstrates that substantial increase in high-density lipoprotein cholesterol (HDL-C) under torcetrapib was associated with plaque regression.
78.
Duivenvoorden R, Fayad ZA. Safety of CETP inhibition. Curr Opin Lipidol 2012;23:518-24
79.
Robinson JG. Dalcetrapib: a review of Phase II data. Expert Opin Investig Drugs 2010;19:795-805
80.
Masson D. Anacetrapib, a cholesterol ester transfer protein (CETP) inhibitor for the treatment of atherosclerosis. Curr Opin Investig Drugs 2009;10:980-7
81.
Nicholls SJ. Evacetrapib. Curr Cardiol Rep 2012;14:245-50
82.
Cannon CP, Shah S, Dansky HM, et al. Determining the Efficacy and Tolerability Investigators. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med 2010;363:2406-15 Demonstrates the clinical efficacy and safety of novel cholesteryl ester transfer protein (CETP) inhibitors.
.
83.
.
Nicholls SJ, Brewer HB, Kastelein JJ, et al. Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. JAMA 2011;306:2099-109 Demonstrates the clinical efficacy and safety of novel CETP inhibitors.
84.
Seidah NG, Awan Z, Chretien M, et al. PCSK9: a key modulator of cardiovascular health. Circ Res 2014;114:1022-36
85.
Dadu RT, Ballantyne CM. Lipid lowering with PCSK9 inhibitors. Nat Rev Cardiol 2014;11:563-75
86.
Zhang DW, Lagace TA, Garuti R, et al. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem 2007;282:18602-12
87.
Mabuchi H, Nohara A, Noguchi T, et al. Hokuriku FH Study Group.
Ongoing challenges for pharmacotherapy for dyslipidemia
Genotypic and phenotypic features in homozygous familial hypercholesterolemia caused by proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutation. Atherosclerosis 2014;236:54-61
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Laurentian University on 12/06/14 For personal use only.
88.
89.
90.
91.
.
92.
.
93.
.
Benn M, Nordestgaard BG, Grande P, et al. PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses. J Am Coll Cardiol 2010;55:2833-42
94.
.
95.
Hooper AJ, Marais AD, Tanyanyiwa DM, et al. The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis 2007;193:445-8 Zhao Z, Tuakli-Wosornu Y, Lagace TA, et al. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet 2006;79:514-23 McKenney JM, Koren MJ, Kereiakes DJ, et al. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol 2012;59:2344-53 Reports the clinical efficacy and safety of proprotein convertase subtilisin kexin-type 9 (PCSK9) inhibitors in various subjects. Roth EM, McKenney JM, Hanotin C, et al. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med 2012;367:1891-900 Reports the clinical efficacy and safety of PCSK9 inhibitors in various subjects. Stein EA, Gipe D, Bergeron J, et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet 2012;380:29-36 Reports the clinical efficacy and safety of PCSK9 inhibitors in various subjects.
.
96.
97.
98.
Giugliano RP, Desai NR, Kohli P, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACETIMI 57): a randomised, placebocontrolled, dose-ranging, phase 2 study. Lancet 2012;380:2007-17 Reports the clinical efficacy and safety of PCSK9 inhibitors in various subjects. Koren MJ, Scott R, Kim JB, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebocontrolled, phase 2 study. Lancet 2012;380:1995-2006 Reports the clinical efficacy and safety of PCSK9 inhibitors in various subjects. Raal F, Scott R, Somaratne R, et al. Low-density lipoprotein cholesterollowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial. Circulation 2012;126:2408-17 Sullivan D, Olsson AG, Scott R, et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA 2012;308:2497-506 Rader DJ, Kastelein JJ. Lomitapide and mipomersen: two first-in-class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. Circulation 2014;129:1022-32
99.
Zheng C. Updates on apolipoprotein CIII: fulfilling promise as a therapeutic target for hypertriglyceridemia and cardiovascular disease. Curr Opin Lipidol 2014;25:35-9
100.
Graham MJ, Lee RG, Bell TA III, et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ Res 2013;112:1479-90
Expert Opin. Pharmacother. (2014) 16(3)
101. Suk Danik J, Rifai N, Buring JE, et al. Lipoprotein(a), hormone replacement therapy, and risk of future cardiovascular events. J Am Coll Cardiol 2008;52:124-31 102. Bochem AE, Kuivenhoven JA, Stroes ES. The promise of cholesteryl ester transfer protein (CETP) inhibition in the treatment of cardiovascular disease. Curr Pharm Des 2013;19:3143-9 103. Sahebkar A, Watts GF. New therapies targeting apoB metabolism for high-risk patients with inherited dyslipidaemias: what can the clinician expect? Cardiovasc Drugs Ther 2013;27:559-67 104. Kingwell BA, Chapman MJ. Future of high-density lipoprotein infusion therapies: potential for clinical management of vascular disease. Circulation 2013;128:1112-21 105. Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 2003;290:2292-300 . Investigates the effect of HDL infusion therapy on coronary atherosclerosis. 106. Tardif JC, Gregoire J, L’Allier PL, et al. Effect of rHDL on Atherosclerosis-Safety and Efficacy (ERASE) Investigators. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA 2007;297:1675-82 . Investigates the effect of HDL infusion therapy on coronary atherosclerosis. 107. Waksman R, Torguson R, Kent KM, et al. A first-in-man, randomized, placebo-controlled study to evaluate the safety and feasibility of autologous delipidated high-density lipoprotein plasma infusions in patients with acute coronary syndrome. J Am Coll Cardiol 2010;55:2727-35 . Investigates the effect of HDL infusion therapy on coronary atherosclerosis. 108. Tardif JC, Ballantyne CM, Barter P, et al. for the Can Hdl Infusions Significantly QUicken Atherosclerosis REgression (CHI-SQUARE) Investigators. Effects of the high-density lipoprotein mimetic agent CER-001 on coronary atherosclerosis in patients with acute coronary syndromes: a randomized trial. Eur Heart J 2014. [Epub ahead of print] . Investigates the effect of HDL infusion therapy on coronary atherosclerosis.
9
A. D. Pisaniello et al.
Affiliation
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Laurentian University on 12/06/14 For personal use only.
Anthony D Pisaniello1 MBBS, Daniel J Scherer2 MBBS, Yu Kataoka1 MD & Stephen J Nicholls†1,2 MBBS PhD † Author for correspondence 1 University of Adelaide, South Australian Health and Medical Research Institute, PO Box 11060, Adelaide, SA, 5001, Australia Tel: +61 8 8128 4510; E-mail: [email protected] 2 Royal Adelaide Hospital, Cardiovascular Investigation Unit, Adelaide, SA, Australia
10
Expert Opin. Pharmacother. (2014) 16(3)
Ongoing challenges for pharmacotherapy for dyslipidemia Anthony D Pisaniello, Daniel J Scherer, Yu Kataoka & Stephen J Nicholls† †
1.
Introduction
2.
Contemporary lipid targets
3.
Unresolved issues with statin
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Laurentian University on 12/06/14 For personal use only.
therapy 4.
Finding a role for fibrates
5.
Implications of recent trials of niacin
6.
Is there a benefit of omega-3 fatty acids?
7.
Cholesteryl ester transfer protein inhibitors
8.
Proprotein convertase subtilisin kexin-type 9 inhibitors
9.
University of Adelaide, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
Introduction: While increasing evidence has led to lipid-modifying therapy achieving an important role in the treatment guidelines for the prevention of cardiovascular disease, these agents are suboptimally used and there remains a considerable risk of clinical events. Accordingly, there is a need to develop more effective lipid-modifying approaches in many patients. Areas covered: A literature search was performed of topical manuscripts focusing on factors influencing use of established therapies and new agents in development that target a range of lipid factors. Expert opinion: More intensive efforts are required to ensure that statin use is maximized in higher risk patients. A range of novel therapies, including proprotein convertase subtilisin kexin-type 9 and cholesteryl ester transfer protein inhibitors, may provide additional protection, although this remains to be established by clinical trials.
Other options for dyslipidemia
10.
Summary
11.
Expert opinion
Keywords: atherosclerosis, cardiovascular risk, lipid-modifying therapy, lipids Expert Opin. Pharmacother. [Early Online]
1.
Introduction
In the 20 years following the first report of clinical benefits of statins [1] these agents have been increasingly used in clinical practice [2] and have had a profound impact in the prevention of cardiovascular events. Despite these benefits, there remains uncertainty with regard to their optimal approach in all patients, challenges in maximizing tolerated doses [3] and a considerable residual risk of clinical events [4,5]. Accordingly, there is an ongoing need to formulate more effective approaches to promote optimal use of established lipid-modifying therapies. In parallel, there is considerable interest in the development of novel agents in order to achieve more effective reductions in cardiovascular risk (Table 1). 2.
Contemporary lipid targets
Accumulating evidence from clinical trials and meta-analyses has reinforced the concept that intensively lowering levels of low-density lipoprotein cholesterol (LDL-C) plays an important role in reducing cardiovascular risk [6-9]. This has supported the concept of proposing increasingly aggressive treatment targets for LDL-C in clinical practice. While most physicians support this concept of intensive lipid lowering, many patients fail to meet prescribed targets. This is likely to reflect some degree of clinical inertia with regard to statin dose escalation and the emergence of statin intolerance [10,11]. Despite this, the most recent updates to treatment guidelines have recommended more widespread use of high-intensity statin therapy, potentially requiring less reliance on treatment targets [12,13]. It is likely that demonstrating clinical benefit with new agents that more aggressively lower LDL-C will lead to further updates of guidelines that endorse lower treatment targets. In parallel, there is increasing interest in the clinical use of lipid biomarkers beyond LDL-C. Novel indices that characterize LDL particle concentration and size including apolipoprotein B (apoB) and nuclear magnetic resonance 10.1517/14656566.2014.986094 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
1
A. D. Pisaniello et al.
Article highlights. .
.
.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Laurentian University on 12/06/14 For personal use only.
.
Current lipid-modifying agents can have a profound impact on cardiovascular outcomes, although they are not optimally used. A range of novel lipid biomarkers beyond low-density lipoprotein cholesterol (LDL-C) may be of use in clinical practice and to guide development of new agents. Despite early failures there remains considerable optimism that cholesteryl ester transfer protein inhibitors that raise high-density lipoprotein cholesterol and lower LDL-C will reduce clinical events. Proprotein convertase subtilisin kexin-type 9 inhibitors produce profound LDL-C lowering in a range of disorders, and their clinical benefit is currently undergoing evaluation in clinical trials.
This box summarizes key points contained in the article.
muscle or other organ injury is low [33,35]. More effective approaches are required to manage the patient with some degree of intolerance to statin therapy [36]. This is demonstrated not only by reports of a high rate of discontinuation of statin therapy in clinical practice [37,38], but also by the fact that this can be significantly mitigated by a comprehensive approach to try and reinstate therapy in many patients. Furthermore, while the data have consistently demonstrated a greater signal of new diagnosis of type 2 diabetes with more potent statin therapy [39,40], their cardiovascular benefits in the appropriate high risk patients would seem to outweigh any adverse effect on glycemic control. Nevertheless, statin therapy will be the standard of care background therapy on top of which all new lipid-modifying therapies are evaluated. 4.
spectroscopy have been reported to provide incremental risk prediction beyond traditional measures of their cholesterol content [14-16]. Similarly, increasing reports have highlighted the potential importance of other atherogenic lipid parameters including triglycerides [17,18], lipoprotein (a) [Lp(a)] [19] and remnant cholesterol [20]. Ultimately, the measurement of non-high-density lipoprotein cholesterol may provide the best utility in clinical practice, given its ability to quantify the full extent of atherogenic lipoproteins. Measures of high-density lipoprotein cholesterol (HDL-C) provide a characterization of protective lipids with consistent reports of an inverse relationship between systemic levels and cardiovascular risk [21-24]. Given the lack of data demonstrating that novel HDL targeted therapies reduce cardiovascular events [25-28], it remains to be determined whether there will ever be a treatment target for HDL-C. To what degree measures of HDL particles or its functional quality will be integrated into clinical practice remains to be determined.
For > 50 years, various fibric acid derivatives have been used to prevent cardiovascular events with variable efficacy [41]. The most efficacious of these agents in clinical trials, gemfibrozil [42,43], proves difficult to administer in addition to statin therapy [44]. While more recent studies of fenofibrate have not positively influenced the primary endpoint in large trials [45,46], there has been some suggestion of benefit on hard clinical endpoints (death, myocardial infarction, stroke) in patients with prior cardiovascular events [45] and on microvascular endpoints in diabetic patients [47,48]. Large metaanalyses of fibrate studies suggest a marginal cardiovascular benefit, which is much greater in patients with baseline hypertriglyceridemia and low HDL-C levels, reflecting the patient in whom these agents are primarily used in clinical practice [49,50]. Additional efforts to develop more potent pharmacological agonists of PPAR-a or dual PPAR-a/g agonists have not proven to be efficacious in clinical trials and have demonstrated considerable safety issues [51,52]. It remains to be determined whether a novel agent from this class will be successful. 5.
3.
Implications of recent trials of niacin
Unresolved issues with statin therapy
As the evidence supporting the use of statins has accumulated, it has become increasingly apparent that a greater benefit is observed with the use of high-intensity statin therapy [29-33]. To what degree this is driven by more aggressive LDL-C lowering or the relative contribution by reported pleiotropic effects of statins remains uncertain. The finding that lowering C-reactive protein independently associates with the benefit of statins on clinical events and plaque progression suggests that anti-inflammatory properties of statins may contribute to their clinical benefit [34]. As the cost of statins has declined, accessibility should increase, enabling recommendations for their increasing use. There needs to be greater emphasis on the safety and efficacy of use of high-intensity statin therapy. Better understanding of the safety of these agents is required. While myalgia is commonly encountered, the incidence of 2
Finding a role for fibrates
Niacin has been widely used to manage a range of forms of dyslipidemia, given its ability to effectively raise HDL-C in addition to lowering triglycerides, LDL-C and Lp(a) [53]. Early studies prior to the development of statins suggested that immediate release formulations of niacin reduce cardiovascular events [54-57], with subsequent reports of a favorable effect on disease progression in the artery wall [58,59]. However, near ubiquitous experience of flushing with niacin has limited its use in many patients resulting in exploration of mechanisms to improve its tolerance [53]. Despite efforts to prolong its pharmacological release or co-administration with a chemical inhibitor of the interaction of niacin with epidermal prostanoid receptors, the presumed mechanism underlying flushing, this has not reduced cardiovascular morbidity and mortality in large trials of statin-treated patients [27,28]. When combined with a number of safety
Expert Opin. Pharmacother. (2014) 16(3)
Ongoing challenges for pharmacotherapy for dyslipidemia
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Laurentian University on 12/06/14 For personal use only.
Table 1. Current and emerging lipid-modifying agents. Therapeutic class
Target
Lipid effects
Clinical notes
Statins
HMGCoA reductase inhibitor
Fibrates
PPAR-a agonist
Lower LDL-C Variable HDL-C raising Lower triglyceride Raise HDL-C
Niacin
G protein receptor agonist
Guidelines promote increasing use of statins and more potent therapy Early benefit with gemfibrozil which is difficult to administer with statins Consistent benefit in patients with baseline hypertriglyceridemia and low HDL-C Early benefit prior to statin use Anti-atherosclerotic properties No convincing benefit in recent large trials
PCSK9 inhibitors
PCSK9 inhibition
Omega-3 fatty acids CETP inhibitors
Variable effects on lipolytic enzymes in blood and factors involved in hepatic lipoprotein synthesis CETP inhibition
Mipomersin
Antisense apoB therapy
Lomitapide
Microsomal transfer protein inhibitor
Anti-apoCIII therapy
Antisense apoCIII therapy
Raising HDL-C Lowering triglyceride Lowering LDL-C Lowering Lp(a) Lower LDL-C Lower Lp(a) Lower triglyceride
Raising HDL-C Lowering LDL-C Lowering Lp(a) Lowering triglyceride Lowering LDL-C Lowering triglyceride Lowering LDL-C Lowering triglyceride Lowering triglyceride Lowering LDL-C
Subcutaneous administration 2 -- 4 weekly Clinical trials in progress Clinical trials in progress
Mortality signal with torcetrapib Clinical futility with dalcetrapib Potent CETP inhibitors without off target toxicity currently in clinical trials Injection site reactions Some hepatic steatosis Clinical trials in progress
Apo: Apolipoprotein; apoC-III: Apolipoprotein C-III; CETP: Cholesteryl ester transfer protein; HDL-C: High-density lipoprotein cholesterol; HMGCoA: 3-hydroxy3-methylglutaryl; LDL-C: Low-density lipoprotein cholesterol; Lp(a): Lipoprotein (a); PCSK9: Proprotein convertase subtilisin kexin 9.
concerns that have emerged in these trials, it would appear that niacin will remain a niche agent for the management of refractory dyslipidemia and not be widely used. 6.
Is there a benefit of omega-3 fatty acids?
Observational studies have demonstrated an inverse relationship between both consumption and systemic levels of omega-3 fatty acids and cardiovascular risk [60,61]. These data have been embraced by treatment guidelines that recommend minimum dietary consumption of omega-3 fatty acids for prevention of cardiovascular disease [62,63]. Their benefit is likely to be multifactorial related to their ability to lower triglycerides and levels of atherogenic lipoproteins, antithrombotic and anti-arrhythmic effects [64-67]. To what degree pharmacological administration of omega-3 fatty acids results in cardiovascular benefit is unknown. While early reports prior to the use of statin therapy suggested some potential benefit [60,68], this has been difficult to confirm in more recent trials. A consistent criticism of failed clinical trials has reflected concerns with regard to use of relatively small doses and evaluation in broader populations, where a more targeted approach may have been more likely to be effective. This is supported by Japanese data demonstrating that larger doses of omega-3 fatty acids reduce cardiovascular events in statintreated patients [69]. Such findings have supported the
development of large programs that are currently evaluating the clinical effects of eicasopentanoic acid either as monotherapy or in combination with docasohexanoic acid in large quantities in statin-treated patients with elevated triglyceride levels. The results of these trials will definitively provide the answer to the question of whether omega-3 supplementation is of clinical benefit. 7.
Cholesteryl ester transfer protein inhibitors
Cholesteryl ester transfer protein (CETP) facilitates the transfer of esterified cholesterol from HDL to very low-density lipoproteins and LDL particles, in exchange for triglyceride [70]. Numerous lines of evidence suggest that CETP may be a promising target for cardiovascular prevention. Populations with low CETP activity and associated higher HDL-C levels appear to be protected from cardiovascular disease [71,72]. This is supported by genetic studies that demonstrate associations between polymorphisms resulting in low CETP activity with high HDL-C levels and less cardiovascular events [73,74], suggesting that CETP may play a causal role in the disease. Attempts to reduce CETP activity in animals that endogenously express CETP have a favorable effect on atherosclerotic plaque [75]. The clinical development of CETP inhibitors has proven challenging. The first agent to reach an advanced stage of
Expert Opin. Pharmacother. (2014) 16(3)
3
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Laurentian University on 12/06/14 For personal use only.
A. D. Pisaniello et al.
clinical development, torcetrapib, had no effect on plaque progression and was demonstrated to have an adverse effect on cardiovascular events and mortality [25,76]. These findings promoted considerable debate whether the problem reflected the generation of dysfunctional HDL with CETP inhibition or a molecule specific problem. Subsequent reports of intact cholesterol efflux to HDL from CETP deficient and torcetrapib-treated patients, plaque regression at the highest HDL-C levels with torcetrapib [77] and the demonstration that torcetrapib has a range of non-CETP mediated adverse effects on blood pressure, adrenal hormone synthesis and endothelin expression within the artery wall supported the concept that the adverse effects were more likely to reflect off-target toxicities [78]. Accordingly, the ability to develop other CETP inhibitors without such toxicity might still prove to be of clinical utility. Dalcetrapib [79], a modest CETP inhibitor in terms of HDL-C raising and no LDL-C lowering, had no clinical impact in a large trial [26]. Two ongoing trials are evaluating the effects of the potent CETP inhibitors, anacetrapib [80] and evacetrapib [81]. These agents raise HDL-C by > 120% and lower LDL-C by at least 25% in statin-treated patients and appear to lack the adverse effects of torcetrapib [82,83]. Whether potential benefit of these agents is due to their profound effects on HDL-C levels or simply due to incremental LDL-C lowering remains unknown. Ultimately, the impact of these agents on cardiovascular outcomes will determine whether they become available in clinical practice.
Proprotein convertase subtilisin kexin-type 9 inhibitors 8.
Proprotein convertase subtilisin kexin-type 9 (PCSK9) plays an important role in lipid homeostasis [84]. Molecular studies have elucidated that following interaction between circulating LDL particles and the LDL receptor on the liver surface, this complex is internalized, the LDL particle removed enabling for shuttling of the receptor back to the liver surface [85]. This provides an elegant mechanism facilitating removal of excess lipid from the circulation. PCSK9 has been identified to inhibit LDL receptor recycling to the liver surface [86] and as result represents an autosomal dominant form of hypercholesterolemia [87]. Further genetic studies have demonstrated that polymorphisms resulting in low PCSK9 activity associate with lower LDL-C levels and considerably lower cardiovascular event rates, reflecting the importance of lifelong exposure to low LDL-C levels [88-90]. Early studies with subcutaneous administration of human monoclonal antibodies against PCSK9 2 -- 4 weekly result in profound dose dependent reductions in LDL-C up to 70% in a broad range of patients [91-95]. Of particular interest is their ability to effectively lower LDL-C in patients with familial hypercholesterolemia or statin intolerance [96,97], both conditions presenting a challenge for strategies to reduce cardiovascular risk. The impact of these agents on cardiovascular events is currently undergoing evaluation in large clinical trials. The extent of 4
LDL-C lowering would suggest that these agents are likely to be clinically efficacious. The degree of benefit, safety, ease of use and cost will ultimately determine to what extent these agents are used in clinical practice. Their use in familial hypercholesterolemia would seem to be most likely. The degree of benefit in broader populations and their cost effectiveness will influence how widely they will be used. 9.
Other options for dyslipidemia
While most focus in the lipid field has concentrated on the development of CETP and PCSK9 inhibitors, there has been considerable activity in other classes as well. Mipomersin is an antisense oligonucleotide based therapy that inhibits apoB expression with evidence of LDL-C lowering up to 50% and is well tolerated apart from injection site reactions [98]. Microsomal transfer protein (MTP) packages neutral lipids into nascent atherogenic lipoproteins within the liver [98]. MTP inhibition with lomitapide lowers LDL-C by up to 50%, although with evidence of hepatic steatosis, the clinical implications of which are unknown. Both of these agents have been approved for use in patients with familial hypercholesterolemia. Apolipoprotein C-III (apoC-III) plays a pivotal role in the metabolism of triglyceride rich lipoproteins and has direct proatherogenic effects at the level of the artery wall [99]. Early experience with antisense therapy directed against apoC-III has demonstrated triglyceride lowering by up to 70% [100]. These encouraging early findings require further exploration in larger trials. While there is considerable interest in Lp(a) as an important factor driving atherosclerosis [19], agents that lower Lp(a) have not been demonstrated to reduce clinical events (niacin, oestrogen) [27,28,101]. While CETP and PCSK9 inhibitors reduce Lp(a) levels [102,103], there remains a need to develop more targeted Lp(a) therapies. From the HDL perspective, there continues to be interest in the concept of infusing lipid-deplete forms of HDL [104], with early evidence of regression in imaging studies [105-108]. Their effect on clinical outcomes is currently not known. 10.
Summary
While statins have been clinically available for two decades, there continues to be activity to achieve more effective lipid management to reduce cardiovascular risk. To what degree this will reflect more optimal use of existing therapies or taking advantage of clinical benefits of emerging therapies will remain to be determined by clinical trials. 11.
Expert opinion
Since the first reports of the clinical efficacy of statins, there has been considerable activity to understand how these agents can be most optimally used. The data supporting a lower-isbetter concept is irrefutable and supports the calls for greater
Expert Opin. Pharmacother. (2014) 16(3)
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Laurentian University on 12/06/14 For personal use only.
Ongoing challenges for pharmacotherapy for dyslipidemia
use of high-intensity statin therapy in patients at a high risk of a cardiovascular event. The degree to which non-lipid lowering effects of statins contribute to their benefits is uncertain. There needs to be increasing efforts to maximize the number of patients who should be treated with a statin. A greater understanding of the safety of these compounds, which, reassuringly, appears to be encouraging from large analyses, will be important in achieving more widespread use of these agents. There is currently no evidence to support the concept of treating everyone with a statin; this decision continues to be driven by the overall cardiovascular risk of the patient. The failure to demonstrate benefit of fibrates and niacin in widespread use in statin-treated patients suggests that their use will remain in a targeted approach for patients with refractory dyslipidemia. As the findings of these trials have influenced clinical guidelines, the emergence of a range of additional lipid based biomarkers beyond LDL-C provide the opportunity for more targeted management of patients and development of novel lipid-modifying agents. CETP inhibitors continue to be of interest, by virtue of their ability to substantially raise HDL-C to a greater extent than previously observed and to incrementally lower LDL-C on top of a statin. Despite the early concerns with torcetrapib, there remains optimism that a potent CETP inhibitor without off-target toxicity will be of clinical benefit. Large outcome trials are currently under way, which will determine their fate. While originally developed on the basis of their ability to raise HDL-C, these agents may ultimately work simply by their lowering of atherogenic lipoprotein levels. PCSK9 inhibitors have been demonstrated to profoundly lower LDL-C levels in a range of settings. Given the Bibliography
2.
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-9 Cohen JD, Cziraky MJ, Cai Q, et al. 30-year trends in serum lipids among United States adults: results from the National Health and Nutrition Examination Surveys II, III, and 1999-2006. Am J Cardiol 2010;106:969-75
3.
Mampuya WM, Frid D, Rocco M, et al. Treatment strategies in patients with statin intolerance: the Cleveland Clinic experience. Am Heart J 2013;166:597-603
4.
Pedersen TR, Faergeman O, Kastelein JJ, et al. Incremental Decrease in End Points
Declaration of interest S Nicholls has received research support from AstraZeneca, Eli Lilly, Amgen, Novartis, Resverlogix, Cerenis and Infraredx and consulting fees from AstraZeneca, Amgen, Eli Lilly, CSL Behring, Boehringer Ingelheim, Merk, Takeda, Roche and Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Through Aggressive Lipid Lowering Study Group. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA 2005;294:2437-45
Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
magnitude of reduction of atherogenic lipoproteins, it would seem likely that this would translate to clinical benefit. The degree to which there is additional benefit in driving LDL-C to very low levels is unknown. Where they may be of much greater clinical utility will be in the patient with either familial hypercholesterolemia or statin intolerance, in whom baseline LDL-C levels are higher and will drive higher cardiovascular event rates. The relative safety of this approach and its ease and cost effectiveness will ultimately determine the extent to which we use these agents. Additional approaches are currently under investigation for their ability to favorably lower levels of atherogenic lipoproteins or to promote the protective functions of HDL. Clinical outcome trials will be required to determine the clinical utility of novel agents. It is likely that moving forward with multiple agents coming to clinical practice we will require implementation studies to determine what is the most effective option in a given patient in addition to statin therapy.
coronary heart disease and a broad range of initial cholesterol levels. The LongTerm Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group. N Engl J Med 1998;339:1349-57 8.
Shepherd J, Blauw GJ, Murphy MB, et al. PROSPER study group. PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360:1623-30
5.
LaRosa JC, Grundy SM, Waters DD, et al. Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425-35
9.
6.
Colhoun HM, Betteridge DJ, Durrington PN, et al. CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebocontrolled trial. Lancet 2004;364:685-96
Cannon CP, Braunwald E, McCabe CH, et al. Pravastatin or Atorvastatin Evaluation and Infection TherapyThrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;35:1495-504
10.
7.
Prevention of cardiovascular events and death with pravastatin in patients with
Austin PC, Mamdani MM. Impact of the pravastatin or atorvastatin evaluation and infection therapy-thrombolysis in
Expert Opin. Pharmacother. (2014) 16(3)
5
A. D. Pisaniello et al.
myocardial infarction 22/Reversal of Atherosclerosis with Aggressive Lipid Lowering trials on trends in intensive versus moderate statin therapy in Ontario, Canada. Circulation 2005;112:1296-300 11.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Laurentian University on 12/06/14 For personal use only.
12.
.
13.
.
14.
.
15.
.
16.
6
Carroll MD, Lacher DA, Sorlie PD, et al. Trends in serum lipids and lipoproteins of adults, 1960-2002. JAMA 2005;294:1773-81 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 2014;63:2889-934 Summarizes the current treatment guideline for dyslipidemia. European Association for Cardiovascular Prevention & Rehabilitation. Reiner Z, Catapano AL, De Backer G, et al. ESC Committee for Practice Guidelines (CPG) 2008-2010 and 2010-2012 Committees. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32:1769-818 Summarizes the current treatment guideline for dyslipidemia. Mora S, Otvos JD, Rifai N, et al. Lipoprotein particle profiles by nuclear magnetic resonance compared with standard lipids and apolipoproteins in predicting incident cardiovascular disease in women. Circulation 2009;119:931-9 Describes the importance of lipoprotein particle size in evaluating cardiovascular risks. El Harchaoui K, van der Steeg WA, Stroes ES, et al. Value of low-density lipoprotein particle number and size as predictors of coronary artery disease in apparently healthy men and women: the EPIC-Norfolk Prospective Population Study. J Am Coll Cardiol 2007;49:547-53 Describes the importance of lipoprotein particle size in evaluating cardiovascular risks. Otvos JD, Collins D, Freedman DS, et al. Low-density lipoprotein and highdensity lipoprotein particle subclasses
.
17.
.
18.
.
19.
.
20.
.
predict coronary events and are favorably changed by gemfibrozil therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial. Circulation 2006;113:1556-63 Describes the importance of lipoprotein particle size in evaluating cardiovascular risks. Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation 2007;115:450-8 Indicates the importance of other biomarkers to identify highrisk subjects. Miller M, Cannon CP, Murphy SA, et al. PROVE IT-TIMI 22 Investigators. Impact of triglyceride levels beyond lowdensity lipoprotein cholesterol after acute coronary syndrome in the PROVE ITTIMI 22 trial. J Am Coll Cardiol 2008;51:724-30 Indicates the importance of other biomarkers to identify highrisk subjects. Emerging Risk Factors Collaboration. Erqou S, Kaptoge S, Perry PL, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 2009;302:412-23 Indicates the importance of other biomarkers to identify highrisk subjects. Kugiyama K, Doi H, Takazoe K, et al. Remnant lipoprotein levels in fasting serum predict coronary events in patients with coronary artery disease. Circulation 1999;99:2858-60 Indicates the importance of other biomarkers to identify highrisk subjects.
21.
Gordon DJ, Probstfield JL, Garrison RJ, et al. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation 1989;79:8-15
22.
Gordon DJ, Rifkind BM. High-density lipoprotein - the clinical implications of recent studies. N Engl J Med 1989;321:1311-16
23.
Gordon T, Castelli WP, Hjortland MC, et al. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med 1977;62:707-14
Expert Opin. Pharmacother. (2014) 16(3)
24.
Barter P, Gotto AM, LaRosa JC, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007;357:1301-10
25.
Barter PJ, Caulfield M, Eriksson M, et al. ILLUMINATE Investigators. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109-22
26.
Schwartz GG, Olsson AG, Abt M, et al. dal-OUTCOMES Investigators. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012;367:2089-99
27.
AIM-HIGH Investigators. 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;365:2255-67 Reports the absence of benefit to use niacin for further reduction of cardiovascular events.
.
28.
.
29.
..
30.
..
31.
HPS2-THRIVE Collaborative Group. Landray MJ, Haynes R, Hopewell JC, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014;371:203-12 Reports the absence of benefit to use niacin for further reduction of cardiovascular events. Cannon CP, Braunwald E, McCabe CH, et al. Pravastatin or Atorvastatin Evaluation and Infection TherapyThrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;35:1495-504 Demonstrates more beneficial effect of potent statin on cardiovascular events and plaque progression. Pedersen TR, Faergeman O, Kastelein JJ, et al. Incremental Decrease in End Points Through Aggressive Lipid Lowering Study Group. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA 2005;294:2437-45 Demonstrates more beneficial effect of potent statin on cardiovascular events and plaque progression. LaRosa JC, Grundy SM, Waters DD, et al. Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable
Ongoing challenges for pharmacotherapy for dyslipidemia
..
32.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Laurentian University on 12/06/14 For personal use only.
..
33.
..
34.
..
35.
coronary disease. N Engl J Med 2005;352:1425-35 Demonstrates more beneficial effect of potent statin on cardiovascular events and plaque progression. Nissen SE, Nicholls SJ, Sipahi I, et al. ASTEROID Investigators. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006;295:1556-65 Demonstrates more beneficial effect of potent statin on cardiovascular events and plaque progression. Nicholls SJ, Ballantyne CM, Barter PJ, et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med 2011;365:2078-87 Demonstrates more beneficial effect of potent statin on cardiovascular events and plaque progression. Puri R, Nissen SE, Libby P, et al. C-reactive protein, but not low-density lipoprotein cholesterol levels, associate with coronary atheroma regression and cardiovascular events after maximally intensive statin therapy. Circulation 2013;128:2395-403 Highlights a key role of inflammation in plaque progression and cardiovascular event even in patients who achieved low low-density lipoprotein cholesterol level under potent statin therapy. Newman C, Tsai J, Szarek M, et al. Comparative safety of atorvastatin 80 mg versus 10 mg derived from analysis of 49 completed trials in 14,236 patients. Am J Cardiol 2006;97:61-7
36.
Bitzur R, Cohen H, Kamari Y, et al. Intolerance to statins: mechanisms and management. Diabetes Care 2013;36(Suppl 2):S325-30
37.
Grundy SM. Statin discontinuation and intolerance: the challenge of lifelong therapy. Ann Intern Med 2013;158:562-3
38.
Phan K, Gomez YH, Elbaz L, et al. Statin treatment non-adherence and discontinuation: clinical implications and potential solutions. Curr Pharm Des 2014;20(40):6314-24
39.
Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensivedose compared with moderate-dose statin therapy: a meta-analysis. JAMA 2011;305:2556-64
40.
Dormuth CR, Filion KB, Paterson JM, et al. Canadian Network for Observational Drug Effect Studies Investigators. Higher potency statins and the risk of new diabetes: multicentre, observational study of administrative databases. BMJ 2014;348:g3244
41.
Maki KC, Bays HE, Dicklin MR. Treatment options for the management of hypertriglyceridemia: strategies based on the best-available evidence. J Clin Lipidol 2012;6:413-26
42.
Koskinen P, Ma¨ntta¨ri M, Manninen V, et al. Coronary heart disease incidence in NIDDM patients in the Helsinki Heart Study. Diabetes Care 1992;15:820-5
43.
Rubins HB, Robins SJ, Collins D, et al. Diabetes, plasma insulin and cardiovascular disease. Subgroup analysis from the Department of Veterans Affairs high-density lipoprotein intervention trial (VA-HIT). Arch Intern Med 2002;162:2597-604
44.
Jacobson TA. Myopathy with statinfibrate combination therapy: clinical considerations. Nat Rev Endocrinol 2009;5:507-18
45.
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;366:1849-61
46.
ACCORD Study Group. Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-74
47.
Keech AC, Mitchell P, Summanen PA, et al. FIELD study investigators. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 2007;370:1687-97
48.
Rajamani K, Colman PG, Li LP, et al. FIELD study investigators. Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial. Lancet 2009;373:1780-8
49.
.
Lee M, Saver JL, Towfighi A, et al. Efficacy of fibrates for cardiovascular risk reduction in persons with atherogenic dyslipidemia: a meta-analysis. Atherosclerosis 2011;217:492-8 Indicates the benefit of fibrates to cardiovascular events. Expert Opin. Pharmacother. (2014) 16(3)
50.
.
Jun M, Foote C, Lv J, et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet 2010;375:1875-84 Indicates the benefit of fibrates to cardiovascular events.
51.
Nissen SE, Nicholls SJ, Wolski K, et al. Effects of a potent and selective PPARalpha agonist in patients with atherogenic dyslipidemia or hypercholesterolemia: two randomized controlled trials. JAMA 2007;297:1362-73
52.
Lincoff AM, Tardif JC, Schwartz GG, et al. AleCardio Investigators. Effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome in patients with type 2 diabetes mellitus: the AleCardio randomized clinical trial. JAMA 2014;311:1515-25
53.
Kamanna VS, Ganji SH, Kashyap ML. Recent advances in niacin and lipid metabolism. Curr Opin Lipidol 2013;24:239-45
54.
Bruckert E, Labreuche J, Amarenco P. Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis. Atherosclerosis 2010;210:353-61
55.
Lee JM, Robson MD, Yu LM, et al. Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function: a randomized, placebocontrolled, magnetic resonance imaging study. J Am Coll Cardiol 2009;54:1787-94
56.
Taylor AJ, Sullenberger LE, Lee HJ, et al. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo- controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 2004;110:3512-7
57.
Taylor AJ, Lee HJ, Sullenberger LE. The effect of 24 months of combination statin and extended-release niacin on carotid intima-media thickness: ARBITER 3. Curr Med Res Opin 2006;22:2243-50
58.
Cashin-Hemphill L, Mack WJ, Pogoda JM, et al. Beneficial effects of colestipol-niacin on coronary atherosclerosis. A 4-year follow-up. JAMA 1990;264:3013-17
59.
Taylor AJ, Sullenberger LE, Lee HJ, et al. Arterial Biology for the Investigation of the Treatment Effects of
7
A. D. Pisaniello et al.
Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 2004;110:3512-17 60.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Laurentian University on 12/06/14 For personal use only.
61.
62.
63.
64.
65.
66.
67.
68.
8
Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet 1989;2:757-61
69.
..
Harris WS, Poston WC, Haddock CK. Tissue n-3 and n-6 fatty acids and risk for coronary heart disease events. Atherosclerosis 2007;193:1-10
70.
Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation 2011;123:2292-333
71.
Berglund L, Brunzell JD, Goldberg AC, et al. Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012;97:2969-89
72.
Saravanan P, Davidson NC, Schmidt EB, et al. Cardiovascular effects of marine omega-3 fatty acids. Lancet 2010;376:540-50 Moertl D, Hammer A, Steiner S, et al. Dose-dependent effects of omega-3-polyunsaturated fatty acids on systolic left ventricular function, endothelial function, and markers of inflammation in chronic heart failure of nonischemic origin: a double-blind, placebo-controlled, 3-arm study. Am Heart J 2011;161:e1-9 Nomura S, Inami N, Shouzu A, et al. The effects of pitavastatin, eicosapentaenoic acid and combined therapy on platelet-derived microparticles and adiponectin in hyperlipidemic, diabetic patients. Platelets 2009;20:16-22 Calo` L, Bianconi L, Colivicchi F, et al. N-3 Fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: a randomized, controlled trial. J Am Coll Cardiol 2005;45:1723-8 Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI--Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet 1999;354:447-55
73.
74.
75.
76.
..
77.
Yokoyama M, Origasa H, Matsuzaki M, et al. Japan EPA lipid intervention study (JELIS) Investigators. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007;369:1090-8 Demonstrates the favorable effect of eicosapentaenoic acid on cardiovascular events. Barter PJ, Rye KA. Cholesteryl ester transfer protein inhibition as a strategy to reduce cardiovascular risk. J Lipid Res 2012;53:1755-66 Boekholdt SM, Kuivenhoven JA, Wareham NJ, et al. Plasma levels of cholesteryl ester transfer protein and the risk of future coronary artery disease in apparently healthy men and women: the prospective EPIC (European Prospective Investigation into Cancer and nutrition)Norfolk population study. Circulation 2004;110:1418-23 Kappelle PJ, Perton F, Hillege HL, et al. High plasma cholesteryl ester transfer but not CETP mass predicts incident cardiovascular disease: a nested casecontrol study. Atherosclerosis 2011;217:249-52 Koizumi J, Mabuchi H, Yoshimura A, et al. Deficiency of serum cholesterylester transfer activity in patients with familial hyperalphalipoproteinaemia. Atherosclerosis 1985;58:175-86 Inazu A, Brown ML, Hesler CB, et al. Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation. N Engl J Med 1990;323:1234-8 Harder C, Lau P, Meng A, et al. Cholesteryl ester transfer protein (CETP) expression protects against diet induced atherosclerosis in SR-BI deficient mice. Arterioscler Thromb Vasc Biol 2007;27:858-64 Nissen SE, Tardif JC, Nicholls SJ, et al. ILLUSTRATE Investigators. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 2007;356:1304-16 Evaluates the effect of torcetrapib on coronary atherosclerosis. Nicholls SJ, Tuzcu EM, Brennan DM, et al. Cholesteryl ester transfer protein inhibition, high-density lipoprotein raising, and progression of coronary atherosclerosis: insights from
Expert Opin. Pharmacother. (2014) 16(3)
..
ILLUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation). Circulation 2008;118:2506-14 Demonstrates that substantial increase in high-density lipoprotein cholesterol (HDL-C) under torcetrapib was associated with plaque regression.
78.
Duivenvoorden R, Fayad ZA. Safety of CETP inhibition. Curr Opin Lipidol 2012;23:518-24
79.
Robinson JG. Dalcetrapib: a review of Phase II data. Expert Opin Investig Drugs 2010;19:795-805
80.
Masson D. Anacetrapib, a cholesterol ester transfer protein (CETP) inhibitor for the treatment of atherosclerosis. Curr Opin Investig Drugs 2009;10:980-7
81.
Nicholls SJ. Evacetrapib. Curr Cardiol Rep 2012;14:245-50
82.
Cannon CP, Shah S, Dansky HM, et al. Determining the Efficacy and Tolerability Investigators. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med 2010;363:2406-15 Demonstrates the clinical efficacy and safety of novel cholesteryl ester transfer protein (CETP) inhibitors.
.
83.
.
Nicholls SJ, Brewer HB, Kastelein JJ, et al. Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. JAMA 2011;306:2099-109 Demonstrates the clinical efficacy and safety of novel CETP inhibitors.
84.
Seidah NG, Awan Z, Chretien M, et al. PCSK9: a key modulator of cardiovascular health. Circ Res 2014;114:1022-36
85.
Dadu RT, Ballantyne CM. Lipid lowering with PCSK9 inhibitors. Nat Rev Cardiol 2014;11:563-75
86.
Zhang DW, Lagace TA, Garuti R, et al. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem 2007;282:18602-12
87.
Mabuchi H, Nohara A, Noguchi T, et al. Hokuriku FH Study Group.
Ongoing challenges for pharmacotherapy for dyslipidemia
Genotypic and phenotypic features in homozygous familial hypercholesterolemia caused by proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutation. Atherosclerosis 2014;236:54-61
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Laurentian University on 12/06/14 For personal use only.
88.
89.
90.
91.
.
92.
.
93.
.
Benn M, Nordestgaard BG, Grande P, et al. PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses. J Am Coll Cardiol 2010;55:2833-42
94.
.
95.
Hooper AJ, Marais AD, Tanyanyiwa DM, et al. The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis 2007;193:445-8 Zhao Z, Tuakli-Wosornu Y, Lagace TA, et al. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet 2006;79:514-23 McKenney JM, Koren MJ, Kereiakes DJ, et al. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol 2012;59:2344-53 Reports the clinical efficacy and safety of proprotein convertase subtilisin kexin-type 9 (PCSK9) inhibitors in various subjects. Roth EM, McKenney JM, Hanotin C, et al. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med 2012;367:1891-900 Reports the clinical efficacy and safety of PCSK9 inhibitors in various subjects. Stein EA, Gipe D, Bergeron J, et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet 2012;380:29-36 Reports the clinical efficacy and safety of PCSK9 inhibitors in various subjects.
.
96.
97.
98.
Giugliano RP, Desai NR, Kohli P, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACETIMI 57): a randomised, placebocontrolled, dose-ranging, phase 2 study. Lancet 2012;380:2007-17 Reports the clinical efficacy and safety of PCSK9 inhibitors in various subjects. Koren MJ, Scott R, Kim JB, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebocontrolled, phase 2 study. Lancet 2012;380:1995-2006 Reports the clinical efficacy and safety of PCSK9 inhibitors in various subjects. Raal F, Scott R, Somaratne R, et al. Low-density lipoprotein cholesterollowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial. Circulation 2012;126:2408-17 Sullivan D, Olsson AG, Scott R, et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA 2012;308:2497-506 Rader DJ, Kastelein JJ. Lomitapide and mipomersen: two first-in-class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. Circulation 2014;129:1022-32
99.
Zheng C. Updates on apolipoprotein CIII: fulfilling promise as a therapeutic target for hypertriglyceridemia and cardiovascular disease. Curr Opin Lipidol 2014;25:35-9
100.
Graham MJ, Lee RG, Bell TA III, et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ Res 2013;112:1479-90
Expert Opin. Pharmacother. (2014) 16(3)
101. Suk Danik J, Rifai N, Buring JE, et al. Lipoprotein(a), hormone replacement therapy, and risk of future cardiovascular events. J Am Coll Cardiol 2008;52:124-31 102. Bochem AE, Kuivenhoven JA, Stroes ES. The promise of cholesteryl ester transfer protein (CETP) inhibition in the treatment of cardiovascular disease. Curr Pharm Des 2013;19:3143-9 103. Sahebkar A, Watts GF. New therapies targeting apoB metabolism for high-risk patients with inherited dyslipidaemias: what can the clinician expect? Cardiovasc Drugs Ther 2013;27:559-67 104. Kingwell BA, Chapman MJ. Future of high-density lipoprotein infusion therapies: potential for clinical management of vascular disease. Circulation 2013;128:1112-21 105. Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 2003;290:2292-300 . Investigates the effect of HDL infusion therapy on coronary atherosclerosis. 106. Tardif JC, Gregoire J, L’Allier PL, et al. Effect of rHDL on Atherosclerosis-Safety and Efficacy (ERASE) Investigators. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA 2007;297:1675-82 . Investigates the effect of HDL infusion therapy on coronary atherosclerosis. 107. Waksman R, Torguson R, Kent KM, et al. A first-in-man, randomized, placebo-controlled study to evaluate the safety and feasibility of autologous delipidated high-density lipoprotein plasma infusions in patients with acute coronary syndrome. J Am Coll Cardiol 2010;55:2727-35 . Investigates the effect of HDL infusion therapy on coronary atherosclerosis. 108. Tardif JC, Ballantyne CM, Barter P, et al. for the Can Hdl Infusions Significantly QUicken Atherosclerosis REgression (CHI-SQUARE) Investigators. Effects of the high-density lipoprotein mimetic agent CER-001 on coronary atherosclerosis in patients with acute coronary syndromes: a randomized trial. Eur Heart J 2014. [Epub ahead of print] . Investigates the effect of HDL infusion therapy on coronary atherosclerosis.
9
A. D. Pisaniello et al.
Affiliation
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Laurentian University on 12/06/14 For personal use only.
Anthony D Pisaniello1 MBBS, Daniel J Scherer2 MBBS, Yu Kataoka1 MD & Stephen J Nicholls†1,2 MBBS PhD † Author for correspondence 1 University of Adelaide, South Australian Health and Medical Research Institute, PO Box 11060, Adelaide, SA, 5001, Australia Tel: +61 8 8128 4510; E-mail: [email protected] 2 Royal Adelaide Hospital, Cardiovascular Investigation Unit, Adelaide, SA, Australia
10
Expert Opin. Pharmacother. (2014) 16(3)
