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Management of residual risk after statin therapy

  • Christina Reith
    Affiliations
    Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK
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  • Jane Armitage
    Correspondence
    Corresponding author.
    Affiliations
    Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK
    Search for articles by this author

      Highlights

      • Statins remain the cornerstone of lipid management for cardiovascular risk reduction.
      • Additional risk reduction can be achieved by concomitant use of other lipid-lowering therapies.
      • Ezetimibe is the drug most commonly added to statins for cardiovascular risk reduction.
      • New drugs such as PCSK9 inhibitors provide additional LDL-lowering and may prove valuable as a therapeutic tool.

      Abstract

      Cardiovascular disease (CVD) is the leading cause of mortality worldwide. Observational data indicate that low-density lipoprotein cholesterol (LDL-C) levels are strongly positively associated with the risk of coronary heart disease (CHD) whilst the level of high-density lipoprotein cholesterol (HDL-C) is strongly inversely associated, with additional associations being observed for other lipid parameters such as triglycerides, apolipoproteins and lipoprotein(a) (Lp(a)). This has led to an interest in the development of a range of lipid intervention therapies. The most widely used of these interventions are statins, but even with intensive statin therapy some groups of patients remain at significant residual cardiovascular (CV) risk. In addition, some people are intolerant of statin therapy. In these circumstances, additional therapeutic agents may be needed. This review considers the evidence behind and the pros and cons of such additional agents.

      1. Introduction

      Cardiovascular disease (CVD) is the leading cause of adult mortality and morbidity worldwide. Preventive measures such as reductions in smoking, blood pressure and atherogenic lipids, and advances in treatments and healthcare have led to large reductions in age-standardised death rates for CVD, particularly in high income regions [
      • GBD 2013 mortality and causes of death Collaborators
      Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the global Burden of disease study 2013.
      ,
      • Institute for Health Metrics and Evaluation (IHME)
      GBD Arrow Diagram.
      ]. However its prevalence is rising in developing countries [
      • GBD 2013 mortality and causes of death Collaborators
      Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the global Burden of disease study 2013.
      ,
      • Institute for Health Metrics and Evaluation (IHME)
      GBD Arrow Diagram.
      ] and it remains a substantial public health issue.
      The aetiological relationship between long-term average blood cholesterol concentrations and risk of cardiovascular (CV) morbidity and mortality has been established reliably by the more than 60 years' of evidence from observational, randomized and genetic studies. Many of the older prospective observational studies which established these relationships were incorporated into comprehensive meta-analyses of the lipid risk factors for CVD undertaken by the Emerging Risk Factors Collaboration (ERFC) [
      • Emerging Risk Factors Collaboration
      Major lipids, apolipoproteins, and risk of vascular disease.
      ]. This confirms the log-linear positive association between non-high-density lipoprotein cholesterol [non-HDL-C] (or, approximately analogously, low-density lipoprotein cholesterol [LDL-C]) and the risk of coronary heart disease (CHD) with no apparent threshold level below which a lower non-HDL-C level does not confer a lower risk (Fig. 1). The pooled data from the ERFC observational studies of about 10 years follow-up shows a hazard ratio of 1.5 (1.39–1.61) per 1 standard deviation (43 mg/dL or 1.1 mmol/L) higher non-HDL-cholesterol; whereas more recent Mendelian Randomisation [MR] studies show that life-long differences in LDL-cholesterol, based on genetics, are associated with CHD risk even more strongly with about a 2-fold increase in risk per mmol/L higher LDL-C. This indicates about a 3-fold greater reduction in the risk of CHD associated with a unit lower LDL-C than that observed during treatment with a statin started later in life [
      • Ference B.A.
      • Yoo W.
      • Alesh I.
      • Mahajan N.
      • Mirowska K.K.
      • Mewada A.
      • et al.
      Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a mendelian randomization analysis.
      ]. This implies that residual risk following standard LDL-lowering treatment may be partly explained by treating late in the course of the disease, and that earlier treatment would increase benefit.
      Figure thumbnail gr1
      Fig. 1Adapted from Prospective Studies Collaboration (S Lewington, personal communication): Ischaemic Heart Disease mortality (2887 deaths) versus usual non-HDL cholesterol on linear scale; and log-linear scale.
      The association between non-HDL-C and risk of ischaemic stroke, although also positive, is much less strong although LDL-C lowering clearly reduces ischaemic stroke in the randomized trials [
      • Emerging Risk Factors Collaboration
      Major lipids, apolipoproteins, and risk of vascular disease.
      ,
      Cholesterol treatment Trialists' Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials.
      ]. MR data has not to date been published to help clarify this. By contrast, observational data indicate that HDL-C levels are strongly inversely associated with CHD and also, although less clearly so, with ischaemic stroke [
      • Emerging Risk Factors Collaboration
      Major lipids, apolipoproteins, and risk of vascular disease.
      ]. However, the MR studies do not imply that HDL-C is causally related to CHD risk and to date the randomized trials support this (discussed below) [
      • Voight B.F.
      • Peloso G.M.
      • Orho-Melander M.
      • Frikke-Schmidt R.
      • Barbalic M.
      • Jensen M.K.
      • et al.
      Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study.
      ]. The positive associations between triglyceride levels and risk of vascular disease typically disappear on adjustment for the other lipid factors [
      • Emerging Risk Factors Collaboration
      Major lipids, apolipoproteins, and risk of vascular disease.
      ], although recently it has become clear that remnant cholesterol, the cholesterol content of triglyceride-rich lipoproteins, is independently associated with CHD even after adjustment for HDL-C [
      • Varbo A.
      • Benn M.
      • Tybjaerg-Hansen A.
      • Jorgensen A.B.
      • Frikke-Schmidt R.
      • Nordestgaard B.G.
      Remnant cholesterol as a causal risk factor for ischemic heart disease.
      ,
      • Varbo A.
      • Nordestgaard B.G.
      Remnant cholesterol and ischemic heart disease.
      ] and MR studies also support the importance of triglyceride pathways in CHD risk [
      • Triglyceride Coronary Disease Genetics Consortium, Emerging Risk Factors Collaboration
      • Sarwar N.
      • Sandhu M.S.
      • Ricketts S.L.
      • Butterworth A.S.
      • et al.
      Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies.
      ].
      In light of these associations, interventions to modify lipids have been a key component of CVD treatment and prevention. People whose diet is relatively high in saturated fat can achieve some reduction in blood cholesterol and LDL-C through dietary intervention, but this effect is modest [
      • Clarke R.
      • Frost C.
      • Collins R.
      • Appleby P.
      • Peto R.
      Dietary lipids and blood cholesterol: quantitative meta-analysis of metabolic ward studies.
      ,
      • Tang J.L.
      • Armitage J.M.
      • Lancaster T.
      • Silagy C.A.
      • Fowler G.H.
      • Neil H.A.
      Systematic review of dietary intervention trials to lower blood total cholesterol in free-living subjects.
      ]. Statins are the cornerstone of lipid modification but, despite intensive statin therapy, many high patients remain at significant risk. This article reviews drug options for the management of this residual risk through further lipid modification. Nevertheless, it should be remembered that effective CVD reduction strategies need to adopt a multi-faceted approach to address other major CVD risk factors, such as blood pressure and diabetes, and ensure smoking cessation and avoidance of obesity. Equally, any intervention is only as effective as its associated compliance, highlighting the importance of patient understanding of any treatment and its acceptability in practice Box 1.
      Types of lipid modification agent
      Tabled 1
      Approved drugs
      • HMG Co A reductase inhibitors (Statins)
      • Cholesterol absorption inhibitors (Ezetimibe)
      • PPARα agonists (Fibrates)
      • Bile acid sequestrants (‘Resins’)
      • Nicotinic acid (also known as ‘niacin’)
      • Antisense oligonucleotides (Mipomersen)
      • Microsomal transfer protein inhibitors (Lomitapide)
      • PCSK9 inhibitors (evolocumab and alirocoumab)
      In development
      • PCSK9 inhibitors (bococizumab)
      • CETP inhibitors
      • Anti-sense technologies targeting ApoC and lipoprotein (a)

      1.1 Statin therapy: current mainstay of treatment

      Statins are inhibitors of 3-hydroxy 3-methylglutaryl Co A (HMG Co A) reductase, a key enzyme in cholesterol biosynthesis whose inhibition leads to reduced intracellular cholesterol synthesis and up-regulation of LDL receptors [
      • Grundy S.M.
      HMG-CoA reductase inhibitors for treatment of hypercholesterolemia.
      ]. This up-regulation leads to reductions in circulating levels of LDL-C by 20–60%, depending on the type of and dose of statin [
      • Knopp R.H.
      Drug treatment of lipid disorders.
      ,
      • Jones P.
      • Kafonek S.
      • Laurora I.
      • Hunninghake D.
      Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study).
      ]. Statins also modestly increase HDL-C and reduce triglyceride concentrations but these effects are not thought to contribute significantly to their clinical impact. Their impact on lipoprotein(a) (Lp(a)) remains uncertain, but is likely to be small [
      • Nordestgaard B.G.
      • Chapman M.J.
      • Ray K.
      • Boren J.
      • Andreotti F.
      • Watts G.F.
      • et al.
      Lipoprotein(a) as a cardiovascular risk factor: current status.
      ,
      • Kolski B.
      • Tsimikas S.
      Emerging therapeutic agents to lower lipoprotein (a) levels.
      ]. Statins were first approved in 1987, and after several pivotal trials in both primary and secondary prevention of CVD, their use in routine clinical practice has become widespread. However, early in their development there were lingering concerns that lowering cholesterol might increase the risk of particular cancers and/or non-vascular mortality [
      • Jacobs D.
      • Blackburn H.
      • Higgins M.
      • Reed D.
      • Iso H.
      • McMillan G.
      • et al.
      Report of the conference on low blood cholesterol: mortality associations.
      ,
      • Oliver M.F.
      Might treatment of hypercholesterolaemia increase non-cardiac mortality?.
      ]. Such issues would not have been addressed by the early statin trials since no single trial would have sufficient statistical power to reliably assess effects on mortality. The Cholesterol Treatment Trialists' (CTT) Collaboration was established in 1994 to bring together individual participant data from all the large, long-term randomized trials of statins in order to assess more reliably the effects of cholesterol-lowering with statins on non-vascular mortality and cancer in addition to quantifying the benefits on CVD [
      • Cholesterol Treatment Trialists Collaboration
      Protocol for a prospective collaborative overview of all current and planned randomized trials of cholesterol treatment regimens.
      ].
      The CTT Collaboration meta-analyses [
      • Cholesterol Treatment Trialists Collaboration
      Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.
      ,
      • Cholesterol Treatment Trialists Collaboration
      Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
      ,
      • Cholesterol Treatment Trialists Collaboration
      The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.
      ,
      • Cholesterol Treatment Trialists Collaboration
      Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials.
      ] have shown clearly that statin therapy proportionally reduces the risk of major vascular events (i.e. myocardial infarction (MI), coronary death, stroke or coronary revascularisation) by about one fifth per mmol/L absolute reduction in LDL-C, largely irrespective of baseline cholesterol concentration (even when LDL-C is already less than 2 mmol/L) or other presenting characteristics. The absolute benefit relates chiefly to an individual's absolute risk of such events and to the absolute reduction in LDL-C achieved [
      • Cholesterol Treatment Trialists Collaboration
      Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.
      ] with further reductions in LDL-C with more intensive statin regimens having been demonstrated to yield further reductions in risk [
      • Cholesterol Treatment Trialists Collaboration
      Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
      ] (Fig. 2). Typically, newer statin regimens will reduce LDL-C by 2 mmol/L or more, leading to reductions in risk of about 40%.
      Figure thumbnail gr2
      Fig. 2Cholesterol Treatment Trialists' meta-analysis
      [
      • Cholesterol Treatment Trialists Collaboration
      The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.
      ]
      : number of Major Vascular Events avoided per 1000 treated over 5 years among people at different levels of risk and by degree of LDL-lowering reduction.
      Statins are well-tolerated with no significant excess of symptomatic side-effects in the blinded randomized trials or their associated meta-analyses [
      • Desai C.S.
      • Martin S.S.
      • Blumenthal R.S.
      Non-cardiovascular effects associated with statins.
      ] but do rarely cause myopathy (typically defined as muscle symptoms with creatine kinase [CK] >10 times the upper limit of normal [ULN]) [
      • Tobert J.A.
      HMG-CoA reductase inhibitors, gemfibrozil, and myopathy.
      ,
      • Tobert J.A.
      Lovastatin and myopathy.
      ]. Although statins are highly effective, even those who have achieved significant LDL-C reductions with intensive statin therapy may still experience CV events, referred to as ‘residual risk’. This risk is particularly high in certain patients such as those with diabetes and atherosclerosis affecting multiple vascular beds (eg, cerebrovascular, peripheral vascular as well as coronary). Some of this risk may be addressed by earlier initiation of statin treatment and better blood pressure and diabetes management, but additional lipid-modifying therapies may be appropriate.

      1.2 Options for additional LDL-lowering/lipid modification

      • Cholesterol absorption inhibitors
      Ezetimibe selectively inhibits the absorption of cholesterol in the small intestine by binding to the transporter Niemann-Pick C1 Like1 (NPC1L1), which is responsible for the uptake of cholesterol and phytosterols (plant sterols) from the intestinal lumen. Only about one-third of the cholesterol delivered to the gut is dietary in origin, with the remainder being derived from biliary cholesterol excretion from the liver. Ezetimibe reduces both dietary and biliary cholesterol absorption by about one-half, resulting in reduced cholesterol delivery to the liver, up-regulation of LDL receptors and, as a consequence, a reduction in circulating LDL-C levels [
      • Ezetimibe Bays H.
      ]. Ezetimibe is metabolized through glucuronidation in the liver and small intestine, after which it undergoes enterohepatic recirculation thereby bringing about repeated delivery to the intestinal site of action [
      • Davis H.R.
      • Veltri E.P.
      Zetia: inhibition of niemann-pick C1 like 1 (NPC1L1) to reduce intestinal cholesterol absorption and treat hyperlipidemia.
      ]. Ezetimibe has been available since 2002, and as monotherapy (10 mg a day, the only dose marketed) reduces LDL-C by 17–18% [
      • Dujovne C.A.
      • Ettinger M.P.
      • McNeer F.
      • Lipka L.J.
      • LeBeaut A.P.
      • Suresh R.
      • et al.
      Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe in patients with primary hypercholesterolemia.
      ,
      • Knopp R.H.
      • Gitter H.
      • Truitt T.
      • Bays H.
      • Manion C.V.
      • Lipka L.J.
      • et al.
      Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia.
      ,
      • Dujovne C.A.
      • Suresh R.
      • McCrary Sisk C.
      • Maccubbin D.
      • Strony J.
      • Veltri E.
      Safety and efficacy of ezetimibe monotherapy in 1624 primary hypercholesterolaemic patients for up to 2 years.
      ]. When added to statins, ezetimibe results in greater reductions in LDL-C levels than with statins alone [
      • Davidson M.H.
      • McGarry T.
      • Bettis R.
      • Melani L.
      • Lipka L.J.
      • LeBeaut A.P.
      • et al.
      Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia.
      ,
      • Ballantyne C.M.
      • Houri J.
      • Notarbartolo A.
      • Melani L.
      • Lipka L.J.
      • Suresh R.
      • et al.
      Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial.
      ,
      • Toth P.P.
      • Davidson M.H.
      Simvastatin plus ezetimibe: combination therapy for the management of dyslipidaemia.
      ]. For example, co-administration of ezetimibe 10 mg with simvastatin 10 mg results in similar reductions in plasma concentrations of LDL-C as would be achieved with simvastatin 80 mg alone [
      • Davidson M.H.
      • McGarry T.
      • Bettis R.
      • Melani L.
      • Lipka L.J.
      • LeBeaut A.P.
      • et al.
      Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia.
      ] (ie, by the equivalent of around three doublings of the statin dose since, typically, the doubling of a statin dose produces an additional 6% absolute decrease in LDL-C [
      • Knopp R.H.
      Drug treatment of lipid disorders.
      ] eg, 20 mg simvastatin daily lowers LDL-C by 35% and 40 mg daily by 41% [
      • Jones P.
      • Kafonek S.
      • Laurora I.
      • Hunninghake D.
      Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study).
      ]). Three significant clinical outcome trials have assessed the impact of ezetimibe on clinical outcomes; two given in combination with simvastatin versus placebo, the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study and the Study of Heart and Renal Protection (SHARP), and one of ezetimibe added to simvastatin versus simvastatin alone, the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT).
      SEAS was a double-blind randomized trial among 1873 patients with mild-to moderate asymptomatic aortic stenosis who were randomized to either 40 mg of simvastatin plus 10 mg of ezetimibe or placebo daily. Median follow-up was just over 4 years, with the combination of simvastatin and ezetimibe resulting in an average reduction in LDL-C of about 2 mmol/L compared with placebo during the trial. There was no significant impact of LDL-C reduction on the composite primary outcome of major CV events including ischaemic events, heart failure and aortic valve replacement (hazard ratio [HR] 0.96; 95% confidence interval [CI] 0.83–1.12, p = 0.59) but, in line with expectations, the secondary composite outcome of ischaemic CV events alone was significantly reduced by 22% (HR 0.78; 95% CI, 0.63 to 0.97; p = 0.02) [
      • Rossebo A.B.
      • Pedersen T.R.
      • Boman K.
      • Brudi P.
      • Chambers J.B.
      • Egstrup K.
      • et al.
      Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis.
      ].
      SHARP was an international double-blind randomized trial involving 9270 people with chronic kidney disease (CKD) and no known history of MI or coronary revascularisation [
      • SHARP Collaborative Group
      Study of heart and renal Protection (SHARP): randomized trial to assess the effects of lowering low-density lipoprotein cholesterol among 9,438 patients with chronic kidney disease.
      ]. Three earlier somewhat smaller trials of statin therapy in patients on renal replacement therapy had not shown significant reductions in vascular outcomes with statin therapy [
      • Holdaas H.
      • Fellstrom B.
      • Jardine A.G.
      • Holme I.
      • Nyberg G.
      • Fauchald P.
      • et al.
      Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial.
      ,
      • Wanner C.
      • Krane V.
      • Marz W.
      • Olschewski M.
      • Mann J.F.
      • Ruf G.
      • et al.
      Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis.
      ,
      • Fellström B.C.
      • Jardine A.G.
      • Schmieder R.E.
      • Holdaas H.
      • Bannister K.
      • Beutler J.
      • et al.
      Rosuvastatin and cardiovascular events in patients undergoing hemodialysis.
      ] and, prior to SHARP, there was substantial uncertainty about the value of LDL-C lowering in patients with renal disease. In SHARP, to achieve maximum LDL-C lowering whilst minimising potential drug toxicity (a possible particular problem in people with CKD), the combination of ezetimibe 10 mg with simvastatin 20 mg was used. SHARP participants were initially randomized three ways between ezetimibe/simvastatin 10/20 mg daily, versus simvastatin 20 mg daily, versus placebo, to allow the assessment of the safety of adding ezetimibe to simvastatin during the first year (with no safety concerns identified) [
      • SHARP Collaborative Group
      Study of heart and renal Protection (SHARP): randomized trial to assess the effects of lowering low-density lipoprotein cholesterol among 9,438 patients with chronic kidney disease.
      ]. After 1 year, those initially allocated simvastatin alone were re-randomized to ezetimibe/simvastatin 10/20 mg or placebo. Allocation to ezetimibe/simvastatin resulted in an average LDL-C difference of 0·85 mmol/L (standard error [SE] 0·02; with about two-thirds compliance) during a median follow-up of 4·9 years and produced a 17% proportional reduction in the key pre-specified outcome of major atherosclerotic events [
      • SHARP Collaborative Group
      Study of heart and renal Protection (SHARP): randomized trial to assess the effects of lowering low-density lipoprotein cholesterol among 9,438 patients with chronic kidney disease.
      ]. The excess risk of myopathy was only two per 10,000 patients per year of treatment with this combination, and there was no evidence of excess risk of hepatitis, gallstones, cancer or death from any non-vascular cause [
      • SHARP Collaborative Group
      Study of heart and renal Protection (SHARP): randomized trial to assess the effects of lowering low-density lipoprotein cholesterol among 9,438 patients with chronic kidney disease.
      ]. The SHARP trial therefore showed that lowering of LDL-C safely reduces the risk of vascular events in a wide range of patients with CKD. This is particularly important because premature mortality from CVD in those with CKD is a leading cause of death (and more common than end stage renal disease) [
      • Gansevoort R.T.
      • Correa-Rotter R.
      • Hemmelgarn B.R.
      • Jafar T.H.
      • Heerspink H.J.
      • Mann J.F.
      • et al.
      Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention.
      ].
      The only trial to assess the impact of ezetimibe added to statins on clinical outcomes recently published its results [
      • Cannon C.P.
      • Blazing M.A.
      • Giugliano R.P.
      • McCagg A.
      • White J.A.
      • Theroux P.
      • et al.
      Ezetimibe added to statin therapy after acute coronary syndromes.
      ]. In IMPROVE-IT, 18,144 patients recently hospitalized for an acute coronary syndrome were randomized to a combination of ezetimibe/simvastatin 10/40 mg daily versus simvastatin 40 mg monotherapy. Allocation to ezetimibe/simvastatin resulted in median time-weighted average LDL-C difference of 0·40 mmol/L during a median follow-up 6 years, and produced a 6.4% (95% CI 1–11%) proportional reduction in the major CV events (a composite of CV death, non-fatal MI, unstable angina requiring re-hospitalization, coronary revascularization ≥30 days after randomization or non-fatal stroke), which was in line with anticipated effects based on the CTT data. No significant safety concerns were identified, with the overall rates of muscle, hepatobiliary and cancer outcomes being similar between the two groups.
      With this solid evidence base, ezetimibe is typically the first drug added to statins when additional LDL-C lowering is required. It is very tolerated with few, if any, significant side-effects [
      • Dujovne C.A.
      • Suresh R.
      • McCrary Sisk C.
      • Maccubbin D.
      • Strony J.
      • Veltri E.
      Safety and efficacy of ezetimibe monotherapy in 1624 primary hypercholesterolaemic patients for up to 2 years.
      ]. Combination preparations with both simvastatin and atorvastatin are available (although only the former in the UK) which can reduce the pill burden for patients but at increased cost compared to treatment with generic statins. Adult patients with heterozygous familial hypercholesterolaemia are typically managed by a combination of high intensity statin and ezetimibe [
      • National Institute for Health and Care Excellence
      Identification and Management of Familial Hypercholesterolaemia. NICE Guidelines [CG71].
      ].

      1.3 Fibrates

      Fibrates are a class of lipid modifying drugs which are agonists of the peroxisome proliferator-activator α receptors (PPAR α). Their principal effects are to raise HDL-C and lower triglyceride concentrations but some (eg, fenofibrate) also lower LDL-C. They are widely used for the management of significant hypertriglyceridaemia [
      • Fruchart J.C.
      • Brewer Jr., H.B.
      • Leitersdorf E.
      Consensus for the use of fibrates in the treatment of dyslipoproteinemia and coronary heart disease. Fibrate consensus Group.
      ,
      • Abourbih S.
      • Filion K.B.
      • Joseph L.
      • Schiffrin E.L.
      • Rinfret S.
      • Poirier P.
      • et al.
      Effect of fibrates on lipid profiles and cardiovascular outcomes: a systematic review.
      ], on average lowering triglycerides by 0.80 mmol/L or 36% (with reductions ranging from 18% up to 48%) [
      • Birjmohun R.S.
      • Hutten B.A.
      • Kastelein J.J.
      • Stroes E.S.
      Efficacy and safety of high-density lipoprotein cholesterol-increasing compounds: a meta-analysis of randomized controlled trials.
      ], but here we consider their role in CVD prevention either alone or as an adjunct to statin therapy to maximise LDL-C lowering.
      Fibrates currently available include fenofibrate, ciprofibrate, bezafibrate and gemfibrozil. The first fibrate (clofibrate) was developed in the mid-60s and assessed in a large randomized trial, the World Health Organization (WHO) Clofibrate trial [
      • A co-operative trial in the primary prevention of ischaemic heart disease using clofibrate
      Report from the committee of principal investigators.
      ,
      • W
      H.O. cooperative trial on primary prevention of ischaemic heart disease using clofibrate to lower serum cholesterol: mortality follow-up. Report of the committee of principal Investigators.
      ,
      • W.H.O
      Cooperative trial on primary prevention of ischaemic heart disease with clofibrate to lower serum cholesterol: final mortality follow-up. Report of the committee of principal Investigators.
      ]. CHD events were reduced but several safety concerns in relation to non-vascular events were raised, especially an increased risk of gallstones leading to cholecystectomies and anxieties about an increased cancer risk. The cancer risk was not confirmed in later analyses [
      • Heady J.A.
      • Morris J.N.
      • Oliver M.F.
      WHO clofibrate/cholesterol trial: clarifications.
      ], but the increased risk of gallstones led to it being withdrawn from the market. This study did, however, help provide proof of principle that cholesterol-lowering might reduce coronary risk. Clofibrate's development led directly to the other fibrates which were the subject of several large outcome trials in the pre-statin era. Two of the most influential were the primary prevention Helsinki Heart Study (HHS) [
      • Frick M.H.
      • Elo O.
      • Haapa K.
      • Heinonen O.P.
      • Heinsalmi P.
      • Helo P.
      • et al.
      Helsinki heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease.
      ] which randomized 4081 men to gemfibrozil or placebo, and the Veterans Affairs HDL-C Intervention Trial (VA-HIT) [
      • Rubins H.B.
      • Robins S.J.
      • Collins D.
      • Fye C.L.
      • Anderson J.W.
      • Elam M.B.
      • et al.
      Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol.
      ] which randomized 2531 men with CHD to gemfibrozil or placebo, both of which reported significant reductions in CHD in those on active treatment. However, the Bezafibrate Infarction Prevention (BIP) Study [
      • Bezafibrate Infarction Prevention Study
      Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease.
      ] in 3090 post-MI or stable angina patients did not show a clear benefit for those randomized to bezafibrate.
      A tabular meta-analysis of 18 randomised trials of fibrate therapy involving >45,000 participants reported an overall 10% relative risk (RR) reduction (95% CI 0.82–1.00) for major CV events (p = 0·048) and a 13% RR reduction (95% CI 0.81–0.93) for coronary events (p < 0·0001) [
      • Jun M.
      • Foote C.
      • Lv J.
      • Neal B.
      • Patel A.
      • Nicholls S.J.
      • et al.
      Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis.
      ], suggesting that fibrates might have a role in some high risk individuals. A subsequent meta-analysis of 6 trials explored this further by specifically looking at the efficacy of fibrates for cardiovascular risk reduction in those with elevated triglycerides and low HDL-C, a pattern associated with small dense LDL levels [
      • Lee M.
      • Saver J.L.
      • Towfighi A.
      • Chow J.
      • Ovbiagele B.
      Efficacy of fibrates for cardiovascular risk reduction in persons with atherogenic dyslipidemia: a meta-analysis.
      ]. This selective meta-analysis showed significant risk reductions in those with high triglycerides or low HDL-C, with the greatest benefit in those with both characteristics (RR 0.71; 95% CI 0.62–0.82, p < 0.001), but no significant benefit for those with neither of these characteristics.
      The dyslipidaemia associated with type 2 diabetes mellitus is characterised by low HDL-C and increased triglyceride concentrations [
      • Mooradian A.D.
      Dyslipidemia in type 2 diabetes mellitus.
      ] and so fibrates have been particularly targeted at this group. There have been two large randomized trials in diabetic populations: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study [
      • Keech A.
      • Simes R.J.
      • Barter P.
      • Best J.
      • Scott R.
      • Taskinen M.R.
      • 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.
      ] which randomized 9795 people with type 2 diabetes, who were not on statin therapy at baseline, to fenofibrate vs placebo; and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study [
      • Study Group A.C.C.O.R.D.
      • Ginsberg H.N.
      • Elam M.B.
      • Lovato L.C.
      • Crouse 3rd, J.R.
      • Leiter L.A.
      • et al.
      Effects of combination lipid therapy in type 2 diabetes mellitus.
      ] which recruited 5518 people with type 2 diabetes who were on open-label simvastatin and randomized them to fenofibrate or placebo. In neither study did fenofibrate clearly reduce CV risk. In FIELD, median follow-up was 5 years, with allocation to fenofibrate resulting in absolute differences in LDL-C and triglycerides of 0.17 mmol/L and 0.41 mmol/L respectively at study close, associated with an 11% RR reduction (95% CI 0.75–1.05; p = 0.16) in coronary events (defined as CHD death or non-fatal MI). However, a reduction in the total number of CV events (the composite of CV death, MI, stroke, and coronary and carotid revascularisation) by 11% (95% CI 0.80–0.99; p = 0.035) was observed, mainly due to fewer non-fatal MIs and revascularisations (with stroke not differing significantly between groups). Fenofibrate was also noted to be associated with less progression of albuminuria (p = 0·002), and retinopathy needing laser treatment (P = 0·0003), suggesting possible microvascular benefits. In ACCORD, mean length of follow-up was 4.7 years. Allocation to fenofibrate resulted in a 0.29 mmol/L difference in median triglyceride levels and negligible difference in mean LDL-C compared to those on placebo by the end of the study, associated with an 8% RR reduction (95% CI 0.79–1.08; p = 0.32) in the primary composite outcome of non-fatal MI, non-fatal stroke, or death from CV causes.
      Despite the disappointing findings of FIELD and ACCORD, fibrates remain valuable, and are widely used in specialist clinical practice (usually as an adjunct therapy to statins) particularly for those with significant hypertriglyceridaemia. They are generally well tolerated, although the administration of statins with fibrates increases the risk of myopathy and rhabdomyolysis, especially if renal function is impaired or if statins are used at high dose. This risk is particularly increased when gemfibrozil is used concomitantly with statins [
      • Bellosta S.
      • Paoletti R.
      • Corsini A.
      Safety of statins: focus on clinical pharmacokinetics and drug interactions.
      ], and this combination is therefore best avoided.
      • Resins
      Bile acid sequestrants, often referred to as resins, such as cholestyramine, colestipol and colesevelam, act by forming insoluble complexes with bile acids in the intestine which are then excreted in the faeces. The interruption of the enterohepatic recirculation of bile acids results in compensatory conversion of plasma cholesterol to bile acids in the liver and consequent lowering of plasma cholesterol levels [
      • Shepherd J.
      Mechanism of action of bile acid sequestrants and other lipid-lowering drugs.
      ]. The only significant clinical outcome trial of bile acid sequestrants was the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) [
      • Lipid Research Clinics Program
      The lipid research clinics coronary primary prevention trial results. I. Reduction in incidence of coronary heart disease.
      ,
      • The Lipid Research Clinics Coronary Primary Prevention Trial results
      II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering.
      ]. This randomized, double-blind study of cholestyramine versus placebo was conducted in 3806 asymptomatic middle-aged men with primary hypercholesterolemia. Results showed that cholestyramine reduced LDL-C by about 20% which led to about a 20% reduction (p < 0.05) in the primary end point of definite CHD death and/or definite nonfatal MI. This trial, published in 1984, provided an important illustration of the ability of cholesterol lowering to reduce CHD risk in the pre-statin era and was in many ways a landmark. However, the introduction of statins which are easier to take and potentially more powerful LDL-C lowering agents means that resins are no longer extensively used in clinical practice. However, they can be added to other lipid-lowering agents such as statins, and newer oral preparations (such as colesevelam ‘Cholestagel’ tablets) which are more acceptable to patients than previous formulations mean they can be useful as adjunctive therapy. However caution is required as they may delay or reduce the absorption of other drugs, particularly acidic drugs and fat-soluble vitamins. When used at high doses, reductions of18–25% in LDL-C can be achieved [
      • Reiner Z.
      • Catapano A.L.
      • De Backer G.
      • Graham I.
      • Taskinen M.R.
      • Wiklund O.
      • et al.
      [ESC/EAS guidelines for the management of dyslipidaemias].
      ], and on average the addition of a bile acid sequestrant to a statin reduces LDL-C further by 10–20% [
      • Reiner Z.
      • Catapano A.L.
      • De Backer G.
      • Graham I.
      • Taskinen M.R.
      • Wiklund O.
      • et al.
      [ESC/EAS guidelines for the management of dyslipidaemias].
      ]. However, there is no evidence of the effect of these agents on clinical outcomes when used in combination with statin therapy.
      • Nicotinic acid (niacin)
      Nicotinic acid is the oldest available lipid-lowering treatment having been known to affect cholesterol in humans since the 1950s [
      • Altschul R.
      • Hoffer A.
      • Stephen J.D.
      Influence of nicotinic acid on serum cholesterol in man.
      ,
      • Altschul R.
      • Hoffer A.
      Effects of salts of nicotinic acid on serum cholesterol.
      ]. In the US it is known as niacin and it is generally referred to as such in the large scale trials. Its principal effects when used in high dose are to lower LDL-C and triglycerides and raise HDL-C [
      • Carlson L.A.
      Nicotinic acid: the broad-spectrum lipid drug. A 50th anniversary review.
      ], with 2 g daily of the extended release preparations increasing HDL-C by 20% and decreasing LDL-C by about 20% [
      • Maccubbin D.
      • Bays H.E.
      • Olsson A.G.
      • Elinoff V.
      • Elis A.
      • Mitchel Y.
      • et al.
      Lipid-modifying efficacy and tolerability of extended-release niacin/laropiprant in patients with primary hypercholesterolaemia or mixed dyslipidaemia.
      ]. However, its use is associated with a number of troublesome side effects including flushing.
      One of the first large trials to assess niacin was the Coronary Drug Project (CDP) [
      Clofibrate and niacin in coronary heart disease.
      ], conducted in the pre-statin era in men with a history of previous MI who were randomly assigned to one of six treatment groups including 1119 to niacin 3 g daily and 2789 to placebo. In the CDP, niacin 3 g daily reduced the total cholesterol level by 0.67 mmol/L from a high baseline level of 6.54 mmol/L and, although lipid fractions were not measured, it can be estimated that LDL-C would have been reduced by about 0.80 mmol/L and HDL-C increased by approximately 0.13 mmol/L. On the basis of the CTT meta-analyses [
      • Cholesterol Treatment Trialists Collaboration
      Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
      ] such changes in lipid levels might reduce CHD risk by 15–20%, which is compatible with the 19% reduction in MI or coronary death observed in the CDP albeit at the expense of a variety of side-effects. A subsequent long-term follow-up study showed evidence of late benefit with niacin (ie, occurring after discontinuation of the drug) with mortality in the niacin group being 11% lower than in the placebo group (p = 0.0004) [
      • Canner P.L.
      • Berge K.G.
      • Wenger N.K.
      • Stamler J.
      • Friedman L.
      • Prineas R.J.
      • et al.
      Fifteen year mortality in coronary drug project patients: long-term benefit with niacin.
      ]. However, the clinical benefit of adding niacin to current treatment such as statin therapy was uncertain until the recent publication of two large randomized trials: the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH), and the Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trials.
      AIM-HIGH involved 3414 high vascular-risk patients who were all receiving background statin therapy. At 2 years, extended-release (ER) niacin was associated with 0.12 mmol/L lower mean LDL-C, 0.13 mmol/L higher mean HDL-C, and 0.35 mmol/L lower median triglyceride levels [
      • Investigators A.I.M.-H.I.G.H.
      • Boden W.E.
      • Probstfield J.L.
      • Anderson T.
      • Chaitman B.R.
      • Desvignes-Nickens P.
      • et al.
      Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.
      ]. However, the trial was stopped prematurely after a mean follow-up of 3 years because of an apparent lack of benefit with niacin. But, given the small differences in blood lipid levels that were observed between randomized groups, AIM-HIGH may have been too small to detect plausible reductions in vascular events.
      The HPS2-THRIVE trial was designed to assess the effects of adding ER niacin in combination with laropiprant to effective statin-based LDL-C-lowering treatment in 25,673 high risk patients with prior vascular disease. Laropiprant is an antagonist of the prostaglandin D2 receptor DP1 that had been shown to improve adherence to niacin therapy by reducing flushing in up to two thirds of patients [
      • Maccubbin D.
      • Bays H.E.
      • Olsson A.G.
      • Elinoff V.
      • Elis A.
      • Mitchel Y.
      • et al.
      Lipid-modifying efficacy and tolerability of extended-release niacin/laropiprant in patients with primary hypercholesterolaemia or mixed dyslipidaemia.
      ,
      • Lai E.
      • De Lepeleire I.
      • Crumley T.M.
      • Liu F.
      • Wenning L.A.
      • Michiels N.
      • et al.
      Suppression of niacin-induced vasodilation with an antagonist to prostaglandin D2 receptor subtype 1.
      ]. In HPS2-THRIVE [
      • HPS2-THRIVE Collaborative Group
      HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment.
      ], assignment to ER niacin-laropiprant was associated with a 0.25 mmol/L lower LDL-C and a 0.16 mmol/L higher HDL-C compared with placebo, but these changes had no significant impact on the incidence of major vascular events (RR 0.96; 95% CI 0.90–1.03; p = 0.29) [
      • HPS2-THRIVE Collaborative Group
      Effects of extended-release niacin with laropiprant in high-risk patients.
      ]. However, the trial identified several significant new hazards of niacin. Firstly, it showed that adding ER niacin to simvastatin 40 mg increased the risk of statin-associated myopathy by about four fold, particularly in Chinese patients who were also more susceptible to myopathy on simvastatin alone [
      • HPS2-THRIVE Collaborative Group
      HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment.
      ,
      • HPS2-THRIVE Collaborative Group
      Effects of extended-release niacin with laropiprant in high-risk patients.
      ]. Secondly, although some hazards were previously recognized as adverse effects of niacin, including diabetes-related, gastrointestinal, musculoskeletal, and skin-related SAEs, the HPS2-THRIVE study showed a highly significant excess of serious complications associated with glucose control (most of which resulted in hospitalization) and a 32% (95% CI 1.16–1.51; p < 0.001) increase in the incidence of new-onset diabetes along with highly significant excesses of serious infections and bleeding. Although it was not possible to determine the separate contributions of ER niacin and laropiprant in HPS2-THRIVE to such hazards, subsequent review of previous trials which had also used niacin including AIM-HIGH [
      • Anderson T.J.
      • Boden W.E.
      • Desvigne-Nickens P.
      • Fleg J.L.
      • Kashyap M.L.
      • McBride R.
      • et al.
      Safety profile of extended-release niacin in the AIM-HIGH trial.
      ] indicated that the findings from HPS2-THRIVE were likely to be generalizable to all high-dose niacin formulations. This led to a major review of the use of nicotinic acid and related substances by drug regulators, with subsequent suspension of the EU marketing authorisation for extended release nicotinic acid/laropiprant [

      European Medicines Agency. Tredaptive, pelzont and trevaclyn suspended across the EU. EMA/402540/2013. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Tredaptive_20/European_Commission_final_decision/WC500156745.pdf. Accessed 13-Oct-2015.

      ] and amendment of advice for other nicotinic acid-related substances [

      European Medicines Agency. PRAC recommends using acipimox only as additional or alternative treatment to lower high triglyceride levels. EMA/168574/2013. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Nicotinic_acid_31/Recommendation_provided_by_Pharmacovigilance_Risk_Assessment_Committee/WC500154012.pdf. Accessed 13-Oct-2015.

      ]. In light of this new safety information, the clinical applicability of niacin as a lipid intervention therapy would seem obsolete, but it is still prescribed in North America.
      • PCSK9 inhibitors
      The proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme is encoded in humans by the PCSK9 gene. It plays a significant role in regulating LDL-C levels by binding to hepatic LDL receptors and promoting their degradation, leading to increased LDL-C levels [
      • Lambert G.
      • Sjouke B.
      • Choque B.
      • Kastelein J.J.
      • Hovingh G.K.
      The PCSK9 decade.
      ,
      • Dadu R.T.
      • Ballantyne C.M.
      Lipid lowering with PCSK9 inhibitors.
      ]. These findings have led to the development of PCSK9 inhibitors, including using monoclonal antibodies (MoAbs), antisense oligonucleotides [
      • Visser M.E.
      • Witztum J.L.
      • Stroes E.S.
      • Kastelein J.J.
      Antisense oligonucleotides for the treatment of dyslipidaemia.
      ] and by RNA interference (RNAi) mechanisms.
      The most extensively studied of these PSCK9 inhibitors are the subcutaneously administered, either fully human or humanised, PCSK9 MoAbs. Multiple trials have been conducted with these agents, which principally involve alirocumab, bococizumab and evolocumab, all of which are in late stage of development or have been recently approved. The phase 3 programme for alirocumab is known as ODYSSEY, whilst that for bococizumab is called Studies of PCSK9 Inhibition and the Reduction of vascular Events (SPIRE), with each programme containing multiple trials prefixed by the associated programme names (e.g. ODYSSEY FH [
      • Kastelein J.J.
      • Ginsberg H.N.
      • Langslet G.
      • Hovingh G.K.
      • Ceska R.
      • Dufour R.
      • et al.
      ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia.
      ], ODYSSEY LONG-TERM [
      • Robinson J.G.
      • Farnier M.
      • Krempf M.
      • Bergeron J.
      • Luc G.
      • Averna M.
      • et al.
      Efficacy and safety of alirocumab in reducing lipids and cardiovascular events.
      ], SPIRE-FH [

      Pfizer A 52 Week Study to Assess the Use of Bococizumab (PF-04950615; RN316) in Subjects with Heterozygous Familial Hypercholesterolemia (SPIRE-fh). In ClinicalTrials.Gov [Internet]. Bethesda (MD): National Library of Medicine (US). Available from: http://clinicaltrials.gov/show/NCT01968980 NLM Identifier: NCT01968980. Accessed 12-Oct-2015. [cited; Available from:.

      ] and SPIRE-LDL [

      Pfizer. Randomized clinical trial of bococizumab (PF-04950615; RN316) in subjects with hyperlipidemia or mixed dyslipidemia at risk of cardiovascular events (SPIRE-LDL). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Available from:: https://clinicaltrials.gov/ct2/show/NCT01968967 NLM Identifier: NCT01968967. Accessed 12-Oct-2015. [cited; Available from:.

      ] trials). The evolocumab phase III trials are encompassed by the Program to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 In Different Populations (PROFICIO, which includes the completed Monoclonal Antibody Against PCSK9 to Reduce Elevated Low-density Lipoprotein Cholesterol (LDL-C) in Adults Currently Not Receiving Drug Therapy for Easing Lipid Levels [MENDEL]-2 [
      • Koren M.J.
      • Lundqvist P.
      • Bolognese M.
      • Neutel J.M.
      • Monsalvo M.L.
      • Yang J.
      • et al.
      Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab.
      ], Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects [GAUSS] [
      • Sullivan D.
      • Olsson A.G.
      • Scott R.
      • Kim J.B.
      • Xue A.
      • Gebski V.
      • et al.
      Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial.
      ], Durable Effect of PCSK9 Antibody CompARed wiTh placEbo Study [DESCARTES] [
      • Blom D.J.
      • Hala T.
      • Bolognese M.
      • Lillestol M.J.
      • Toth P.D.
      • Burgess L.
      • et al.
      A 52-week placebo-controlled trial of evolocumab in hyperlipidemia.
      ], LDL-C Assessment with PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy [LA-PLACE-2] [
      • Robinson J.G.
      • Nedergaard B.S.
      • Rogers W.J.
      • Fialkow J.
      • Neutel J.M.
      • Ramstad D.
      • et al.
      Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial.
      ], Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder [RUTHERFORD]-2 [
      • Raal F.J.
      • Stein E.A.
      • Dufour R.
      • Turner T.
      • Civeira F.
      • Burgess L.
      • et al.
      PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial.
      ] and Open-Label Study of Long-Term Evaluation Against LDL-C [OSLER][
      • Sabatine M.S.
      • Giugliano R.P.
      • Wiviott S.D.
      • Raal F.J.
      • Blom D.J.
      • Robinson J.
      • et al.
      Efficacy and safety of evolocumab in reducing lipids and cardiovascular events.
      ] trials). The development of PCSK9 MoAbs and associated trial results to date are comprehensively summarised elsewhere.78 90
      In summary, PCSK9 MoAbs have been shown to significantly reduce LDL-C levels against both placebo and background lipid therapies, with further LDL-C reductions of ∼60% when used in combination with statin compared to statin alone being reported [
      • Dadu R.T.
      • Ballantyne C.M.
      Lipid lowering with PCSK9 inhibitors.
      ,
      • Robinson J.G.
      • Farnier M.
      • Krempf M.
      • Bergeron J.
      • Luc G.
      • Averna M.
      • et al.
      Efficacy and safety of alirocumab in reducing lipids and cardiovascular events.
      ,
      • Robinson J.G.
      • Nedergaard B.S.
      • Rogers W.J.
      • Fialkow J.
      • Neutel J.M.
      • Ramstad D.
      • et al.
      Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial.
      ,
      • Giugliano R.P.
      • Sabatine M.S.
      Are PCSK9 inhibitors the next breakthrough in the cardiovascular field?.
      ]. Neutralizing antibodies have not been observed, and, based on evidence to date, they appear to be well tolerated. Two studies have specifically looked at PCSK9 MoAbs in statin intolerant patients (the GAUSS-2 [
      • Stroes E.
      • Colquhoun D.
      • Sullivan D.
      • Civeira F.
      • Rosenson R.S.
      • Watts G.F.
      • et al.
      Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab.
      ] and ODYSSEY ALTERNATIVE [
      • Moriarty P.M.
      • Thompson P.D.
      • Cannon C.P.
      • et al.
      Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: the odyssey alternative randomized trial.
      ] trials), with reported results indicating good efficacy and favourable muscle symptomatology compared to other therapies. However, injection–site reactions can occur, and some studies have shown slightly higher rates of myalgia amongst participants receiving PCSK9 MoAbs [
      • Robinson J.G.
      • Farnier M.
      • Krempf M.
      • Bergeron J.
      • Luc G.
      • Averna M.
      • et al.
      Efficacy and safety of alirocumab in reducing lipids and cardiovascular events.
      ,
      • Blom D.J.
      • Hala T.
      • Bolognese M.
      • Lillestol M.J.
      • Toth P.D.
      • Burgess L.
      • et al.
      A 52-week placebo-controlled trial of evolocumab in hyperlipidemia.
      ], although a recent meta-analysis of randomized controlled data from PCSK9 MoAb trials reported no excess of treatment emergent adverse events (including serious events) or discontinuation of treatment [
      • Li C.
      • Lin L.
      • Zhang W.
      • Zhou L.
      • Wang H.
      • Luo X.
      • et al.
      Efficiency and safety of proprotein convertase Subtilisin/Kexin 9 monoclonal antibody on hypercholesterolemia: a meta-analysis of 20 randomized controlled trials.
      ].
      Alirocumab (Praluent™) and Evolocumab (Repatha™) have recently been approved by the European Union (EU) and United States Food and Drug Administration (US FDA) for use in addition to diet and maximally tolerated statin therapy in people with heterozygous familial hypercholesterolemia or who require additional lowering of LDL-C. However, further data are needed to more definitively determine the effect of PCSK9 inhibitors on clinical outcomes, and to confirm their longer-term safety (in particular establishing whether the combination of a PCSK9 inhibitor and statin increases the risk of the rare event of myopathy, as is seen with niacin and rarely with fibrates). Several large outcomes trials are currently ongoing, each involving thousands of participants. These include the ODYSSEY OUTCOMES trial of alirocumab [
      • Schwartz G.G.
      • Bessac L.
      • Berdan L.G.
      • Bhatt D.L.
      • Bittner V.
      • Diaz R.
      • et al.
      Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the odyssey outcomes trial.
      ,

      Sanofi ODYSSEY Outcomes: evaluation of cardiovascular outcomes after an acute coronary syndrome during treatment with alirocumab SAR236553 (REGN727). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Available from: https://clinicaltrials.gov/ct2/show/NCT01663402 NLM Identifier: NCT01663402. Accessed 13-Oct-2015.

      ] (N ∼18,000 participants who have recently been hospitalized for acute coronary syndrome), the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk [FOURIER trial] of evolocumab (N ∼27,000) participants with clinical CVD and high risk of recurrent CVD event) [

      Amgen. Further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk (FOURIER). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Available from: https://clinicaltrials.gov/ct2/show/NCT01764633 NLM Identifier: NCT01764633. Accessed 13-Oct-2015.

      ], and the Studies of PCSK9 Inhibition and the Reduction of vascular Events (SPIRE)-1 and −2 trials of bococizumab (N ∼26,000 participants at high CVD risk) [

      Pfizer. The evaluation of bococizumab (PF-04950615;RN316) in reducing the occurrence of major cardiovascular events in high risk subjects (SPIRE-1). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Available from: https://clinicaltrials.gov/ct2/show/NCT01975376 NLM Identifier: NCT01975376. Accessed 13-Oct-2015.

      ,

      Pfizer. The evaluation of bococizumab (PF-04950615; RN316) in reducing the occurrence of major cardiovascular events in high risk subjects (SPIRE-2). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Available from: https://clinicaltrials.gov/ct2/show/NCT01975389 NLM Identifier: NCT01975389. Accessed 13-Oct-2015.

      ], with results anticipated in 2017/2018.
      There is also ongoing work into the effects of PCSK9 inhibitors in people with the rare (but serious) condition homozygous familial hypercholesterolaemia (homozygous FH). Since these patients have either absent or functionally defective LDL receptors, PCSK9 inhibitors might not be anticipated to be effective in such patients. However, the Trial Evaluating PCSK9 Antibody in Subjects With LDL Receptor Abnormalities Part B (TESLA B) N ∼50 participants with homozygous FH showed that PCSK9 inhibition using evolocumab reduced LDL cholesterol, presumably because of residual LDL receptor function [
      • Raal F.J.
      • Honarpour N.
      • Blom D.J.
      • Hovingh G.K.
      • Xu F.
      • Scott R.
      • et al.
      Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial.
      ], and evolocumab has now also been approved for use in this condition. The ongoing Trial Assessing Long Term USe of PCSK9 Inhibition in Subjects With Genetic LDL Disorders (TAUSSIG; N ∼300 participants) study [

      Amgen. Trial assessing long term USe of PCSK9 inhibition in subjects with genetic LDL disorders (TAUSSIG). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Available from: https://clinicaltrials.gov/ct2/show/NCT01624142 NLM Identifier: NCT01624142. Accessed 13-Oct-2015.

      ] has been designed to assess this question further and is expected to finish in 2020.
      PCSK9 inhibitors look to be highly promising agents. Questions have been raised about their patient acceptability given their method of administration, but others have argued that the low frequency of such injections (typically 2- or 4-weekly) means that this should not significantly impact on patient compliance. Instead, the main factor which is likely to determine the extent to which they are used post-approval will be their cost effectiveness which will be closely scrutinised by payers and reimbursement agencies.
      Antisense oligonucleotides have also been developed against PCSK9 [
      • Visser M.E.
      • Witztum J.L.
      • Stroes E.S.
      • Kastelein J.J.
      Antisense oligonucleotides for the treatment of dyslipidaemia.
      ,
      • Gupta N.
      • Fisker N.
      • Asselin M.C.
      • Lindholm M.
      • Rosenbohm C.
      • Orum H.
      • et al.
      A locked nucleic acid antisense oligonucleotide (LNA) silences PCSK9 and enhances LDLR expression in vitro and in vivo.
      ,
      • Lindholm M.W.
      • Elmen J.
      • Fisker N.
      • Hansen H.F.
      • Persson R.
      • Moller M.R.
      • et al.
      PCSK9 LNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates. Molecular therapy.
      ]. A small phase 1 dose escalation study has been conducted in healthy volunteers. Although this study was not powered to detect changes in PCSK9 or LDL cholesterol, a significant lowering of plasma PCSK9 and serum LDL cholesterol was noted in the higher-dose groups, and the therapy was generally well tolerated [
      • Fitzgerald K.
      • Frank-Kamenetsky M.
      • Shulga-Morskaya S.
      • Liebow A.
      • Bettencourt B.R.
      • Sutherland J.E.
      • et al.
      Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial.
      ]. Another approach to target PCSK9 which is being developed is anti-PCSK9 vaccines [
      • Galabova G.
      • Brunner S.
      • Winsauer G.
      • Juno C.
      • Wanko B.
      • Mairhofer A.
      • et al.
      Peptide-based anti-PCSK9 vaccines - an approach for long-term LDLc management.
      ,
      • Crossey E.
      • Amar M.J.
      • Sampson M.
      • Peabody J.
      • Schiller J.T.
      • Chackerian B.
      • et al.
      A cholesterol-lowering VLP vaccine that targets PCSK9.
      ]. However, this method is still in early development.

      1.4 Future potential lipid intervention therapies

      Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from HDL-C to apo-B containing particles, mainly very low density lipoprotein (VLDL) and LDL, with subsequent uptake primarily by hepatic LDL receptors [
      • Chapman M.J.
      • Le Goff W.
      • Guerin M.
      • Kontush A.
      Cholesteryl ester transfer protein: at the heart of the action of lipid-modulating therapy with statins, fibrates, niacin, and cholesteryl ester transfer protein inhibitors.
      ]. Several analyses of genetic polymorphisms associated with lower mass or activity of CETP have been shown to be associated with higher HDL-C levels, lower LDL-C levels, and a lower risk of CHD [
      • Thompson A.
      • Di Angelantonio E.
      • Sarwar N.
      • Erqou S.
      • Saleheen D.
      • Dullaart R.P.
      • et al.
      Association of cholesteryl ester transfer protein genotypes with CETP mass and activity, lipid levels, and coronary risk.
      ,
      • Ridker P.M.
      • Pare G.
      • Parker A.N.
      • Zee R.Y.
      • Miletich J.P.
      • Chasman D.I.
      Polymorphism in the CETP gene region, HDL cholesterol, and risk of future myocardial infarction: genomewide analysis among 18 245 initially healthy women from the Women's genome health Study.
      ,
      • Johannsen T.H.
      • Frikke-Schmidt R.
      • Schou J.
      • Nordestgaard B.G.
      • Tybjaerg-Hansen A.
      Genetic inhibition of CETP, ischemic vascular disease and mortality, and possible adverse effects.
      ]. This evidence has lent support to the development of several CETP inhibitors, although there has also been evidence contrary to such an approach [
      • Voight B.F.
      • Peloso G.M.
      • Orho-Melander M.
      • Frikke-Schmidt R.
      • Barbalic M.
      • Jensen M.K.
      • et al.
      Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study.
      ,
      • Haase C.L.
      • Tybjaerg-Hansen A.
      • Grande P.
      • Frikke-Schmidt R.
      Genetically elevated apolipoprotein A-I, high-density lipoprotein cholesterol levels, and risk of ischemic heart disease.
      ]. Three large randomized trials have reported results for CETP inhibitors to date: the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial, the dal-OUTCOMES study and the Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib (DEFINE) study. In addition, The Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High-Risk for Vascular Outcomes (ACCELERATE) trial [

      Eli Lilly and Company. A study of evacetrapib in high-risk vascular disease (ACCELERATE). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Available from:: https://clinicaltrials.gov/ct2/show/NCT01687998 NLM Identifier: NCT01687998. Accessed 13-Oct-2015.

      ] has recently been stopped following a futility analysis.
      The ILLUMINATE trial randomized 15,067 patients at high CV risk to the CETP inhibitor torcetrapib plus atorvastatin, or atorvastatin alone [
      • Barter P.J.
      • Caulfield M.
      • Eriksson M.
      • Grundy S.M.
      • Kastelein J.J.
      • Komajda M.
      • et al.
      Effects of torcetrapib in patients at high risk for coronary events.
      ]. At 12 months, patients who had received torcetrapib had about a 70% increase in HDL-C and a 25% decrease in LDL-C, as compared with baseline, but an increased risk of CV events (HR 1.25; 95% CI 1.09–1.44; p = 0.001) and death from any cause (HR 1.58; 95% CI 1.14–2.19; p = 0.006). However, torcetrapib also increased systolic blood pressure by about 5 mm Hg, possibly via off-target effects on aldosterone. These findings led to suspension of the development of torcetrapib.
      The Dal-OUTCOMES trial randomized 15,871 patients, also at high CV risk, to the CETP inhibitor dalcetrapib or placebo in addition to best available evidence-based care. This trial was stopped after a median of 31 months for futility [
      • Schwartz G.G.
      • Olsson A.G.
      • Abt M.
      • Ballantyne C.M.
      • Barter P.J.
      • Brumm J.
      • et al.
      Effects of dalcetrapib in patients with a recent acute coronary syndrome.
      ]. Like torcetrapib, dalcetrapib increased HDL-C by about 30%, but unlike torcetrapib minimally affected LDL-C levels. The HDL-C changes had no significant effect on major CV outcomes, raising potential questions about the validity of HDL-C as a therapeutic target. However, no major hazards were identified. The DEFINE study involved 1623 patients with (or at high risk for) CHD on statin therapy, who were randomized to anacetrapib 100 mg daily versus placebo for 18 months [
      • Cannon C.P.
      • Shah S.
      • Dansky Hayes M.
      • et al.
      for the DEFINE Investigators.
      ]. The main outcomes of interest of the study were biochemical and safety end-points. Results showed a 40% reduction in LDL-C with anacetrapib compared to placebo, with an approximate 140% increase in HDL-C. No major safety concerns were identified and no significant changes in blood pressure, electrolyte or aldosterone levels observed.
      The ACCELERATE trial [

      Eli Lilly and Company. A study of evacetrapib in high-risk vascular disease (ACCELERATE). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Available from:: https://clinicaltrials.gov/ct2/show/NCT01687998 NLM Identifier: NCT01687998. Accessed 13-Oct-2015.

      ] which was discontinued in October 2015, had randomized approximately 12,000 participants with high risk vascular disease, and was expected to finish in 2016. The study was terminated early by its academic leaders following recommendation by the independent data monitoring committee due to insufficient efficacy, which suggested there was a low probability the study would achieve its primary endpoint; it was not stopped for safety findings [

      Eli Lilly and Company. Lilly to discontinue development of evacetrapib for high-risk atherosclerotic cardiovascular disease. https://investor.lilly.com/releasedetail.cfm?ReleaseID=936130. Accessed 13-Oct-2015.

      ]. The development programme has also been stopped. Evacetrapib was being assessed against a background of best statin therapy and it would be expected that there might be a lag before the impact of additional lipid modification would become apparent, it is not clear therefore whether after relatively short-follow-up there would have been sufficient statistical power to exclude a modest benefit of treatment.
      One large randomized phase 3 trial of a CETP inhibitor remains ongoing. The Randomized Evaluation of the Effects of Anacetrapib through Lipid modification (REVEAL) study [

      Oxford Uo. REVEAL: randomized EValuation of the effects of anacetrapib through lipid-modification. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Available from: https://clinicaltrials.gov/ct2/show/NCT01252953 NLM Identifier: NCT01252953. Accessed 13-Oct-2015.

      ] has randomized >30,000 high CV risk participants and, as such, will be the largest CETP inhibitor trial to date, with results expected in 2017. The results of this trial should help elucidate any role that CETP inhibitors may play in clinical practice.
      • Other agents
      Two other agents have recently gained approval for treatment of the rare but difficult to treat disorder homozygous FH.
      Mipomersen is a second generation antisense oligonucleotide that targets apolipoprotein B [
      • Gouni-Berthold I.
      • Berthold H.K.
      Mipomersen and lomitapide: two new drugs for the treatment of homozygous familial hypercholesterolemia.
      ,
      • Crooke S.T.
      • Geary R.S.
      Clinical pharmacological properties of mipomersen (Kynamro), a second generation antisense inhibitor of apolipoprotein B.
      ]. It is administered subcutaneously and has been shown to reduce LDL-C concentrations by approximately 25% in patients with homozygous FH who are already receiving lipid-lowering drugs, including high-dose statins [
      • Raal F.J.
      • Santos R.D.
      • Blom D.J.
      • Marais A.D.
      • Charng M.J.
      • Cromwell W.C.
      • et al.
      Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial.
      ]. However, it appears to be hepatotoxic leading to the European Medicines Agency not approving the drug in the EU and it is associated with a variety of other side-effects [
      • Raal F.J.
      • Santos R.D.
      • Blom D.J.
      • Marais A.D.
      • Charng M.J.
      • Cromwell W.C.
      • et al.
      Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial.
      ,
      • Thomas G.S.
      • Cromwell W.C.
      • Ali S.
      • Chin W.
      • Flaim J.D.
      • Davidson M.
      Mipomersen, an apolipoprotein B synthesis inhibitor, reduces atherogenic lipoproteins in patients with severe hypercholesterolemia at high cardiovascular risk: a randomized, double-blind, placebo-controlled trial.
      ]. In the US whilst it is approved for use in homozygous FH, it can only be prescribed through a risk evaluation mitigation strategy (REMS) programme, limiting its clinical usefulness.
      Microsomal transfer protein (MTP) is involved in the manufacture of apoB-containing lipoproteins in the liver and intestine, with mutations in the MTP gene causing the rare, autosomal recessive condition abetalipoproteinemia. Lomitapide binds to and inhibits MTP, resulting in a reduction in plasma LDL-C levels. It has been approved for treatment of homozygous FH in the US and EU, although it is associated with some gastrointestinal side effects and has also been noted to cause an increase in liver transaminases [
      • Gouni-Berthold I.
      • Berthold H.K.
      Mipomersen and lomitapide: two new drugs for the treatment of homozygous familial hypercholesterolemia.
      ,
      • Raal F.J.
      Lomitapide for homozygous familial hypercholesterolaemia.
      ].

      1.5 Other treatments in development

      Lipoprotein(a) [Lp(a)] is an LDL particle attached to an apolipoprotein(a) molecule with a variable number of kringle IV (KIV) domains that define apo(a) isoform size and which has been known to be a risk factor for CHD for many years [
      • Emerging Risk Factors C
      • Erqou S.
      • Kaptoge S.
      • Perry P.L.
      • Di Angelantonio E.
      • Thompson A.
      • et al.
      Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality.
      ]. Lp(a) levels are predominantly genetically determined and strongly inversely associated with the number of KIV domains and vary widely in populations. Recent MR studies indicate that lifelong higher Lp(a) levels are causally associated with coronary heart disease: the variant alleles, carried by 1 in 6 people of European ancestry, are associated with about a 50% higher risk of coronary heart disease [
      • Clarke R.
      • Peden J.F.
      • Hopewell J.C.
      • Kyriakou T.
      • Goel A.
      • Heath S.C.
      • et al.
      Genetic variants associated with Lp(a) lipoprotein level and coronary disease.
      ,
      • IBC 50K CAD Consortium
      Large-scale gene-centric analysis identifies novel variants for coronary artery disease.
      ]. Niacin and PCSK9 inhibitors both modestly reduce Lp(a) alongside LDL-C reductions but statins have little or no effect on Lp(a) levels. There is therefore growing interest in other newer technologies that specifically target Lp(a). A second generation anti-sense oligonucleotide designed to reduce the synthesis of Lp(a) has been shown in a phase 1 study to decrease Lp(a) levels by up to 80% and to be well tolerated [
      • Tsimikas S.
      • Viney N.J.
      • Hughes S.G.
      • Singleton W.
      • Graham M.J.
      • Baker B.F.
      • et al.
      Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study.
      ]. Further studies are awaited with interest.
      Another area of development is in inhibition of apolipoprotein (apo) C3 by anti-sense technologies. ApoC3 is a multifunctional protein that is involved in the metabolism of triglyceride rich lipoproteins. Current literature is limited, but a meta-analysis of prospective studies indicates a modest positive association between blood levels of apoC3 and cardiovascular events [
      • Wyler von Ballmoos M.C.
      • Haring B.
      • Sacks F.M.
      The risk of cardiovascular events with increased apolipoprotein CIII: a systematic review and meta-analysis.
      ]. A pooled estimate from 6 published studies showed a relative risk of 1.33 (1.07–1.66) for a 5 mg/dL higher total apoC3 with a somewhat stronger association for the ApoC3 in non-HDL [
      • Wyler von Ballmoos M.C.
      • Haring B.
      • Sacks F.M.
      The risk of cardiovascular events with increased apolipoprotein CIII: a systematic review and meta-analysis.
      ]. Anti-sense oligonucleotides (ASO) have been developed which produce dose-dependent reductions in apoC3 levels in animal models and man [
      • Graham M.J.
      • Lee R.G.
      • Bell 3rd, T.A.
      • Fu W.
      • Mullick A.E.
      • Alexander V.J.
      • et al.
      Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans.
      ]. The ISIS 304801 ASO has been well tolerated in early phase studies and produced significant reductions in apoC3 levels and 30–70% reductions in triglycerides in a group of hypertriglyceridaemic patients [
      • Gaudet D.
      • Alexander V.J.
      • Baker B.F.
      • Brisson D.
      • Tremblay K.
      • Singleton W.
      • et al.
      Antisense inhibition of apolipoprotein c-III in patients with hypertriglyceridemia.
      ].

      2. Conclusions

      Statins remain the cornerstone of lipid management for both primary and secondary prevention of CVD. A variety of other lipid modifying therapies are available which can be added to statin therapy to further reduce CV risk. Ezetimibe is the most effective and evidence-based treatment that can be safely added to statins, and is increasingly used in clinical practice. Other options include fibrates, resins or nicotinic acid. Fibrates remain widely used in lipid clinics to manage significant hypertriglyceridaemia but their role for further CV reduction in the absence of high triglycerides or low HDL-C has not been proven. Bile acid sequestrants, such as the newer tablet preparations of colesevelam, also have a role in a limited number of patients and are effective LDL-C lowering agents if given at sufficiently high dose, but without recent trial data to support their use. In contrast, nicotinic acid, despite modifying lipids, has not been shown to reduce CV risk when added to statins and has been shown to be associated with significant hazards. Several large phase 3 trials of CETP inhibitors have been initiated, but only one (REVEAL) remains ongoing after the ILLUMINATE trial was stopped for safety concerns and the dal-OUTCOMES and ACCELERATE trials stopped for futility. PCSK9 inhibitors appear promising agents with multiple trials demonstrating that these agents can modify lipids substantially. Several large PCSK9 inhibitor clinical outcomes trials (ODYSSEY-OUTCOMES, FOURIER and the SPIRE-I and II trials) are currently ongoing, which should elucidate their place in clinical practice. A variety of novel anti-sense oligonucleotides are also in development, with vaccines offering a further potential opportunity for lipid intervention in the future.

      Acknowledgements

      CR and JA are members of the Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU) in the Nuffield Department of Population Health at the University of Oxford. The CTSU receives core funding from the UK Medical Research Council, the British Heart Foundation and Cancer Research UK and has received funding from pharmaceutical companies to conduct randomised trials, but these trials are undertaken, analysed and reported independently of the funders. CTSU has a staff policy of not accepting honoraria or consultancy fees.

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