Decade in Review—Dyslipidaemia: Resurgence of Targets And

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DECADE IN REVIEW—DYSLIPIDAEMIA trial.3 Ridker et al. selected patients with an elevated C‑reactive protein level (measured Resurgence of targets and by high-sensitivity assay), but who were free from CAD, and demonstrated that a daily compounds to treat dyslipidaemia dose of 20 mg rosuvastatin robustly reduced John J. P. Kastelein the incidence of major adverse cardiovascular events by 44% compared with placebo Over the past decade, we have witnessed the unparalleled success (P <0.00001).3 Again, efficacy was observed of statins to treat dyslipidaemia. Target identification by Mendelian in all subgroups, including men and women, randomization, human monoclonal antibodies, gene therapy, RNA-based the elderly and young, tobacco smokers and targets, and atherogenic lipoproteins other than LDL cholesterol have nonsmokers, and those with or without fuelled intense development efforts that might bear fruit in the very metabolic syndrome. More importantly, the JUPITER trial3 results highlighted the link near future. between inflammation, dyslipidaemia, and Kastelein, J. J. P. Nat. Rev. Cardiol. 11, 629–631 (2014); published online 9 September 2014; atherosclerotic vascular disease, which has doi:10.1038/nrcardio.2014.132 led to the current development of selective anti-inflammatory strategies in outcome When Terje Pedersen first presented the which turned the hypothesis that ‘lower trials by the same research group. results of the Scandinavian Simvastatin LDL cholesterol is better’ into a core princi- In two papers published in 2006 and Survival Study at the AHA Scientific Sessions ple. In the PROVE‑IT study,1 Cannon and 2008, respectively, investigators applied on 16 November 1994 in Dallas, TX, USA, co-workers convincingly demonstrated advanced molecular biology techniques he probably did not realize that the study that 80 mg of atorvastatin was superior to to the study of lipid control.4,5 In the first would initiate a global revolution in statin 40 mg of pravastatin in outcome parameters study, mRNA inhibition by subcutaneously therapy. Today, statins are the most widely including death, myocardial infarction, administered small oligonucleotides against prescribed class of drugs, and although the unstable angina, and revascularization (a apolipoprotein B‑100 (apoB‑100) lowered results of this study were presented 20 years 16% risk reduction in favour or atorvastatin; the levels of all atherogenic lipoproteins in ago, no other drug has since been shown to P = 0.005), when administered shortly after human volunteers with mild dyslipidaemia.4 have any additional benefit for patients with an acute coronary syndrome (ACS).1 This These results have led to the development dyslipidaemia. Inhibitors of phospholipases, study transformed care for patients with of small inhibitory RNAs, mRNA inhibi- cholesteryl ester transfer protein (CETP), ACS; 80 mg of atorvastatin straight after tors, and locked nucleic acid inhibitors and cholesterol absorption, as well as ago- an ACS episode has now become routine that target angiopoietin-related protein 3, nists of peroxisome proliferator-activated clinical practice in coronary care units in apoB‑100, apolipoprotein C‑III (apoC‑III), receptor, thyroxin receptor, and nicotinic most countries. This strategy has saved apolipoprotein(a) [apo(a)], and PCSK9, and acid have either been toxic or not provided innumerable lives of patients with coronary which have all reached phase I and further a beneficial outcome for patients. However, artery disease (CAD) and protected them clinical studies. These developments are just not all discoveries in the past decade for against recurrent events. the beginning, and many more will come in the therapeutic control of dyslipidaemia In the TNT study,2 also published in the next decade. In the second paper, which can be claimed by statins. In 2003, Boileau 2004, LaRosa and colleagues demonstrated garnered little attention when first pub- and colleagues mapped a locus associated that 80 mg was superior to 10 mg of ator- lished, Stroes and colleagues performed the with familial hypercholesterolaemia in vastatin for treating patients with stable first proof-of-concept study of gene therapy the gene encoding proprotein convertase CAD. High-dose atorvastatin reduced the for dyslipidaemia. Alipogene tiparvovec subtilisin/kexin type 9 (PCSK9). As with the primary end point (occurrence of a major increases the removal of postprandial chylo Scandinavian Simvastatin Survival Study, cardiovascular event) by 22% compared microns, the particles known to cause the Boileau et al. could not have foreseen that with the lower dose of the drug (P <0.001).2 acute and potentially lethal haemorrhagic their discovery would develop into the cur- This study has also enabled many second- pancreatitis associated with the chylo rently most exciting class of lipid-lowering ary analyses that aid our understanding micronaemia syndrome. Alipogene tipar- drugs—monoclonal antibodies against cir- of renal function during statin therapy, vovec (commercially known as Glybera®; culating PCSK9. These two discoveries have the clinical safety of low LDL-cholesterol UniQure, Netherlands) became the first led to an unprecedented number of devel- levels, and that a reduction in adverse clini- gene therapy product to be approved for any opments in the field of dyslipidaemia in the cal outcomes is independent of almost any indication in the Western world.5 past decade. baseline patient characteristic, including Many developments since 1994 have In 2004, the authors of two papers first LDL-cholesterol level itself. These ‘statin revolved around the biology, pathology, established the clinical importance of statins principles’ were extended into the realm of and therapeutic lowering of LDL-cholesterol in the treatment of cardiovascular disease, primary prevention in 2008 in the JUPITER levels. Only after a number of international

1986 2013 approach in the development of drugs to apoC‑III, triglyceride metabolism, and treat dyslipidaemia. CAD risk.9,10 The fact that the apoC‑III 450 First Synvinolin Of all the developments over the past inhibitor is already in clinical development 400 study decade, a paper by Stein and colleagues in is, therefore, timely and fortuitous. With all 2012 deserves the title of ‘game changer’. In of these results comes the hope that novel 350 this study, a monoclonal antibody against small-molecule compounds, monoclonal 300 PCSK9 (alirocumab), reduced the relative antibodies, and RNA technology will trans- LDL-cholesterol level by >60% in both form dyslipidaemia treatment in the coming RUTHERFORD 250 volunteers with normal lipid levels and decade, for a second time since 1994. We ENHANCE ASAP patients with familial hypercholesterol- might finally be able to eliminate dys 200 aemia.8 The excellent safety profile of this lipidaemia and subsequent atherosclerotic RADIANCE drug class has been a relief for clinicians, vascular disease for our patients in the very LDL-C levels (mg/dl) LDL-C levels 150 especially given the previous toxicity- near future. 100 related failures of other compounds. Simi Department of Vascular Medicine, Academic lar results were obtained in studies with Medical Center, University of Amsterdam, 50 bococizumab and evolocumab, and all three Meibergdreef 9, 1105 AZ Amsterdam, Netherlands. 0 monoclonal antibodies targeted against PCSK9 are already in advanced, phase III [email protected] mg mg mg mg mg statin statin outcome trials. Only 9 years have passed Competing interests

Eze 10 J.J.P.K. declares that he has acted as a consultant No therapy mg + mg + between Boileau and colleagues’ initial + Simva 40Atorva 80Simva 40Simva 80 and received honouraria from the following mg PCSK9 discovery and Stein and co-workers’ companies: Aegerion, Amgen, AstraZeneca, Torcet 60Evo 420 2012 paper. This rapid development has Atheronova, Boehringer Ingelheim, Catabasis, Simva 80 been made possible by recombinant DNA Cerenis, CSL Behring, Dezima Pharmaceuticals, Eli Lilly, Esperion, Genzyme, Isis, Merck, Novartis, Therapy and antibody technology. Compared with Omthera, Pronova, Regeneron, Sanofi, The Medicines Figure 1 | LDL-cholesterol levels achieved by the >25 years between cloning of the lipo- Company, UniQure, and Vascular Biogenics. lipid-lowering therapies developed during the protein lipase (LPL) gene and the LPL gene past 3 decades in patients with familial therapy trial by our own group, the devel- 1. Cannon, C. P. et al. Intensive versus moderate lipid lowering with statins after acute coronary hypercholesterolaemia. Dosing frequencies are opment of PCSK9-based technologies has syndromes. N. Engl. J. Med. 350, 1495–1504 per day unless otherwise stated. Abbreviations: been a remarkable achievement. (2004). Atorva, atorvastatixn; Evo, evolocumab; Eze, However, for which patients is the dis- 2. LaRosa, J. C. et al. Intensive lipid lowering with ezetimibe; LDL‑C, LDL-cholesterol; Simva, atorvastatin in patients with stable coronary covery of PCSK9 monoclonal antibodies simvastatin; Torcet, torcetrapib. disease. N. Engl. J. Med. 352, 1425–1435 most beneficial in the short term? To have (2005). personally witnessed the ever-decreasing 3. Ridker, P. M. et al. Rosuvastatin to prevent consortia performed large Mendelian LDL-cholesterol levels that different thera- vascular events in men and women with elevated C‑reactive protein. N. Engl. J. Med. randomization studies was the link made pies have achieved in patients with familial 359, 2195–2207 (2008). between CAD and apo(a), triglyceride- hypercholesterolaemia has been immensely 4. Kastelein, J. J. P. et al. Potent reduction of rich lipoproteins, and remnant choles- gratifying. Between the first simvasta- apolipoprotein B and low-density lipoprotein 6,7 cholesterol by short-term administration of terol. These observations are seminal for tin trial in 1986 and the RUTHERFORD an antisense inhibitor of apolipoprotein B. our understanding of atherogenesis and study of evolocumab just last year, a steady Circulation 114, 1729–1735 (2006). initiated an international effort to iden- decrease in LDL-cholesterol levels from 5. Stroes, E. S. et al. Intramuscular administration tify novel strategies to decrease circulat- 9.6 mmol/l (371 mg/dl) to ~1.7 mmol/l of AAV1-lipoprotein lipase S447X lowers triglycerides in lipoprotein lipase-deficient ing levels of these lipoproteins. Moreover, (65 mg/dl) has been achieved (Figure 1). patients. Arterioscler. Thromb. Vasc. Biol. 28, the results of these Mendelian randomi- The discovery that monoclonal antibodies 2303–2304 (2008). zation studies, such as those performed against PCSK9 can lower LDL-cholesterol 6. Kamstrup, P. R., Tybjærg-Hansen, A., 6 7 Steffensen, R. & Nordestgaard, B. G. by Nordestgaard and Kathiresan, have levels to such an extent has essentially Genetically elevated lipoprotein(a) and questioned the relationship between HDL cured familial hypercholesterolaemia; in increased risk of myocardial infarction. cholesterol and CAD, which might explain fact, the LDL-cholesterol levels achieved JAMA 301, 2331–2339 (2009). 7. Do, R. et al. Common variants associated with the disappointing results of strategies that in these patients are now lower than in the plasma triglycerides and risk for coronary raise HDL-cholesterol levels. By contrast, general population. Who would have had artery disease. Nat. Genet. 45, 1345–1352 Mendelian randomization and interven- the temerity to predict that in 2003? (2013). tion studies have both validated the role of The final discovery that I would like to 8. Stein, E. A. et al. Effect of a monoclonal antibodies to PCSK9 on LDL cholesterol. lowering LDL-cholesterol levels to treat dys- highlight was reported in two papers in N. Engl. J. Med. 366, 1108–1118 (2012). lipidaemia. Consequently, the discoveries which triglyceride-rich lipoprotein and 9. Jørgensen, A. B., Frikke-Schmidt, R., by investigators that CETP, triglyceride- remnant cholesterol levels were causally Nordestgaard, B. G. & Tybjærg-Hansen, A. 9,10 Loss‑of-function mutations in APOC3 and risk of rich lipoproteins, and apo(a) are indeed linked to apoC‑III and CAD. ApoC‑ ischemic vascular disease. N. Engl. J. Med. 371, involved in atherogenesis have led to a III was first hypothesized to reduce tri 32–41 (2014). search for compounds to safely lower the glyceride levels and contribute to the risk 10. The TG and HDL Group of the Exome levels of these proteins, as well as those of of CAD, and on that basis a mRNA inhibi- Sequencing Project, National, Heart, Lung, and Blood Institute. Loss-of-function mutations in apoC‑III and, of course, PCSK9. Mendelian tor of apoC‑III was developed. These two APOC3, triglycerides, and coronary heart randomization studies are now an integral papers strengthen the association between disease. N. Engl. J. Med. 371, 22–31 (2014).