Twenty-five years of statins: where do we go from here?

References

• Carroll MD, Kit BK, Lacher DA, Shero ST, Mussolino ME. Trends in lipids and lipoproteins in US adults. JAMA 308(15), 1545–1554 (2012).
   Google Scholar
• Müller C. Angina pectoris in hereditary xanthomatosis. Arch. Int. Med. 64(4), 675–700 (1939).
   Google Scholar
• Gofman JW. Serum lipoproteins and the evaluation of atherosclerosis. Ann. NY Acad. Sci. 64(4), 590–595 (1956).
   Google Scholar
• Kannel WB, Dawber TR, Kagan A, Revotskie N, Stokes J. Factors of risk in the development of coronary heart disease – six year follow-up experience. The Framingham Study. Ann. Intern. Med. 55, 33–50 (1961).
   Google Scholar
• Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High-density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am. J. Med. 62(5), 707–714 (1977).
   Google Scholar
• Verschuren WM, Jacobs DR, Bloemberg BP et al. Serum total cholesterol and long-term coronary heart disease mortality in different cultures. Twenty-five-year follow-up of the seven countries study. JAMA 274(2), 131–136 (1995).
   Google Scholar
• Estruch R, Ros E, Salas-Salvado J et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N. Engl. J. Med. 369(8), 1279–1290 (2013).
   Google Scholar
• Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 302(18), 1993–2000 (2009).
   Google Scholar
• Goldstein JL, Brown MS. The low-density lipoprotein pathway and its relation to atherosclerosis. Annu. Rev. Biochem. 46, 897–930 (1977).
   Google Scholar
• Endo A, Kuroda M, Tanzawa K. Competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by ML-236A and ML-236B fungal metabolites, having hypocholesterolemic activity. FEBS Lett. 72, 323–326 (1976).
   Google Scholar
• Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344(8934), 1383–1389 (1994).
   Google Scholar
• Shepherd J, Cobbe SM, Ford I et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N. Engl. J. Med. 333, 1301–1307 (1995).
   Google Scholar
• Downs JR, Clearfield M, Weis S et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. Results of AFCAPS/TexCAPS. JAMA 279(20), 1615–1622 (1998).
   Google Scholar
• Kostis WJ, Cheng JQ, Dobrzynski JM, Cabrera J, Kostis JB. Meta-analysis of statin effects in women versus men. J. Am. Coll. Cardiol. 59(6), 572–582 (2012).
   Google Scholar
• LaRosa JC. Treatment of cholesterol in the elderly: statins and beyond. Curr. Atheroscler. Rep. 16(2), 385 (2014).
   Google Scholar
• Cannon CP. The IDEAL cholesterol: lower is better. JAMA 294(19), 2492–2494 (2005).
   Google Scholar
• ACCORD Study Group. Effects of intensive blood-pressure control in Type 2 diabetes mellitus. N. Engl. J. Med. 362(17), 1575–1585 (2010).
   Google Scholar
• Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in Type 2 diabetes. N. Engl. J. Med. 358(24), 2545–2559 (2008).
   Google Scholar
• 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. Lancet 376(9753), 1670–1681 (2010). •• Strong evidence regarding clinical benefit and safety of statin therapy.
   Google Scholar
• Boekholdt SM, Hovingh GK, Mora S et al. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. J. Am. Coll. Cardiol. 64(5), 485–494 (2014).
   Google Scholar
• Baigent C, Keech A, Kearney PM et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis from 90,056 participants in 14 randomised trials of statins. Lancet 366(9493), 1267–1278 (2005).
   Google Scholar
• Sattar N, Preiss D, Murray HM et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomized statin trials. Lancet 375(9716), 735–742 (2010).
   Google Scholar
• Stone NJ, Robinson J, Lichtenstein AH et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 129(25 Suppl. 2), S1–S45 (2014). •• New guidelines for lipid-lowering therapy.
   Google Scholar
• Pencina MJ, Navar-Boggan AM, D’Agostino RB Sr et al. Application of new cholesterol guidelines to a populationbased sample. N. Engl. J. Med. 379(15), 1422–1431 (2014).
   Google Scholar
• Rabar S, Harker M, O’Flynn N, Wierzbicki AS. Guideline Development Group. Lipid modification and cardiovascular risk assessment for the primary and secondary prevention of cardiovascular disease: summary of updated NICE guidance. BMJ 17(349), g4356 (2014).
   Google Scholar
• LaRosa JC, Grundy SM, Waters DD et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N. Engl. J. Med. 352(14), 1425–1435 (2005).
   Google Scholar
• Cannon CP, Braunwald E, McCabe CH et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N. Engl. J. Med. 350(15), 1495–1504 (2004).
   Google Scholar
• Ridker PM, Danielson E, Fonseca FA et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N. Engl. J. Med. 359(21), 2195–2207 (2008).
   Google Scholar
• Fruchart JC, Davignon J, Hermans MP et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc. Diabetol. 13, 26 (2013).
   Google Scholar
• Pandor A, Ara RM, Tumur I et al. Ezetimibe monotherapy for cholesterol lowering in 2,722 people: systematic review and meta-analysis of randomized controlled trials. J. Intern. Med. 265(5), 568–580 (2009).
   Google Scholar
• Mikhailidis DP, Lawson RW, McCormick AL et al. Comparative efficacy of the addition of ezetimibe to statin vs statin titration in patients with hypercholesterolemia: systematic review and meta-analysis. Curr. Med. Res. Opin. 27(6), 1191–1210 (2011).
   Google Scholar
• Baigent C, Landray MJ, Reith C et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomized placebo-controlled trial. Lancet 377(9784), 2181–2192 (2011).
   Google Scholar
• Kastelein JJ, Akdim F, Stroes ES et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N. Engl. J. Med. 358(14), 1431–1443 (2008).
   Google Scholar
• Taylor AJ, Villines TC, Stanek EJ et al. Extended-Release Niacin or Ezetimibe and Carotid Intima-Media Thickness. N. Engl. J. Med. 361(22), 2113–2122 (2009).
   Google Scholar
• Cannon CP. IMPROVE-IT Trial: A Comparison of Ezetimibe/Simvastatin versus Simvastatin Monotherapy on Cardiovascular Outcomes After Acute Coronary Syndromes. Presented at: American Heart Association Scientific Sessions. Chicago, IL, USA, 17 November 2014.
   Google Scholar
• Sjouke B, Kusters DM, Kindt I et al. Homozygous autosomal dominant hypercholesterolemia in The Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome. Eur. Heart. J. (2014) (Epub ahead of print).
   Google Scholar
• Austin MA, Zimmern RL, Humphries SE. High “population attributable fraction” for coronary heart disease mortality among relatives in monogenic familial hypercholesterolemia. Genet. Med. 4(4), 275–278 (2002).
   Google Scholar
• Visser ME, Witztum JL, Stroes ES, Kastelein JJ. Antisense oligonucleotides for the treatment of dyslipidemia. Eur. Heart J. 33(12), 1451–1458 (2012). • Detailed review of mipomersen containing additional details on its pharmacology and clinical use.
   Google Scholar
• Raal FJ, Santos RD, Blom DJ et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolemia: a randomized, double-blind, placebo-controlled trial. Lancet 375(9719), 998–1006 (2010).
   Google Scholar
• Stein EA, Dufour R, Gagne C et al. Apolipoprotein B synthesis inhibition with mipomersen in heterozygous familial hypercholesterolemia: results of a randomized, double-blind, placebo-controlled trial to assess efficacy and safety as add-on therapy in patients with coronary artery disease. Circulation 126(19), 2283–2292 (2012).
   Google Scholar
• McGowan MP, Tardif JC, Ceska R et al. Randomized, placebo-controlled trial of mipomersen in patients with severe hypercholesterolemia receiving maximally tolerated lipid-lowering therapy. PLoS ONE 7(11), 49006 (2012).
   Google Scholar
• Visser ME, Wagener G, Baker BF et al. Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial. Eur. Heart J. 33(9), 1142–1149 (2012).
   Google Scholar
• US Food and Drug Administration. Mipomersen Sodium Injection 200 mg/mL. Endocrinologic and Metabolic Drugs Advisory Committee Meeting; October 18, 2012. FDA Briefing Document NDA 203568. www.fda.gov
   Google Scholar
• Cuchel M, Meagher EA, du Toit Theron H et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolemia: a single-arm, open-label, Phase 3 study. Lancet 381(9860), 40–46 (2013).
   Google Scholar
• Cuchel M, Blom DJ, Averna MR. Clinical experience of lomitapide therapy in patients with homozygous familial hypercholesterolaemia. Atheroscler. Suppl. 15(2), 33–45 (2014). • Detailed review of lomitapide containing additional details on its pharmacology and clinical use.
   Google Scholar
• Ouguerram K, Chetiveaux M, Zair Y et al. Apolipoprotein B100 metabolism in autosomal-dominant hypercholesterolemia related to mutations in PCSK9. Arterioscler. Thromb. Vasc. Biol. 24(8), 1448–1453 (2004).
   Google Scholar
• Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med. 354(12), 1264–1272 (2006).
   Google Scholar
• Petrides F, Shearston K, Chatelais M, Guilbaud F, Meilhac O, Lambert G. The promises of PCSK9 inhibition. Curr. Opin. Lipidol. 24(4), 307–312 (2013). • Review of promising experimental class of drugs.
   Google Scholar
• Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N. Engl. J. Med. 367(20), 1891–1900 (2012).
   Google Scholar
• Koren MJ, Scott R, Kim JB et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, Phase 2 study. Lancet 380(9858), 1995–2006 (2012).
   Google Scholar
• Giugliano RP, Desai NR, Kohli P et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaema (LAPLACE-TIMI 57): a randomized, placebo-controlled, dose-ranging, Phase 2 study. Lancet 380(9858), 2007–2017 (2012).
   Google Scholar
• Voight BF, Peloso GM, Orho-Melander M et al. Plasma HDL cholesterol and risk of myocardial infarction: A Mendelian randomisation study. Lancet 380(9841), 572–580 (2012). • Raises doubts about HDL-c-raising hypothesis based on genetic data.
   Google Scholar
• Otocka-Kmiecik A, Mikhailidis DP, Nicholls SJ, Davidson M, Rysz J, Banach M. Dysfunctional HDL: a novel important diagnostic and therapeutic target in cardiovascular disease? Prog. Lipid Res. 51(4), 314–324 (2012).
   Google Scholar
• Khera AV, Cuchel M, de la Llera-Moya M et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N. Engl. J. Med. 364(2), 127–135 (2011).
   Google Scholar
• Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 384(9943), 626–635 (2014). • Indicates resurgence of interest in triglycerides as a cardiovascular marker and target.
   Google Scholar
• Chapman MJ, Ginsberg HN, Amarenco P et al. Triglyceriderich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur. Heart J. 32(11), 1345–1361 (2011).
   Google Scholar
• Miller M, Stone NJ, Ballantyne C et al. Triglycerides and cardiovascular disease. Circulation 123(20), 2292–2333 (2011).
   Google Scholar
• Canner PL, Berge KG, Wenger NK et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J. Am. Coll. Cardiol. 8(6), 1245–1255 (1986).
   Google Scholar
• Frick MH, Elo O, Haapa K et al. Helsinki Heart Study: primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N. Engl. J. Med. 317(20), 1237–1245 (1987).
   Google Scholar
• Rubins HB, Robins SJ, Collins D et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N. Engl. J. Med. 341(6), 410–418 (1999).
   Google Scholar
• Bays HE, Ballantyne CM, Kastelein JJ, Isaacsohn JL, Braeckman RA, Soni PN. Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the Multi-center, placebo-controlled, randomized, double-blind 12-week study with an open-label extension [MARINE] trial). Am. J. Cardiol. 108(5), 682–690 (2011).
   Google Scholar
• Ballantyne CM, Bays HE, Kastelein JJ et al. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am. J. Cardiol. 110(7), 984–992 (2012).
   Google Scholar
• AIM-HIGH Investigators, Boden WE, Probstfield JL et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N. Engl. J. Med. 365(24), 2255–2267 (2011).
   Google Scholar
• HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N. Engl. J. Med. 371(3), 203–212 (2014).
   Google Scholar
• Keech A, Simes RJ, Barter P et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with Type 2 diabetes mellitus (the FIELD study): randomized controlled trial. Lancet 366(9500), 1849–1861 (2005).
   Google Scholar
• ACCORD Study Group. Effects of combination lipid therapy in Type 2 diabetes mellitus. N. Engl. J. Med. 362(17), 1563–1574 (2010).
   Google Scholar
• Scott R, O’Brien R, Fulcher G et al. Effects of fenofibrate treatment on cardiovascular disease risk in 9,795 individuals with Type 2 diabetes and various components of the metabolic syndrome: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetes Care 32(3), 493–498 (2009).
   Google Scholar
• Krause BR, Remaley AT. Reconstituted HDL for the acute treatment of acute coronary syndrome. Curr. Opin. Lipidol. 24(6), 480–486 (2013).
   Google Scholar
• Waksman R, Torguson R, Kent KM et al. A first-in-man, randomized, placebo-controlled study to evaluate the safety and feasibility of autologous delipidated high-density lipoprotein plasma infusions in patients with acute coronary syndrome. J. Am. Coll. Cardiol. 55(24), 2727–2735 (2010).
   Google Scholar
• Nicholls SJ, Tuzcu EM, Sipahi I et al. Relationship between atheroma regression and change in lumen size after infusion of apolipoprotein A-I Milano. J. Am. Coll. Cardiol. 47(5), 992–997 (2006).
   Google Scholar
• Hovingh GK, Bochem AE, Kastelein JJ. Apolipoprotein A-I mimetic peptides. Curr. Opin. Lipidol. 21(6), 481–486 (2010).
   Google Scholar
• Davidson MH. Apolipoprotein A-I therapy promise, challenges, and disappointment. J. Am. Coll. Cardiol. 57(9), 1120–1121 (2011).
   Google Scholar
• Bailey D, Jahagirdar R, Gordon A et al. RVX-208: a small molecule that increases apolipoprotein A-I and high-density lipoprotein cholesterol in vitro and in vivo. J. Am. Coll. Cardiol. 55(23), 2580–2589 (2010).
   Google Scholar
• Nicholls SJ, Gordon A, Johansson J et al. Efficacy and safety of a novel oral inducer of apolipoprotein A-I synthesis in statin-treated patients with stable coronary artery disease a randomized controlled trial. J. Am. Coll. Cardiol. 57(9), 1111–1119 (2011).
   Google Scholar
• Graham MJ, Lee RG, Bell TA et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ. Res. 112(11), 1479–1490 (2013).
   Google Scholar
• TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N. Engl. J. Med. 371(1), 22–31 (2014).
   Google Scholar
• Barter PJ, Brewer HB Jr, Chapman MJ, Hennekens CH, Rader DJ, Tall AR. Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 23(2), 160–167 (2003).
   Google Scholar
• Barter PJ, Caulfield M, Eriksson M et al. Effects of torcetrapib in patients at high risk for coronary events. N. Engl. J. Med. 357(21), 2109–2122 (2007).
   Google Scholar
• Schwartz GG, Olsson AG, Abt M et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N. Engl. J. Med. 367(22), 2089–2099 (2012).
   Google Scholar
• Cannon CP, Shah S, Dansky HM et al. Safety of anacetrapib in patient with or at high risk for coronary heart disease. N. Engl. J. Med. 363(25), 2406–2415 (2010).
   Google Scholar
• Gotto AM Jr, Cannon CP, Shah S et al. Effects on lipids and safety following cessation of treatment with cholesteryl ester transfer protein inhibitor anacetrapib in patients with or at high risk for coronary heart disease. Circulation 124, A15035 (2011).
   Google Scholar
• Gotto AM Jr, Cannon CP, Li XS et al. Evaluation of lipids, drug concentration, and safety parameters following cessation of treatment with the cholesteryl ester transfer protein inhibitor anacetrapib in patients with or at high risk for coronary heart disease. Am. J. Cardiol. 113(1), 76–83 (2014).
   Google Scholar
• Nicholls SJ, Brewer HB, Kastelein JJ et al. Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. JAMA 306(19), 2099–2109 (2011).
   Google Scholar
• Libby P, Ridker PM, Hansson GK. Leducq Transatlantic Network on Atherothrombosis. Inflammation in atherosclerosis: from pathophysiology to practice. J. Am. Coll. Cardiol. 54(23), 2129–2138 (2009).
   Google Scholar
• Gustafsson M, Borén J. Mechanism of lipoprotein retention by the extracellular matrix. Curr. Opin. Lipidol. 15(5), 505–514 (2004).
   Google Scholar
• STABILITY Investigators. Darapladib for preventing ischemic events in stable coronary heart disease. N. Engl. J. Med. 370(18), 1702–1711 (2014).
   Google Scholar
• Nicholls SJ, Kastelein JJP, Schwartz GG et al. Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial. JAMA 311(3), 252–262 (2014).
   Google Scholar
• Ridker PM. Moving beyond JUPITER: will inhibiting inflammation reduce vascular event rates? Curr. Atheroscler. Rep. 15(1), 295 (2013).
   Google Scholar
• Ference BA, Yoo W, Alesh I 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. J. Am. Coll. Cardiol. 60(25), 2631–2639 (2012). •• Shows importance of early lifestyle interventions in cardiovascular risk reduction.
   Google Scholar