Advertisement

Molecular Medicine

, Volume 20, Supplement 1, pp S20–S23 | Cite as

Statins: Definitive Translational Research

  • Scott M. Grundy
Retrospective

The development of cholesterol-lowering statins is one of the highlights of transitional medicine. Statins reduce serum low-density lipoprotein cholesterol (LDL-C) and other atherogenic lipoproteins. Statin use in clinical practice is the outgrowth of extensive research into cholesterol and lipoprotein metabolism, drug discovery and randomized clinical trials (RCTs). Each of these areas is worthy of some review.

Cholesterol was first discovered in gallstones. It was named cholesterine by the French chemist Chevreul in 1816. In 1856, Virchow found that lipid (cholesterol) is a key component of atherosclerotic plaques. Subsequently, 13 Nobel Prizes have been awarded to scientists who have studied the structure, chemistry, biochemistry and biology of cholesterol. It has been known for 100 years that high serum cholesterol produces atherosclerosis in animals (1). In the 1940s and 1950s, it was observed that high serum cholesterol consistently associates with premature atherosclerotic...

Notes

Acknowledgments

This paper is dedicated to Dr. Anthony Cerami, founder of the journal Molecular Medicine and longtime friend and colleague.

References

  1. 1.
    Anitschkow NN, Chalatov S. (1913) Ueber experimentelle Choleserinsteatose und ihre Bedeutung fur die Entstehung einiger pathologischer Prozesse [On experimental cholesterol steatosis and its significance for the development of some pathological processes]. Zentralbl Allg Pathol 24:1–9.Google Scholar
  2. 2.
    Gofman JW, et al. (1950) The role of lipids and lipoproteins in atherosclerosis. Science. 111:166–71.CrossRefGoogle Scholar
  3. 3.
    Steinberg D. (2005) Thematic review series: the pathogenesis of atherosclerosis: an interpretive history of the cholesterol controversy, part III: mechanistically defining the role of hyperlipidemia. J. Lipid Res. 46:2037–51.CrossRefGoogle Scholar
  4. 4.
    Fuster V. (1995) Elucidation of the role of plaque instability and rupture in acute coronary events. Am. J. Cardiol. 76:24C–33C.CrossRefGoogle Scholar
  5. 5.
    Brown MS, Goldstein JL. (1986) A receptor-mediated pathway for cholesterol homeostasis. Science. 232:34–47.CrossRefGoogle Scholar
  6. 6.
    Goldstein JL, Brown MS. (2009) The LDL receptor. Arterioscler. Thromb. Vasc. Biol. 29:431–8.CrossRefGoogle Scholar
  7. 7.
    Hobbs HH, Brown MS, Goldstein JL. (1992) Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum. Mutat 1:445–66.CrossRefGoogle Scholar
  8. 8.
    Bilheimer DW, Stone NJ, Grundy SM. (1979) Metabolic studies in familial hypercholesterolemia: evidence for a gene-dosage effect in vivo. J. Clin. Invest. 64:524–33.CrossRefGoogle Scholar
  9. 9.
    Vega GL, Denke MA, Grundy SM. (1991) Metabolic basis of primary hypercholesterolemia. Circulation. 84:118–28.CrossRefGoogle Scholar
  10. 10.
    (1984) The Lipid Research Clinics Coronary Primary Prevention Trial results: I. Reduction in incidence of coronary heart disease. JAMA. 251:351–64.Google Scholar
  11. 11.
    Endo A. (2008) A gift from nature: the birth of the statins. Nat. Med. 14:1050–2.CrossRefGoogle Scholar
  12. 12.
    Yamamoto A, Sudo H, Endo A. (1980) Therapeutic effects of ML-236B in primary hypercholesterolemia. Atherosclerosis. 35:259–66.CrossRefGoogle Scholar
  13. 13.
    Mabuchi H, et al. (1981) Effects of an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase on serum lipoprotein and ubiquinone-10-levels in patients with familial hypercholesterolemia. N. Engl. J. Med. 305:478–82.CrossRefGoogle Scholar
  14. 14.
    Alberts AW, et al. (1980) Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc. Natl. Acad. Sci. U. S. A. 77:3957–61.CrossRefGoogle Scholar
  15. 15.
    Tobert JA, et al. (1982) Cholesterol-lowering effect of mevinolin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme a reductase, in healthy volunteers. J. Clin. Invest. 69:913–9.CrossRefGoogle Scholar
  16. 16.
    Bilheimer DW, Grundy SM, Brown MS, Goldstein JL. (1983) Mevinolin stimulates receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes. Trans. Assoc. Am. Physicians 96:1–9.PubMedGoogle Scholar
  17. 17.
    Uauy R, Vega GL, Grundy SM. (1991) Coinheritance of two mild defects in low density lipoprotein receptor function produces severe hypercholesterolemia. J. Clin. Endocrinol. Metab. 72:179–87.CrossRefGoogle Scholar
  18. 18.
    Vega GL, East C, Grundy SM. (1989) Effects of combined therapy with lovastatin and colestipol in heterozygous familial hypercholesterolemia: effects on kinetics of apolipoprotein B. Arteriosclerosis. 9 (1 Suppl.):I135–44.PubMedGoogle Scholar
  19. 19.
    Uauy R, Vega GL, Grundy SM, Bilheimer DM. (1988) Lovastatin therapy in receptor-negative homozygous familial hypercholesterolemia: lack of effect on low-density lipoprotein concentrations or turnover. J. Pediatr. 113:387–92.CrossRefGoogle Scholar
  20. 20.
    Denke MA, Grundy SM. (1995) Efficacy of low-dose cholesterol-lowering drug therapy in men S23 with moderate hypercholesterolemia. Arch. Intern. Med. 155:393–9.CrossRefGoogle Scholar
  21. 21.
    Vega GL, Krauss RM, Grundy SM. (1990) Pravastatin therapy in primary moderate hypercholesterolaemia: changes in metabolism of apolipoprotein B-containing lipoproteins. J. Intern. Med. 227:81–94.CrossRefGoogle Scholar
  22. 22.
    East CA, Grundy SM, Bilheimer DW. (1986) Preliminary report: treatment of type 3 hyperlipoproteinemia with mevinolin. Metabolism. 35:97–8.CrossRefGoogle Scholar
  23. 23.
    Vega GL, East C, Grundy SM. (1988) Lovastatin therapy in familial dysbetalipoproteinemia: effects on kinetics of apolipoprotein B. Atherosclerosis. 70:131–43.CrossRefGoogle Scholar
  24. 24.
    Arca M, Vega GL, Grundy SM. (1994) Hypercholesterolemia in postmenopausal women: metabolic defects and response to low-dose lovastatin. JAMA. 271:453–9.CrossRefGoogle Scholar
  25. 25.
    Vega GL, Grundy SM. (1991) Influence of lovastatin therapy on metabolism of low density lipoproteins in mixed hyperlipidaemia. J. Intern. Med. 230:341–9.CrossRefGoogle Scholar
  26. 26.
    Vega GL, Grundy SM. (1990) Management of primary mixed hyperlipidemia with lovastatin. Arch. Intern. Med. 150:1313–9.CrossRefGoogle Scholar
  27. 27.
    East C, Bilheimer DW, Grundy SM. (1988) Combination drug therapy for familial combined hyperlipidemia. Ann. Intern. Med. 109:25–32.CrossRefGoogle Scholar
  28. 28.
    Gianturco SH, Bradley WA, Nozaki S, Vega GL, Grundy SM. (1993) Effects of lovastatin on the levels, structure, and atherogenicity of VLDL in patients with moderate hypertriglyceridemia. Arterioscler. Thromb. 13:472–81.CrossRefGoogle Scholar
  29. 29.
    Vega GL, Grundy SM. (1990) Primary hyper-triglyceridemia with borderline high cholesterol and elevated apolipoprotein B concentrations: comparison of gemfibrozil vs lovastatin therapy. JAMA. 264:2759–63.CrossRefGoogle Scholar
  30. 30.
    Vega GL, Grundy SM. (1989) Comparison of lovastatin and gemfibrozil in normolipidemic patients with hypoalphalipoproteinemia. JAMA. 262:3148–53.CrossRefGoogle Scholar
  31. 31.
    Vega GL, Grundy SM. (1994) Lipoprotein responses to treatment with lovastatin, gemfibrozil, and nicotinic acid in normolipidemic patients with hypoalphalipoproteinemia. Arch. Intern. Med. 154:73–82.CrossRefGoogle Scholar
  32. 32.
    Vega GL, Grundy SM. (1988) Lovastatin therapy in nephrotic hyperlipidemia: effects on lipoprotein metabolism. Kidney Int. 33:1160–8.CrossRefGoogle Scholar
  33. 33.
    Garg A, Grundy SM. (1988) Treatment of dyslipidemia in non-insulin-dependent diabetes mellitus with lovastatin. Am. J. Cardiol. 62:44J–49J.CrossRefGoogle Scholar
  34. 34.
    Scandinavian Simvastatin Survival Study Group. (1994) Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 344:1383–9.Google Scholar
  35. 35.
    Shepherd J, et al. (1995) Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N. Engl. J. Med. 333:1301–7.CrossRefGoogle Scholar
  36. 36.
    Sacks FM, et al. (1996) The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels: Cholesterol and Recurrent Events Trial investigators. N. Engl. J. Med. 335:1001–9.CrossRefGoogle Scholar
  37. 37.
    Post Coronary Artery Bypass Graft Trial Investigators. (1997) The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N. Engl. J. Med. 336:153–62.CrossRefGoogle Scholar
  38. 38.
    Downs JR, et al. (1998) Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA. 279:1615–22.CrossRefGoogle Scholar
  39. 39.
    Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. (1998) Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N. Engl. J. Med. 339:1349–57.CrossRefGoogle Scholar
  40. 40.
    Serruys PWJC, et al. (2002) Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention. JAMA. 287:3215–22.CrossRefGoogle Scholar
  41. 41.
    Heart Protection Study Collaborative Group. (2002) MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 360:7–22.CrossRefGoogle Scholar
  42. 42.
    Shepherd J, et al. (2002) Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 360:1623–30.CrossRefGoogle Scholar
  43. 43.
    ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. (2002) Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care. JAMA. 288:2998–3007.CrossRefGoogle Scholar
  44. 44.
    Sever PS, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm(ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 361:1149–58.Google Scholar
  45. 45.
    Colhoun HM, et al. (2004) Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 364:685–96.CrossRefGoogle Scholar
  46. 46.
    de Lemos JA, et al. (2004) Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA. 292:1307–16.CrossRefGoogle Scholar
  47. 47.
    Cannon CP, et al. (2004). Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N. Engl. J. Med. 350:1495–504.CrossRefGoogle Scholar
  48. 48.
    Pedersen TR, et al. (2005) High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA. 294:2437–45.CrossRefGoogle Scholar
  49. 49.
    LaRosa JC, et al. (2005) Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N. Engl. J. Med. 352:1425–35.CrossRefGoogle Scholar
  50. 50.
    Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group [Armitage J, et al.]. (2010) Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12 064 survivors of myocardial infarction: a double-blind randomised trial. Lancet. 376:1658–69.CrossRefGoogle Scholar
  51. 51.
    Baigent C, et al. (2005) Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 366:1267–78.CrossRefGoogle Scholar
  52. 52.
    Horton JD, Cohen JC, Hobbs HH. (2009) PCSK9: a convertase that coordinates LDL catabolism. J. Lipid Res. 50 Suppl:S172–7.CrossRefGoogle Scholar
  53. 53.
    Stein EA, et al. (2012) Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet. 380:29–36.CrossRefGoogle Scholar
  54. 54.
    (1993) Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA. 269:3015–23.Google Scholar
  55. 55.
    (2002) Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106:3143–421.Google Scholar
  56. 56.
    Grundy SM, et al. (2004) Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 110:227–39.CrossRefGoogle Scholar
  57. 57.
    Stone NJ, et al. (2014) 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):S1–45.CrossRefGoogle Scholar

Copyright information

© The Author(s) 2014

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Authors and Affiliations

  1. 1.Department of Internal MedicineUniversity of Texas Southwestern Medical CenterDallasUSA
  2. 2.Center for Human Nutrition (Room Y3-206)University of Texas Southwestern Medical CenterDallasUSA
  3. 3.Medical ServiceVeterans Affairs Medical CenterDallasUSA

Personalised recommendations