Abstract
Summary: Numerous studies have demonstrated that treatments designed to reduce low‐density lipoprotein cholesterol (LDL‐C) can reduce the risk of coronary heart disease (CHD) events in the setting of either primary or secondary prevention. The rationale for aggressive lowering of LDL‐C, supported by large observational studies, is the concept that no threshold exists below which reductions fail to provide additional benefit. The statins are widely considered first‐line therapy for preventing CHD events because these agents yield the greatest reductions in LDL‐C. However, many patients do not achieve target LDL‐C levels with the currently available statins. Newer, more effective statins may permit the benefits of aggressive LDL‐C reduction to be extended to larger numbers of patients. A novel, highly efficacious statin, rosuvastatin (CrestorTM, AstraZeneca group of companies), is currently undergoing clinical investigation. Dose‐ranging studies in hypercholesterolemic patients have shown that rosuvastatin produces significant, dose‐dependent decreases in LDL‐C when compared with placebo. Reductions have ranged from 34% at a dose of 1 mg/day to 65% at 80 mg/day. This agent has been found to be well tolerated across the range of doses studied. Phase III studies indicate that rosuvastatin is more effective than atorvastatin, pravastatin, and simvastatin in improving the atherogenic lipid profiles of hypercholesterolemic patients, and more effective than atorvastatin in improving the atherogenic lipid profiles of patients with heterozygous familial hypercholesterolemia. Overall, these findings suggest that rosuvastatin is a promising new medication for the treatment of dyslipidemias.
Keywords: low‐density lipoprotein cholesterol, coronary heart disease, statins, rosuvastatin, dyslipidemia
Full Text
The Full Text of this article is available as a PDF (725.2 KB).
References
- 1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults : 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). J Am Med Assoc 1993; 269: 3015–3023 [PubMed] [Google Scholar]
- 2. Second Joint Task Force of European and Other Societies on Coronary Prevention : Prevention of coronary heart disease in clinical practice. Recommendations of the Second Joint Task Force of European and Other Societies on Coronary Prevention. Eur Heart J 1998; 19: 1434–1503 [DOI] [PubMed] [Google Scholar]
- 3. Lipid Research Clinics Program : The Lipid Research Clinics Coronary Primary Prevention Trial results II: The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. J Am Med Assoc 1984; 251: 365–374 [PubMed] [Google Scholar]
- 4. Manninen V., Elo MO, Frick MH, Haapa K., Heinonen OP, Heinsalmi P., Helo P., Huttunen JK, Kaitaniemi P., Koskinen P., Mäenpää H., Mälkönen M., Mänttäri M., Norola S., Pasternack A., Pikkareinen J., Romo M, Sjöblom T., Nikkilä EA, Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study. J Am Med Assoc 1988; 260: 641–651 [PubMed] [Google Scholar]
- 5. Pedersen TR : Aggressive lipid‐lowering therapy: A clinical imperative. Eur Heart J 1998: 19 (suppl M): M15–M21 [PubMed] [Google Scholar]
- 6. Scandinavian Simvastatin Survival Study Group : Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 334: 1383–1389 [PubMed] [Google Scholar]
- 7. Pedersen TR, Olsson AG, Færgeman O., Kjekshus J., Wedel H., Berg K, Wilhelmsen L., Haghfelt T., Thorgeirrson G., Pyöärälä K., Miettinen T., Christophersen B., Tobert JA, Musliner TA, Cook TJ, for the Scandinavian Simvastatin Survival Study Group : Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S). Circulation 1998; 97: 1453–1460 [DOI] [PubMed] [Google Scholar]
- 8. Brown G., Albers JJ, Fisher LD, Schaefer SM, Lin J‐T, Kaplan C., Zhao X‐O, Bisson BD, Fitzpatrick VF, Dodge HT, Regression of coronary artery disease as a result of intensive lipid‐lowering therapy in men with high levels of apolipoprotein B. N Engl J Med 1990; 323: 1289–1298 [DOI] [PubMed] [Google Scholar]
- 9. Kane JP, Malloy MJ, Ports TA, Phillips NR, Diehl JC, Havel RJ, Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens. J Am Med Assoc 1990; 264: 3007–3012 [PubMed] [Google Scholar]
- 10. Blankenhorn DH, Azen SR, Kramsch DM, Mack WJ, Cashin‐Hemphill L., Hodis HN, DeBoes LWV, Mahrer PR, Masteller MJ, Vailas LI, Alaupovic P., Hirsch LJ, and the MARS Research Group : Coronary angiographic changes with lovastatin therapy: The Monitored Atherosclerosis Regression Study (MARS). Ann Intern Med 1993; 119: 969–976 [DOI] [PubMed] [Google Scholar]
- 11. MAAS Investigators : Effect of simvastatin on coronary atheroma: The Multicentre Anti‐Atheroma Study (MAAS). Lancet 1994; 344: 633–638 [PubMed] [Google Scholar]
- 12. Sacks FM, Pasternak RC, Gibson CM, Rosner B., Stone PH, for the Harvard Atherosclerosis Reversibility Project (HARP) Group : Effect on coronary atherosclerosis of decrease in plasma cholesterol concentrations in normocholesterolaemic patients. Lancet 1994; 344: 1182–1186 [DOI] [PubMed] [Google Scholar]
- 13. Waters D., Higginson L., Gladstone P., Kimball B., Le May M., Boccuzzi SJ, Lespérance J., for the CCAIT Study Group : Effects of monotherapy with an HMG‐CoA reductase inhibitor on the progression of coronary atherosclerosis as assessed by serial quantitative arteriography. The Canadian Coronary Atherosclerosis Intervention Trial. Circulation 1994; 89: 959–968 [DOI] [PubMed] [Google Scholar]
- 14. Pitt B., Mancini GB, Ellis SG, Rosman HS, Park J‐S, McGovern ME, for the PLAC I Investigators: Pravastatin limitation of atherosclerosis in the coronary arteries (PLAC I) : Reduction in atherosclerosis progression and clinical events. J Am Coll Cardiol 1995; 26: 1133–1139 [DOI] [PubMed] [Google Scholar]
- 15. Thompson GR, Maher VM, Matthews S., Kitano Y., Neuwirth C., Schrott MB, Davies G., Rees A., Mir A., Prescott RJ, Feyter PD, Henderson A., Familial Hypercholesterolaemia Regression Study: A randomised trial of low‐density‐lipoprotein apheresis. Lancet 1995; 345: 811–816 [DOI] [PubMed] [Google Scholar]
- 16. Thompson GR, What targets should lipid‐modulating therapy achieve to optimise the prevention of coronary heart disease? Atherosclerosis 1997; 131: 1–5 [DOI] [PubMed] [Google Scholar]
- 17. Knopp RH, Drug treatment of lipid disorders. N Engl J Med 1999; 341: 498–511 [DOI] [PubMed] [Google Scholar]
- 18. Brown AS, Bakker‐Arkema RG, Yellen L., Henley RW, Guthrie R., Campbell CF, Koren M., Woo W., McLain R., Black DM, Treating patients with documented atherosclerosis to National Cholesterol Education Program‐recommended low‐density‐lipoprotein cholesterol goals with atorvastatin, fluvastatin, lovastatin and simvastatin. J Am Coll Cardiol 1998; 32: 665–672 [DOI] [PubMed] [Google Scholar]
- 19. Hunninghake D., Bakker‐Arkema RG, Wigand JP, Drehobl M., Schrott H., Early JL, Abdallah P., McBride S, Black DM, Treating to meet NCEP‐recommended LDL cholesterol concentrations with atorvastatin. fluvastatin. lovastatin, or simvastatin in patients with risk factors for coronary heart disease. J Fam Pract 1998; 47: 349–356 [PubMed] [Google Scholar]
- 20. Jones P., Kafonek S., Laurora I., Hunninghake D., for the CURVES Investigators : Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol 1998; 81: 582–587 [DOI] [PubMed] [Google Scholar]
- 21. Koren MJ, Smith DG, Hunninghake DB, Davidson MH, McKenney JM, Weiss SR, Schrott HG, Henley RW Jr., Tresh P., McLain RW, Bakker‐Arkema RG, Black DM, The cost of reaching National Cholesterol Education Program (NCEP) goals in hypercholesterolaemic patients. A comparison of atorvastatin. simvastatin, lowstatin, and fluvastatin. Pharmacoeconomics 1998; 14: 59–70 [DOI] [PubMed] [Google Scholar]
- 22. März W., Wollschläger H., Klein G., Neiss A., Wehling M., Safety of low‐density lipoprotein cholesterol reduction with atorvastatin versus simvastatin in a coronary heart disease population (the TARGET TANGIBLE trial). Am J Cardiol 1999; 84: 7–13 [DOI] [PubMed] [Google Scholar]
- 23. McCormick AD, McKillop D., Bulters CJ, Miles GS, Baba T., Touchi A., Yamaguchi Y., ZD4522—an HMG‐CoA reductase inhibitor free of metabolically mediated drug interactions: Metabolic studies in human in vitro systems (abstr). J Clin Pharmacol 2000: 40: 1055 [Google Scholar]
- 24. Buckett L., Ballard P., Davidson R., Dunkley C., Stafford MJ, McTaggart F., Selectivity of ZD4522 for inhibition of cholesterol synthesis in hepatic versus non‐hepatic cells (abstr) Atherosclerosis 2000: 151 (suppl): MoP29: W6 [Google Scholar]
- 25. Nezasa K., Higaki K., Hasegawa H., Inazawa K., Takeuehi M., Yukawa T., McTaggart F., Nakano M., Uptake of HMG‐CoA reductase inhibitor ZD4522 into hepatocytes and distribution into liver and other tissues of the rat (abstr). Atherosclerosis 2000: 151 (suppl):MoP21: W6 [Google Scholar]
- 26. Smith G., Davidson R., Bloor S., Burns K., Calnan C., McAulay P., Torr N., Ward D., McTaggart F., Pharmacological properties of ZD4522—a new HMG‐CoA reductase inhibitor (abstr). Atherosclerosis 2000: 15l (suppl):MoP20: W6 [Google Scholar]
- 27. Warwick MJ, Dane AL, Raza A., Schneck DW, Single‐ and multiple‐dose pharmacokinetics and safety of the new HMG‐CoA reductase inhibitor ZD4522 (abstr). Atherosclerosis 2000: 151 (suppl): MoP16: W6 [Google Scholar]
- 28. Olsson AG, Pears JS, McKellar J., Caplan RJ, Raza A., Pharmacodynamics of new HMG‐CoA reductase inhibitor ZD4522 in patients with primary hypercholesterolemia, Paper presented at the XIIth International Symposium on Atherosclerosis; June 28, 2000; Stockholm, Sweden
- 29. Davidson MH, Ma P., Stein E., Hutchinson HG, Chitra R., Raza A., Gotto AM, ZD4522 is superior to atorvastatin in decreasing low‐density lipoprotein cholesterol and increasing high‐density lipoprotein cholesterol in patients with type IIa or IIb hypercholesterolemia (abstr). J Am Coll Cardiol 2001: 37 (suppl A): Abstr 1261–175 [DOI] [PubMed] [Google Scholar]
- 30. Paoletti R., Fahmy M., Mahla G., Mizan J., Southworth H., ZD4522 is superior to pravastatin and simvastatin in reducing low‐density lipoprotein cholesterol, enabling more hypercholesterolemic patients to achieve target low‐density lipoprotein cholesterol guidelines. J Am Coll Cardiol 2001. (suppl A): Abstr 1261–174 [Google Scholar]
- 31. Stein E., Strutt KL, Miller E., Southworth H., ZD455 is superior to atorvastatin in the treatment of patients with heterozygous familial hypercholesterolemia (abstr). J Am Coll Cardiol 2001. (suppl A): Abstr 1261–176 [Google Scholar]