Duální inhibice cholesterolu prostřednictvím přípravku ezetimib/simavastatin (Inegy^®) - nejsnadnější cesta k dosažení cílových hodnot LDL-cholesterolu?

Czech version

Authors: H. Vaverková
Authors‘ workplace: III. interní klinika Lékařské fakulty UP a FN Olomouc, přednosta prof. MUDr. Vlastimil Ščudla, CSc.
Published in: Vnitř Lék 2007; 53(4): 421-427
Category: Reviews

Overview

The latest clinical intervention studies of statins have shown that more aggressive reductions in LDL-cholesterol to values lower than existing target values for persons with a high risk of cardiovascular disease produce greater success in terms of halted progression and even regression of the atherosclerotic process and fewer cardiovascular events. This has lead to a series of international and national recommendations for a further reduction in target values for LDL-cholesterol, which is often difficult to achieve with the usual dosage of statins. The combination of a statin with ezetimibe, acting as a dual inhibition mechanism against the synthesis and absorption of cholesterol, reduces LDL-cholesterol significantly more than treatment with a statin in monotherapy. This allows many more patients to achieve the target value for LDL-cholesterol. At present a drug combination comprising ezetimibe 10 mg and simvastatin in all doses (10, 20, 40 and 80 mg) is being introduced into our market under the company name Inegy®. In addition to reducing LDL-cholesterol by up to 61% this combination has a positive effect on a range of other parameters for lipid metabolism and inflamation. A typical initial dose of ezetimibe 10 mg/simvastatin 20 mg reduces LDL-cholesterol by around 50%, which is necessary for the stabilisation of atherosclerotic plaque. For patients requiring more aggressive reduction of LDL-cholesterol it is best to start with a dose of ezetimibe 10 mg/simvastatin 40 mg. The highest dose of 10 mg/80 mg is intended for patients with the highest level of risk and reduces LDL-cholesterol by around 60%. In all the studies that have been carried out so far, the combination of ezetimibe and statin was very well tolerated and the safety profile of this combination was the same a treatment with the statin alone. At present a wide range of large clinical studies are underway to test whether LDL-cholesterol reduction using the ezetimibe + statin combination will also lead to a lower risk of cardiovascular events.

Key words:
dyslipidemia – LDL-cholesterol – ezetimibe – cholesterol absorption inhibitor – statins – dual cholesterol inhibition

Sources

1. Stamler J, Wentworth D, Neaton JD (for the MRFIT Research Group). Is the relationship between serum cholesterol and risk of premature death from coronary heart disease continous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA 1986; 256: 2823-2828.

2. Baigent C, Keech A, Kearney PM et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366: 1267-1278.

3. Tailor AJ, Kent SM, Flaherty PJ et al. ARBITER: ARterial Biology for the Investigation of the Treatment Effects of Reducing cholesterol: a randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima media thickness. Circulation 2002; 106: 2055-2060.

4. Nissen S, Tuzcu EM, Schoenhagen P et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004; 291: 1071-1080.

5. Cannon CP, Braunwald E, Mccabe CH et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350: 1495-1504.

6. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360: 7-22.

7. LaRosa JC, Grundy SM, Waters DD et al. Intensive lipid lowering with atorvastatin in patiens with stable coronary disease. N Engl J Med 2005; 352: 1425-1435.

8. Nissen SE, Nicholls SJ, Sipahi I et al. Effect of Very High-Intensity Statin Therapy on Regression of Coronary Atherosclerosis: The ASTEROID Trial. JAMA 2006; 295: 1556-1565.

9. Cannon CP, Steinberg BA, Murphy SA et al. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. J Am Coll Cardiol 2006; 48: 438-445.

10. Grundy SM, Cleeman JI, Merz CN et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004; 110: 227-239.

11. De Backer G, Ambrosioni E, Borch-Johnsen K et al. European Society of Cardiology; American Heart Association, American College of Cardiology European guidelines on cardiovascular disease prevention in clinical practice. Third Joint Task Force of European and other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of eight societies and by invited experts). Atherosclerosis 2004; 173: 381-391

12. Joint British Societies. JBS 2: Joint British Societies’guidelines on prevention of cardiovascular disease in clinical practice. Heart 2005; 91(Suppl 5): 1-52.

13. McPherson R, Frohlich J, Fodor G et al. Canadian Cardiovascular Society position statement - Recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease. Can J Cardiol 2006; 22: 913-927.

14. Cífková R, Býma S, Češka R et al. Prevence kardiovaskulárních onemocnění v dospělém věku. Cor Vasa 2005; 47(Suppl): 3-14.

15. Vaverková H, Soška V, Rosolová H et al. Doporučení pro diagnostiku a léčbu dyslipidémii v dospělosti, vypracované výborem České společnosti pro aterosklerózu. Vnitř Lék 2007; 53(2): 181-197.

16. Pearson TA, Aurora I, Chu H et al. The lipid treatment assessment project (L-TAP): a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med 2000; 160: 459-467.

17. Euroaspire II Study Group. Lifestyle and risk factor management and use of drug therapies in coronary patients from 15 countries. Principal results from EUROASPIRE II Euro Heart Survey Programme. Eur Heart J 2001; 22: 554-572.

18. Garcia Ruiz FJ, Marin Ibanez A, Perez Jimenez F et al (and the REALITY Study Group). Current lipid management and low cholesterol goal attainment in common daily practice in Spain. The REALITY Study. Pharmacoeconomics 2004; 22 (Suppl 3): 1-14.

19. Davis HR, Compton DS, Hoos L et al. Ezetimibe (SCH58235) localizes to the brush border of small intestinal enterocytes and inhibits enterocyte cholesterol uptake and absorption. Eur Heart J 2000; 21 (Suppl): 636.

20. Altman SW, Davis HR jr, Zhu L et al. Niemann-Pick C1 like 1 protein is critical for intestinal cholesterol absorption. Science 2004; 303: 1201-1204.

21. Davis HR, Compton DS, Hoos L et al. Ezetimibe (SCH58235) inhibits cholesterol absorption, reduces plasma cholesterol, and inhibits the developmentof atherosclerosis in Apo E knockout mice fed a cholesterol free diet. Eur Heart J 2000; 21(Suppl): 631.

22. van Heek M, Farley C, Compton DS et al. Comparison of the activity and disposition of the novel cholesterol absorption inhibitor, SCH58235, and its glucuronide, SCH60663. Br J Pharmacol 2000; 129: 1748-1754.

23. Zaks A, Dodds DR. Enzymatic glucuronidation of a novel cholesterol absorption inhibitor, SCH 58235. Appl Biochem Biotechnol 1998; 73: 205-214.

24. Bays HE, Moore PB, Drehobl MA et al. Effectiveness and Tolerability of Ezetimibe in Patients with Primary Hypercholesterolemia: Pooled Analysis of Two Phase II Studies. Clin Ther 2001; 23: 1209-1230.

25. Lipka LJ, LeBeaut AP, Veltri EO et al. Reduction of LDL-cholesterol and elevation of HDL-cholesterol in subjects with primary hypercholesterolemia by ezetimibe (SCH58235): pooled analysis of two phase II studies. J Am Coll Cardiol 2000; 35(Suppl A): 257A.

26. Darkes MJM, Poole RM, Goa KL. Ezetimibe. Am J Cardiovasc Drugs 2003; 3: 67-76.

27. Dujovne CA, Ettinger MP, McNeer JF et al. Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia. Am J Cardiol 2002; 90: 1092-1097.

28. Knopp RH, Gitter H, Truitt T et al. Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia. Europ Heart J 2003; 24: 729-741.

29. Davidson M, Mc Garry T, Bettis R et al. Ezetimibe co-administered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol 2002; 40: 2125-2134.

30. Mata P, Gumbiner B, Musliner T et al. Addition of ezetimibe to ongoing statin therapy: incremental reduction in low-density lipoprotein cholesterol is independent of statin type (abstrakt). Eur Heart J 2002; 23 (Suppl.): 19.

31. Gagne C, Bays H, Weiss SR et al. Efficacy and Safety of Ezetimibe Added to Ongoing Statin Therapy for Treatment of Patients With Primary Hypercholesterolemia. Am J Cardiol 2002; 90: 1084-1091.

32. Lipka L, Kerzner B, Corbelli J et al. Efficacy and safety of ezetimibe co-administered with lovastatin in primary hypercholesterolemia. Am J Cardiol 2003; 91: 418-424.

33. Ballantyne CM, Houri J, Notarbartolo A et al (for the Ezetimibe Study Group). Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation 2003; 107: 2409-2415.

34. Masana L, Mata P, Gagne C et al (for the Ezetimibe Study Group). Long-Term Safety and Tolerability Profiles and Lipid-Modifying Efficacy of Ezetimibe Coadministered with Ongoing Simvastatin Treatment: Multicenter, Randomized, Double-Blind, Placebo-Controlled, 48-Week Extension Study. Clin Ther 2005; 27: 174-184.

35. Bays HE, Ose L, Fraser N et al. A multicenter, randomized, double-blind, placebo-controlled, factorial design study to evaluate the lipid-altering efficacy, safety, and tolerability profile of the ezetimibe/simvastatin tablet compared with ezetimibe and simvastatin monotherapy in patients with primary hypercholesterolemia. Clin Ther 2004; 26: 1758-1773.

36. Ballantyne ChM, Abate N, Yuang Z et al. Dose-comparison study of the combination of ezetimibe and simvastatin (Vytorin) versus atorvastatin in patiens with hypercholesterolemia: The Vytorin Versus Atorvastatin (VYVA) Study. Am Heart J 2005; 149: 464-473.

37. Catapano AL, Davidson MH, Ballantyne ChM et al. Lipid-altering efficacy of the ezetimibe/simvastatin single tablet versus rosuvastatin in hypercholesterolemic patients. Curr Med Res Opin 2006; 22: 2041-2053.

38. Davidson MH, Maccubbin D, Stepanavage M et al. Striated Muscle Safety of Ezetimibe/Simvastatin (Vytorin). Am J Cardiol 2006; 97: 223-228.

39. Fuessl HS. MMW-Drug Prize 2005 for simvastatin/ezetimib (Inegy®). LDL goal values are easier to reach now. MMW Fortschr Med 2005; 147: 13.

40. Meyers ChD, Moon YSK, Ghanem H et al. Type of preexisting lipid therapy predicts LDL-C response to ezetimibe. Ann Pharmacother 2006; 40: 818-823.

41. Hegele RA, Guy J, Ban MR, Wang J. NPC1L1 haplotype associated with inter-individual variation in plasma low-density lipoprotein response to ezetimibe. Lipids Health Dis 2005; 4: 16.

Farnier M, Freeman MW, Macdonell G et al. Efficacy and safety of the co administration of ezetimibe with fenofibrate in patiens with mixed hyperlipidemia. European Heart J 2005; 26: 897-905.

Gaudiani LM, Lewin A, Meneghini L et al. Efficacy and safety of ezetimibe co-administered with simvastatin in thiazolidinedione-treated type 2 diabetic patiens. Diab Obes Metab 2005; 7: 88-97.

Kastelein JJ, Sankatsing RR. Ezetimibe/simvastatin (INEGY) in the treatment of hyperlipidemia. Int J Clin Pract 2005; 59: 1464-1471.