Ezetimibe for the treatment of adult patients with hypercholesterolemia

04 Feb 2008 Ezetimibe for the treatment of adult patients with hypercholesterolemia

Background information of the condition¹

Drug therapy reduces total cholesterol levels, but their benefit in terms of mortality and morbidity vary with different drug classes. Statins have been shown to provide a cardiovascular and total mortality benefit in four secondary prevention trials. Despite the lack of reporting of total serious adverse events in these 4 trials, one measure of overall health benefit, total mortality, was reduced, pooled RR 0.84 [0.79–0.88], ARR 2.1%, NNT= 48 for 3 to 5 years. Analysis of serious adverse events and mortality does not support the use of statins for primary prevention or the use of fibrates for primary or secondary prevention. The Coronary Drug Project secondary prevention study compared niacin to placebo in men with CHD, age 30 to 64. Niacin reduced total cholesterol by 10% and was associated with a statistically significant reduction in the incidence of definite MI and/or CV death (ARR=5.0%, NNT= 20 for 6 yrs). There were, however, statistically significant increases in side effects including flushing, cutaneous reactions, gastrointestinal problems, acute gout (ARR=2.1%, NNH= 48 for 6 years) and atrial fibrillation (ARR=1.8%, NNH = 56 for 6 years). Resins have not been studied in any large secondary prevention trials.

Drug (Product monograph)²

Category
Ezetimibe is a new class of lipid-lowering compounds that selectively inhibit the intestinal absorption of cholesterol and related plant sterols.

Mechanism of action:
Ezetimibe inhibits the intestinal absorption of cholesterol and related plant sterols. The molecular target of ezetimibe is the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is responsible for the intestinal uptake of cholesterol and phytosterols.

Indication:
Ezetimibe is indicated as an adjunct to lifestyle changes, including diet, when the response to diet and other non-pharmacological measures alone have been inadequate in patients with primary (heterozygous familial and non-familial) hypercholesterolemia, homozygous familial hypercholesterolemia (HoFH) and homozygous familial sitosterolemia.

Dose:
The recommended dose of ezetimibe is 10 mg once daily orally, alone or with a statin. Ezetimibe can be taken with or without food at any time of the day but preferably at the same time each day

Duration of therapy:
Not specified in the product monograph.

Methodology of systematic review

Research questions:
1. In DBRCTs, does ezetimibe monotherapy provide a therapeutic advantage in terms of mortality and/or morbidity compared to placebo or other cholesterol lowering drug monotherapy in adult patients with primary hypercholesterolemia, HoFH or homozygous sitosterolemia?
2. In DBRCTs, does ezetimibe in combination with statin once a day provide a therapeutic advantage in terms of mortality and/or morbidity compared to statin monotherapy or statin in combination with other cholesterol lowering drug therapy in adult patients with primary hypercholesterolemia, HoFH or homozygous sitosterolemia?

Assessment principles:
We critically appraised double-blind randomized controlled trials (> 24 weeks duration) comparing ezetimibe 10mg/day as monotherapy or in combination with statin to statin monotherapy or other appropriate comparators for the treatment of adult patients with primary hypercholesterolemia, HoFH or sitosterolemia. Short-term DBRCTs (≤ 24 weeks duration) were summarized. Appropriate comparators include lifestyle changes plus TLC diet in addition to placebo; statins, fibrates or niacin.
We examined results according to the following hierarchy of health outcomes – all cause mortality (including cardiovascular mortality and non-cardiovascular mortality); non-fatal serious adverse events; drug tolerability (including withdrawal due to adverse events) and surrogate markers such as serum lipid levels-total cholesterol, LDL-C, HDL-C and triglycerides.

Search strategy: Databases searched Medline (1966-may 2007) EMBASE (1988-May 2007) and Cochrane database issue2, 2007.

Search findings:
2 long-term DBRCTs ^3,4 for primary hypercholesterolemia.

30 short-term DBRCTs (≤ 24 weeks duration):
– Primary hypercholesterolemia – 28 RCTs
Ezetimibe vs. placebo ^5–11 ; Ezetimibe vs. statins ^12,15; Ezetimibe vs. fenofibrate⁹; Ezetimibe vs. plant sterol¹¹; Ezetimibe plus statin vs. statin plus placebo ^12,32
– Homozygous familial hypercholesterolemia – One RCT
Ezetimibe plus statin vs. statin plus placebo ³³
– Homozygous sitosterolemia -One RCT
Ezetimibe vs. placebo ³⁴

Results:
Two long-term trials compared combination therapy with [ezetimibe + statin] vs. statin alone in primary prevention patients. One 9-month DBRCT³ demonstrated a 0.4mmol/l difference in LDL-C change from baseline with ezetimibe (dose) plus atorvastatin(dose or range used) vs. atorvastatin (dose) monotherapy;. Serious morbidity, mortality or other health outcomes were not reported according to the allocated treatment group. Therefore, it was not possible to assess the benefits or harm of ezetimibe therapy.
Masana et al 2005⁴ is a 48-week extension study of Gagne 2002¹⁶. On enrollment in the extension study, patients entered a 6-week open-label simavastatin run-in phase before they were randomized to receive ezetimibe 10mg or placebo once daily in addition to the ongoing simvastatin for 48 weeks. This extension study includes 56.3% of the originally randomized patients in the Gagne et al¹⁶ study. Almost half of the patients were lost to follow-up; therefore it is not possible to draw conclusions regarding long-term health outcomes.

Trials < 24weeks duration^5–34
None of the 30 DBRCTs studied the effectiveness of ezetimibe therapy on mortality and/or morbidity in adult patients with primary hypercholesterolemia, familial homozygous hypercholesterolemia and sitosterolemia. All trials focused on a decrease in LDL-C level, which is a surrogate outcome measure for ezetimibe and has not been validated to predict clinically relevant outcomes. In these trials the percentage decrease in LDL –C levels from baseline ranged from 3% to 34%^25–26 over a duration of 6 to 24 weeks.

Conclusions:

• There is insufficient evidence that ezetimibe 10mg/day as monotherapy provides a therapeutic advantage over placebo or other cholesterol lowering drug monotherapy for the treatment primary hypercholesterolemia, HoFH or sitosterolemia.
• There is insufficient evidence that ezetimibe 10mg/day as adjunctive therapy to statin provides a therapeutic advantage over statins alone for the treatment primary hypercholesterolemia, HoFH or sitosterolemia.
• There are no double-blind randomized clinical trials that compare the combination ezetimibe 10mg/day plus statin with other statin combination therapies for the treatment primary hypercholesterolemia, HoFH or sitosterolemia.

References:

1. http://www.ti.ubc.ca (TI letters: 24, 27, 42, 48 and 49)
2. Product monograph (e-CPS, 2007)
3. Ballantyne CM, Lipka LJ, Sager PT, Strony J, Alizadeh J, Suresh R et al. Long-term safety and tolerability profile of ezetimibe and atorvastatin coadministration therapy in patients with primary hypercholesterolaemia. International Journal of Clinical Practice Vol 58(7)()(pp 653-658), 2004 2004;(7):653-658.
4. Masana L et al. Long-term safety and tolerability profiles and lipid-modifying efficacy of ezetimibe coadministered with ongoing simvastatin treatment: A multicenter, randomized, double-blind, placebo-controlled, 48-week extension study. Clinical Therapeutics. 27(2): 174-184, 2005 (5) Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.[see comment]. Lancet 360(9346):1623-30, 2002.
5. Knopp RH GH. Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia. European Heart Journal 24(8):729-41, 2003.
6. Dujovne CA, Ettinger MP, McNeer JF. Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia. American Journal of Cardiology 90(10):1092-7, 2002.
7. Goldberg AC, Sapre A, Liu J, Capece R, Mitchel YB, Ezetimibe Study Group. Efficacy and safety of ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia: a randomized, double-blind, placebo-controlled trial. Mayo Clinic Proceedings 79(5):620-9, 2004.
8. Bays HE, Ose L, Fraser N, Tribble DL, Quinto K, Reyes R et al. A multicenter, randomized, double-blind, placebo-controlled, factorial design study to evaluate the lipid-altering efficacy and safety profile of the ezetimibe/simvastatin tablet compared with ezetimibe and simvastatin monotherapy in patients with primary hypercholesterolemia. Clinical Therapeutics Vol 26(11)()(pp 1758-1773), 2004 2004;(11):1758-1773.
9. Farnier M et al. Efficacy and safety of the coadministration of ezetimiibe with fenofibrate in patients with mixed byperlipdemia. European Heart Journal. 26: 897- 905
10. Gonzalez-ortiz M et al. Effect of ezetimibe on insulin sensitivity and lipid profile in obese and dyslipidaemic patients. Cardiovascular Drugs and Therapy 20 143-6, 2006
11. Jakulj L. Trip MD. Sudhop T. von Bergmann K. Kastelein JJ. Vissers MN. Inhibition of cholesterol absorption by the combination of dietary plant sterols and ezetimibe: effects on plasma lipid levels. Journal of Lipid Research. 46(12):2692- 8, 2005
12. Kerzner B. Efficacy and safety of ezetimibe coadministered with lovastatin in primary hypercholesterolemia. American Journal of Cardiology 91(4):418-24, 2003.
13. Melani L. Efficacy and safety of ezetimibe coadministered with pravastatin in patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial.[see comment]. European Heart Journal 24(8):717-28, 2003.
14. Davidson MH MT. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia.[see comment]. Journal of the American College of Cardiology 40(12):2125-34, 2002.
15. Ballantyne CM HJ. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial.[see comment]. Circulation 107(19):2409-15, 2003.
16. Gagne C. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia.[see comment]. American Journal of Cardiology 90(10):1084-91, 2002.
17. Ballantyne CM, Blazing MA, King TR, Brady WE, Palmisano J. Efficacy and safety of ezetimibe co-administered with simvastatin compared with atorvastatin in adults with hypercholesterolemia. American Journal of Cardiology 93(12):1487-94, 2004.
18. Goldberg AC, Sapre A, Liu J, Capece R, Mitchel YB, Ezetimibe Study Group. Efficacy and safety of ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia: a randomized, double-blind, placebo-controlled trial. Mayo Clinic Proceedings 79(5):620-9, 2004.
19. Bays HE, Ose L, Fraser N, Tribble DL, Quinto K, Reyes R et al. A multicenter, randomized, double-blind, placebo-controlled, factorial design study to evaluate the lipid-altering efficacy and safety profile of the ezetimibe/simvastatin tablet compared with ezetimibe and simvastatin monotherapy in patients with primary hypercholesterolemia. Clinical Therapeutics Vol 26(11)()(pp 1758-1773), 2004 2004;(11):1758-1773.
20. Gaudiani LM, Lewin A, Meneghini L, Perevozskaya I, Plotkin D, Mitchel Y et al. Efficacy and safety of ezetimibe co-administered with simvastatin in thiazolidinedione-treated type 2 diabetic patients. Diabetes, Obesity & Metabolism 7(1):88-97, 2005.
21. Patel JV. Hughes EA. Efficacy, safety and LDL-C goal attainment of ezetimibe 10mg-simvastatin 20 mg vs. placebo-simvastatin 20 mg in UK-based adults with coronary heart disease and hypercholesterolaemia. International Journal of Clinical Practice. 60(8):914-21, 2006
22. Ballantyne CM. Abate N. Yuan Z. King TR. Palmisano J. Dose-comparison study of the combination of ezetimibe and simvastatin (Vytorin) versus atorvastatin in patients with hypercholesterolemia: the Vytorin Versus Atorvastatin (VYVA) study. American Heart Journal. 149(3):464-73, 2005 Mar.
23. Barrios V. Amabile N. Paganelli F. Chen JW. Allen C. Johnson-Levonas AO. Massaad R. Vandormael K. Lipid-altering efficacy of switching from atorvastatin 10 mg/day to ezetimibe/simvastatin 10/20 mg/day compared to doubling the dose of atorvastatin in hypercholesterolaemic patients with atherosclerosis or coronary heart disease. International Journal of Clinical Practice. 59(12):1377-86, 2005
24. Goldberg, Ronald B. Guyton, John R. Mazzone, Theodore. Weinstock, Ruth S. Polis, Adam. Edwards, Patricia. Tomassini, Joanne E. Tershakovec, Andrew M. Ezetimibe/simvastatin vs atorvastatin in patients with type 2 diabetes mellitus and hypercholesterolemia: the VYTAL study. Mayo Clinic Proceedings. 81(12):1579-88, 2006 Dec.
25. Rodney RA. Sugimoto D. Wagman B. Zieve F. Kerzner B. Strony J. Yang B. Suresh R. Veltri E. Efficacy and safety of coadministration of ezetimibe and simvastatin in African-American patients with primary hypercholesterolemia. Journal of the National Medical Association. 98(5):772-8, 2006 May.
26. Catapano AL. Davidson MH. Ballantyne CM. Brady WE. Gazzara RA. Tomassini JE. Tershakovec AM. Lipid-altering efficacy of the ezetimibe/simvastatin single tablet versus rosuvastatin in hypercholesterolemic patients. Current Medical Research & Opinion. 22(10):2041-53, 2006 Oct.
27. Geiss HC. Otto C. Parhofer KG. Effect of ezetimibe on low-density lipoprotein subtype distribution: results of a placebo-controlled, double-blind trial in patients treated by regular low-density lipoprotein apheresis and statins. Metabolism: Clinical & Experimental. 55(5):599-604, 2006 May.
28. Pearson TA. Denke MA. McBride PE. Battisti WP. Brady WE. Palmisano J.A community-based, randomized trial of ezetimibe added to statin therapy to attain NCEP ATP III goals for LDL cholesterol in hypercholesterolemic patients: the ezetimibe add-on to statin for effectiveness (EASE) trial. Mayo Clinic Proceedings. 80(5):587-95, 2005 May.
29. Cruz-Fernandez JM. Bedarida GV. Adgey J. Allen C. Johnson-Levonas AO. Massaad R. Efficacy and safety of ezetimibe co-administered with ongoing atorvastatin therapy in achieving low-density lipoprotein goal in patients with hypercholesterolemia and coronary heart disease. International Journal of Clinical Practice. 59(6):619-27, 2005 Jun.
30. Brohet C. Banai S. Alings AM. Massaad R. Davies MJ. Allen C. LDL-C goal attainment with the addition of ezetimibe to ongoing simvastatin treatment in coronary heart disease patients with hypercholesterolemia. Current Medical Research & Opinion. 21(4):571-8, 2005 Apr.
31. Farnier M. Volpe M. Massaad R. Davies MJ. Allen C. Effect of co-administering ezetimibe with on-going simvastatin treatment on LDL-C goal attainment in hypercholesterolemic patients with coronary heart disease. International Journal of Cardiology. 102(2):327-32, 2005 Jul 10
32. Stein E, Stender S, Mata P, Sager P, Ponsonnet D, Melani L et al. Achieving lipoprotein goals in patients at high risk with severe hypercholesterolemia: efficacy and safety of ezetimibe co-administered with atorvastatin. American Heart Journal 148(3):447-55, 2004.
33. Gagne C. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation 105(21):2469-75, 2002.
34. Salen G, von Bergmann K, Lutjohann D, Kwiterovich P, Kane J, Patel SB et al. Ezetimibe effectively reduces plasma plant sterols in patients with sitosterolemia. Circulation 109(8):966-71, 2004.