Response by sex to statin plus ezetimibe or statin monotherapy: A pooled analysis of 22,231 hyperlipidemic patients

Lipids in Health and Disease

Andrew M Tershakovec³  Arvind Shah³  Jianxin Lin³  Mary E Hanson³  Pascale Benlian²  Beth L Abramson¹ 

[1] St. Michael's Hospital, Toronto, Ontario, Canada;CHRU-Lille, Université Lille 2, Lille, France;Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA

关键词: statin;    ezetimibe;    hyperlipidemia;    low-density lipoprotein cholesterol;   

Others  :  1212539
DOI  :  10.1186/1476-511X-10-146

 received in 2011-07-28, accepted in 2011-08-22,  发布年份 2011

【 摘 要 】

Background

Despite documented benefits of lipid-lowering treatment in women, a considerable number are undertreated, and fewer achieve treatment targets vs. men.

Methods

Data were combined from 27 double-blind, active or placebo-controlled studies that randomized adult hypercholesterolemic patients to statin or statin+ezetimibe. Consistency of treatment effect among men (n = 11,295) and women (n = 10,499) was assessed and percent of men and women was calculated to evaluate the between-treatment ability to achieve specified treatment levels between sexes.

Results

Baseline lipids and hs-CRP were generally higher in women vs. men. Between-treatment differences were significant for both sexes (all p < 0.001 except apolipoprotein A-I in men = 0.0389). Men treated with ezetimibe+statin experienced significantly greater changes in LDL-C (p = 0.0066), non-HDL-C, total cholesterol, triglycerides, HDL-C, apolipoprotein A-I (all p < 0.0001) and apolipoprotein B (p = 0.0055) compared with women treated with ezetimibe+statin. The odds of achieving LDL-C < 100 mg/dL, apolipoprotein B < 90 mg/dL and the dual target [LDL-C < 100 mg/dL & apoliprotein B < 90 mg/dL] was significantly greater for women vs. men and the odds of achieving hs-CRP < 1 and < 2 mg/L and dual specified levels of [LDL-C < 100 mg/dL and hs-CRP < 2 mg/L] were significantly greater for men vs. women. Women reported significantly more gall-bladder-related, gastrointestinal-related, and allergic reaction or rash-related adverse events (AEs) vs. men (no differences between treatments). Men reported significantly more CK elevations (no differences between treatments) and hepatitis-related AEs vs. women (significantly more with ezetimibe+simvastatin vs. statin).

Conclusions

These results suggest that small sex-related differences may exist in response to lipid-lowering treatment and achievement of specified lipid and hs-CRP levels, which may have implications when managing hypercholesterolemia in women.

【 授权许可】

   
2011 Abramson et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Lloyd-Jones DM: Short-term versus long-term risk for coronary artery disease: implications for lipid guidelines. Curr Opin Lipidol 2006, 17:619-625.
• [2]Mosca L, Benjamin EJ, Berra K, Bezanson JL, Dolor RJ, Lloyd-Jones DM, Newby LK, Pina IL, Roger VL, Shaw LJ, Zhao D, Beckie TM, Bushnell C, D'Armiento J, Kris-Etherton PM, Fang J, Ganiats TG, Gomes AS, Gracia CR, Haan CK, Jackson EA, Judelson DR, Kelepouris E, Lavie CJ, Moore A, Nussmeier NA, Ofili E, Oparil S, Ouyang P, Pinn VW, Sherif K, Smith SC Jr, Sopko G, Chandra-Strobos N, Urbina EM, Vaccarino V, Wenger NK: Effectiveness-based guidelines for the prevention of cardiovascular disease in women--2011 update: a guideline from the american heart association. Circulation 2011, 123:1243-1262.
• [3]Expert panel on detection evaluation and treatment of high blood cholesterol in adults: Executive Summary of The 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). JAMA 2001, 285:2486-2497.
• [4]Wenger NK: Lipid abnormalities in women: data for risk, data for management. Cardiol Rev 2006, 14:276-280.
• [5]Harris DJ, Douglas PS: Enrollment of women in cardiovascular clinical trials funded by the National Heart, Lung, and Blood Institute. N Engl J Med 2000, 343:475-480.
• [6]Blauwet LA, Redberg RF: The role of sex-specific results reporting in cardiovascular disease. Cardiol Rev 2007, 15:275-278.
• [7]Mora S, Glynn RJ, Hsia J, MacFadyen JG, Genest J, Ridker PM: Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia: results from the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) and meta-analysis of women from primary prevention trials. Circulation 2010, 121:1069-1077.
• [8]Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E: Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998, 280:605-613.
• [9]Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002, 288:321-333.
• [10]Kim C, Hofer TP, Kerr EA: Review of evidence and explanations for suboptimal screening and treatment of dyslipidemia in women. A conceptual model. J Gen Intern Med 2003, 18:854-863.
• [11]Bays HE, Ose L, Fraser N, Tribble DL, Quinto K, Reyes R, Johnson-Levonas AO, Sapre A, Donahue SR: 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. Clin Ther 2004, 26:1758-1773.
• [12]Conard SE, Bays HE, Leiter LA, Bird SR, Rubino J, Lowe RS, Tomassini JE, Tershakovec AM: Efficacy and safety of ezetimibe added on to atorvastatin (20 mg) versus uptitration of atorvastatin (to 40 mg) in hypercholesterolemic patients at moderately high risk for coronary heart disease. Am J Cardiol 2008, 102:1489-1494.
• [13]Farnier M, Averna M, Missault L, Vaverkova H, Viigimaa M, Massaad R, Vandormael K, Johnson-Levonas AO, Brudi P: Lipid-altering efficacy of ezetimibe/simvastatin 10/20 mg compared with rosuvastatin 10 mg in high-risk hypercholesterolaemic patients inadequately controlled with prior statin monotherapy - The IN-CROSS study. Int J Clin Pract 2009, 63:547-559.
• [14]Gagne C, Bays HE, Weiss SR, Mata P, Quinto K, Melino M, Cho M, Musliner TA, Gumbiner B: Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol 2002, 90:1084-1091.
• [15]Gaudiani LM, Lewin A, Meneghini L, Perevozskaya I, Plotkin D, Mitchel Y, Shah S: Efficacy and safety of ezetimibe co-administered with simvastatin in thiazolidinedione-treated type 2 diabetic patients. Diabetes Obes Metab 2005, 7:88-97.
• [16]Leiter LA, Bays H, Conard S, Bird S, Rubino J, Hanson ME, Tomassini JE, Tershakovec AM: Efficacy and safety of ezetimibe added on to atorvastatin (40 mg) compared with uptitration of atorvastatin (to 80 mg) in hypercholesterolemic patients at high risk of coronary heart disease. Am J Cardiol 2008, 102:1495-1501.
• [17]Melani L, Mills R, Hassman D, Lipetz R, Lipka L, LeBeaut A, Suresh R, Mukhopadhyay P, Veltri E: Efficacy and safety of ezetimibe coadministered with pravastatin in patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Eur Heart J 2003, 24:717-728.
• [18]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 Clin Proc 2005, 80:587-595.
• [19]Reckless JP, Henry P, Pomykaj T, Lim ST, Massaad R, Vandormael K, Johnson-Levonas AO, Lis K, Brudi P, Allen C: Lipid-altering efficacy of ezetimibe/simvastatin 10/40 mg compared with doubling the statin dose in patients admitted to the hospital for a recent coronary event: the INFORCE study. Int J Clin Pract 2008, 62:539-554.
• [20]Robinson JG, Ballantyne CM, Grundy SM, Hsueh WA, Parving HH, Rosen JB, Adewale AJ, Polis AB, Tomassini JE, Tershakovec AM: Lipid-altering efficacy and safety of ezetimibe/simvastatin versus atorvastatin in patients with hypercholesterolemia and the metabolic syndrome (from the VYMET study). Am J Cardiol 2009, 103:1694-1702.
• [21]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. J Natl Med Assoc 2006, 98:772-778.
• [22]Zieve F, Wenger NK, Ben Yehuda O, Constance C, Bird S, Lee R, Hanson ME, Jones-Burton C, Tershakovec AM: Safety and efficacy of ezetimibe added to atorvastatin versus up titration of atorvastatin to 40 mg in Patients > or = 65 years of age (from the ZETia in the ELDerly [ZETELD] study). Am J Cardiol 2010, 105:656-663.
• [23]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. Curr Med Res Opin 2005, 21:571-578.
• [24]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. Int J Clin Pract 2005, 59:619-627.
• [25]Feldman T, Koren M, Insull W Jr, McKenney J, Schrott H, Lewin A, Shah S, Sidisin M, Cho M, Kush D, Mitchel Y: Treatment of high-risk patients with ezetimibe plus simvastatin co-administration versus simvastatin alone to attain National Cholesterol Education Program Adult Treatment Panel III low-density lipoprotein cholesterol goals. Am J Cardiol 2004, 93:1481-1486.
• [26]Kirilmaz B, Asgun F, Alioglu E, Ercan E, Tengiz I, Turk U, Saygi S, Ozerkan F: High inflammatory activity related to the number of metabolic syndrome components. J Clin Hypertens (Greenwich) 2010, 12:136-144.
• [27]LaRosa JC, He J, Vupputuri S: Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA 1999, 282:2340-2346.
• [28]Grundy SM: Should women be offered cholesterol lowering drugs to prevent cardiovascular disease? Yes. BMJ 2007, 334:982.
• [29]Kendrick M: Should women be offered cholesterol lowering drugs to prevent cardiovascular disease? No. BMJ 2007, 334:983.
• [30]Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, Collins R: Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010, 376:1670-1681.
• [31]Califf RM, Lokhnygina Y, Cannon CP, Stepanavage ME, McCabe CH, Musliner TA, Pasternak RC, Blazing MA, Giugliano RP, Harrington RA, Braunwald E: An update on the IMProved reduction of outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) design. Am Heart J 2010, 159:705-709.
• [32]Gerdts E, Rossebo AB, Pedersen TR, Boman K, Brudi P, Chambers JB, Egstrup K, Gohlke-Barwolf C, Holme I, Kesaniemi YA, Malbecq W, Nienaber C, Ray S, Skjaerpe T, Wachtell K, Willenheimer R: Impact of baseline severity of aortic valve stenosis on effect of intensive lipid lowering therapy (from the SEAS study). Am J Cardiol 2010, 106:1634-1639.
• [33]Rossebo AB, Pedersen TR, Boman K, Brudi P, Chambers JB, Egstrup K, Gerdts E, Gohlke-Barwolf C, Holme I, Kesaniemi YA, Malbecq W, Nienaber CA, Ray S, Skjaerpe T, Wachtell K, Willenheimer R: Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008, 359:1343-1356.
• [34]SHARP Collaborative Group: Study of Heart and Renal Protection (SHARP): randomized trial to assess the effects of lowering low-density lipoprotein cholesterol among 9,438 patients with chronic kidney disease. Am Heart J 2010, 160:785-794.
• [35]Merck/Schering-Plough Pharmaceuticals: Vytorin (ezetimibe/simvastatin) [package insert]. In USA. North Wales, PA, Merck/Schering-Plough Pharmaceuticals; 2009.
• [36]Bennett S, Sager P, Lipka L, Melani L, Suresh R, Veltri E: Consistency in efficacy and safety of ezetimibe coadministered with statins for treatment of hypercholesterolemia in women and men. J Womens Health (Larchmt) 2004, 13:1101-1107.
• [37]Goldberg AC, Sapre A, Liu J, Capece R, Mitchel YB: Efficacy and safety of ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia: a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc 2004, 79:620-629.
• [38]Davidson MH, McGarry T, Bettis R, Melani L, Lipka LJ, LeBeaut AP, Suresh R, Sun S, Veltri EP: Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol 2002, 40:2125-2134.
• [39]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. Am J Cardiol 2004, 93:1487-1494.
• [40]Stein E, Stender S, Mata P, Sager P, Ponsonnet D, Melani L, Lipka L, Suresh R, Maccubbin D, Veltri E: Achieving lipoprotein goals in patients at high risk with severe hypercholesterolemia: efficacy and safety of ezetimibe co-administered with atorvastatin. Am Heart J 2004, 148:447-455.
• [41]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. Am Heart J 2005, 149:464-473.
• [42]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. Curr Med Res Opin 2006, 22:2041-2053.
• [43]Goldberg RB, Guyton JR, Mazzone T, Weinstock RS, Polis A, Edwards P, Tomassini JE, Tershakovec AM: Ezetimibe/simvastatin vs atorvastatin in patients with type 2 diabetes mellitus and hypercholesterolemia: the VYTAL study. Mayo Clin Proc 2006, 81:1579-1588.
• [44]Kerzner B, Corbelli J, Sharp S, Lipka LJ, Melani L, LeBeaut A, Suresh R, Mukhopadhyay P, Veltri EP: Efficacy and safety of ezetimibe coadministered with lovastatin in primary hypercholesterolemia. Am J Cardiol 2003, 91:418-424.
• [45]Ballantyne CM, Houri J, Notarbartolo A, Melani L, Lipka LJ, Suresh R, Sun S, LeBeaut AP, Sager PT, Veltri EP: Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation 2003, 107:2409-2415.
• [46]Dobs AS, Guyton JR, McClusky D, Ponsonnet D, Melani L, LeBeaut A, Yang B, Veltri E, for the Ezetimibe Study Group: Coadministration of ezetimibe with simvastatin. J Am Coll Cardiol 2003, 41:227A.
• [47]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. Int J Cardiol 2005, 102:327-332.
• [48]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. Int J Clin Pract 2005, 59:1377-1386.
• [49]Constance C, Westphal S, Chung N, Lund M, McCrary SC, Johnson-Levonas AO, Massaad R, Allen C: Efficacy of ezetimibe/simvastatin 10/20 and 10/40 mg compared with atorvastatin 20 mg in patients with type 2 diabetes mellitus. Diabetes Obes Metab 2007, 9:575-584.