Impact of Female Sex on Lipid Lowering, Clinical Outcomes, and Adverse Effects in Atorvastatin Trials

Published:November 29, 2014DOI:
      The aim of this study was to evaluate the effect of atorvastatin on lipid lowering, cardiovascular (CV) events, and adverse events in women compared with men in 6 clinical trials. In the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) trial (atorvastatin 80 mg vs simvastatin 20 to 40 mg), the Treating to New Targets (TNT) trial (atorvastatin 80 vs 10 mg), the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial (atorvastatin 80 mg vs placebo), and the Collaborative Atorvastatin Diabetes Study (CARDS), the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), and the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN) (atorvastatin 10 mg vs placebo), lipid changes on treatment were compared between genders with studies grouped by dose. The association of on-study low-density lipoprotein (LDL) cholesterol and CV events by gender was evaluated in the combined studies and the impact of gender on adverse events in each study separately. Major CV events occurred in 3,083 of 30,000 men (10.3%) and 823 of 9,173 women (9.0%). Changes in lipids were similar in women and men. Major CV events were associated with gender-specific quintiles of on-treatment LDL cholesterol for women and men. In women, LDL cholesterol was a significant predictor of stroke, but not in men. Discontinuation rates due to adverse events were higher in women in 4 of 6 trials, but in only 1 trial was a significant treatment-gender interaction seen. Myalgia rates were slightly higher in women in both statin and placebo groups. In conclusion, the response of women to atorvastatin was similar to that of men, with slightly more discontinuations due to adverse events. Higher on-treatment LDL cholesterol was significantly associated with more CV events in both genders, but the association was stronger for stroke in women and for coronary heart disease death in men.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to American Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Cholesterol Treatment Trialists’ (CTT) Collaboration
        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
        • Cholesterol Treatment Trialists’ (CTT) Collaborators
        The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.
        Lancet. 2012; 380: 581-590
        • Walsh J.M.
        • Pignone M.
        Drug treatment of hyperlipidemia in women.
        JAMA. 2004; 291: 2243-2252
        • Mora S.
        • Glynn R.J.
        • Hsia J.
        • MacFadyen J.G.
        • Genest J.
        • Ridker P.M.
        Statins for 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 in primary prevention trials.
        Circulation. 2010; 121: 1069-1077
        • Gutierrez J.
        • Ramirez G.
        • Rundek T.
        • Sacco R.L.
        Statin therapy in the prevention of recurrent cardiovascular events: a sex-based meta-analysis.
        Arch Intern Med. 2012; 172: 909-919
        • Kostis W.J.
        • Cheng J.Q.
        • Dobrzynski J.M.
        • Cabrera J.
        • Kostis J.B.
        Meta-analysis of statin effects in women versus men.
        J Am Coll Cardiol. 2012; 59: 572-582
        • Caspard H.
        • Chan A.K.
        • Walker A.M.
        Compliance with a statin treatment in a usual-care setting: retrospective database analysis over 3 years after treatment initiation in health maintenance organization enrollees with dyslipidemia.
        Clin Ther. 2005; 127: 1639-1646
        • LaRosa J.C.
        • Grundy S.M.
        • Waters D.D.
        • Shear C.
        • Barter P.
        • Fruchart J.C.
        • Gotto A.M.
        • Greten H.
        • Kastelein J.J.
        • Shepherd J.
        • Wenger N.K.
        • Treating to New Targets (TNT) Investigators
        Intensive lipid lowering with atorvastatin in patients with stable coronary disease.
        N Engl J Med. 2005; 352: 1425-1435
        • Pedersen T.R.
        • Faergeman O.
        • Kastelein J.J.
        • Olsson A.G.
        • Tikkanen M.J.
        • Holme I.
        • Larsen M.L.
        • Bendiksen F.S.
        • Lindahl C.
        • Szarek M.
        • Tsai J.
        • Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group
        High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial.
        JAMA. 2005; 294: 2437-2445
        • Amarenco P.
        • Bogousslavsky J.
        • Callahan 3rd, A.
        • Goldstein L.B.
        • Hennerici M.
        • Rudolph A.E.
        • Sillesen H.
        • Simunovic L.
        • Szarek M.
        • Welch K.M.
        • Zivin J.A.
        • Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators
        High-dose atorvastatin after stroke or transient ischemic attack.
        N Engl J Med. 2006; 355: 549-559
        • Colhoun H.M.
        • Betteridge D.J.
        • Durrington P.N.
        • Hitman G.A.
        • Neil H.A.
        • Livingstone S.J.
        • Thomason M.J.
        • Mackness M.I.
        • Charlton-Menys V.
        • Fuller J.H.
        • CARDS Investigators
        Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial.
        Lancet. 2004; 364: 685-696
        • Knopp R.H.
        • d’Emden M.
        • Smilde J.G.
        • Pocock S.J.
        Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN).
        Diabetes Care. 2006; 29: 1478-1485
        • Sever P.S.
        • Dahlöf B.
        • Poulter N.R.
        • Wedel H.
        • Beevers G.
        • Caulfield M.
        • Collins R.
        • Kjeldsen S.E.
        • Kristinsson A.
        • McInnes G.T.
        • Mehlsen J.
        • Nieminen M.
        • O'Brien E.
        • Ostergren J.
        • ASCOT Investigators
        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. 2003; 361: 1149-1158
        • Naci H.
        • Brugts J.J.
        • Fleurence R.
        • Ades A.E.
        Dose-comparative effects of different statins on serum lipid levels: a network meta-analysis of 256,827 individuals in 181 randomized controlled trials.
        Eur J Prev Cardiol. 2013; 20: 658-670
        • Mosca L.
        • Benjamin E.J.
        • Berra K.
        • Bezanson J.L.
        • Dolor R.J.
        • Lloyd-Jones D.M.
        • Newby L.K.
        • Piña I.L.
        • Roger V.L.
        • Shaw L.J.
        • Zhao D.
        • Beckie T.M.
        • Bushnell C.
        • D'Armiento J.
        • Kris-Etherton P.M.
        • Fang J.
        • Ganiats T.G.
        • Gomes A.S.
        • Gracia C.R.
        • Haan C.K.
        • Jackson E.A.
        • Judelson D.R.
        • Kelepouris E.
        • Lavie C.J.
        • Moore A.
        • Nussmeier N.A.
        • Ofili E.
        • Oparil S.
        • Ouyang P.
        • Pinn V.W.
        • Sherif K.
        • Smith Jr., S.C.
        • Sopko G.
        • Chandra-Strobos N.
        • Urbina E.M.
        • Vaccarino V.
        • Wenger N.K.
        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
        • Goldstein L.B.
        • Amarenco P.
        • Lamonte M.
        • Gilbert S.
        • Messig M.
        • Callahan A.
        • Hennerici M.
        • Sillesen H.
        • Welch K.M.
        • SPARCL Investigators
        Relative effects of statin therapy on stroke and cardiovascular events in men and women: secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Study.
        Stroke. 2008; 39: 2444-2448
        • Armitage J.
        The safety of statins in clinical practice.
        Lancet. 2007; 370: 1781-1790
        • Tomlinson S.S.
        • Mangione K.K.
        Potential adverse effects of statins on muscle.
        Phys Ther. 2005; 85: 459-465
        • Waters D.D.
        • Ho J.E.
        • DeMicco D.A.
        • Breazna A.
        • Arsenault B.J.
        • Chuan-Chuan W.
        • Kastelein J.J.
        • Colhoun H.
        • Barter P.
        Predictors of new-onset diabetes in patients treated with atorvastatin. Results from 3 large randomized clinical trials.
        J Am Coll Cardiol. 2011; 57: 1535-1545
        • Gupta A.K.
        • Dahlof B.
        • Dobson J.
        • Sever P.S.
        • Wedel H.
        • Poulter N.R.
        • Anglo-Scandinavian Cardiac Outcomes Trial Investigators
        Determinants of new-onset diabetes among 19,257 hypertensive patients randomized in the Anglo-Scandinavian Cardiac Outcomes Trial – Blood Pressure Lowering Arm and the relative influence of antihypertensive medication.
        Diabetes Care. 2008; 31: 982-988