Effect of rosuvastatin on low-density lipoprotein cholesterol in patients with hypercholesterolemia

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Effect of rosuvastatin on low-density lipoprotein cholesterol in patients with hypercholesterolemia
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  Effect of  Rosuvastatin  on Low-DensityLipoprotein Cholesterol in PatientsWith Hypercholesterolemia Anders G. Olsson,  MD ,  PhD , John Pears,  MB ,  ChB ,  MD , John McKellar,  BSc ,  CStat , Jacques Mizan,  MD , and Ali Raza,  MD Rosuvastatin is a new, synthetic, orally active statin, withmarked low-density lipoprotein (LDL) cholesterol-lower-ing activity. We conducted 2 dose-ranging studies. In thefirst study, after a 6-week dietary run-in, 142 moder-ately hypercholesterolemic patients were randomizedequally to receive double-blind placebo or rosuvastatin1, 2.5, 5, 10, 20, or 40 mg or open-label atorvastatin 10or 80 mg once daily for 6 weeks; in the second study,conducted to extend the rosuvastatin dose range, 64patients were randomized to double-blind, once-daily placebo or rosuvastatin 40 or 80 mg (1:1:2 ratio) for 6 weeks. Data from both studies were combined for anal- ysis of lipid effects. No statistical comparison of atorva-statin arms with placebo or rosuvastatin was performed.Rosuvastatin was associated with highly significant dose-dependent reductions in LDL cholesterol compared with placebo (p < 0.001); decreases ranged from 34% (1mg) to 65% (80 mg). Linear regression analysis indi-cated an additional 4.5% LDL cholesterol reduction foreach doubling of the rosuvastatin dose. Across the doserange, approximately 90% of LDL cholesterol reductionoccurred within the first 2 weeks of treatment. Signifi-cant, dose-dependent reductions in total cholesterol andapolipoprotein B with rosuvastatin were also observed(p  < 0.001). High-density lipoprotein cholesterol in-creases and triglyceride reductions were consistently ob-served and statistically significant at some dose levels. All lipid ratios were significantly reduced at all rosuvas-tatin dose levels (p  < 0.001). Adverse events were sim-ilar across placebo and active treatments. No significant increases in alanine aminotransferase or creatine kinase were seen in any patient. Over 6 weeks, rosuvastatinproduced large, rapid, dose-dependent LDL cholesterolreductions and was well tolerated in hypercholester-olemic patients.   2001 by Excerpta Medica, Inc.(Am J Cardiol 2001;88:504–508) R osuvastatin (CRESTOR, Astra Zeneca, Cheshire,United Kingdom), formerly known as ZD4522, isa new, synthetic, orally active inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase with markedlow-density lipoprotein (LDL) cholesterol-loweringactivity in vitro and in vivo. 1,2 We conducted placebo-controlled, multicenter, dose-response studies of rosu-vastatin in patients with mild to moderate hypercho-lesterolemia in 2 stages. In the first study (4522IL/ 0008), the effects of rosuvastatin 1 to 40 mg for up to6 weeks were assessed; in addition, low and highdoses of atorvastatin—a synthetic statin with well-documented efficacy and safety—were administeredto benchmark rosuvastatin responses. 3,4 A secondstudy (4522IL/0023), using the same methods andconducted at the same centers, extended the doserange of rosuvastatin to 80 mg and was prospectivelydesigned to be analyzed in combination with the firststudy. We report combined results of these studieshere. METHODS Men aged 18 to 70 years and postmenopausalwomen aged 50 to 70 years with fasting LDL choles-terol levels   4.14 mmol/L (  160 mg/dl) and   6.21mmol/L (  240 mg/dl), triglyceride levels   3.39mmol/L (  300 mg/dl), and body mass index   30kg/m 2 were enrolled at 14 northern European centers(see Appendix) into randomized, parallel-group, pla-cebo-controlled, rosuvastatin dose-response studies.During a 6-week dietary run-in period performed todetermine eligibility for the 6-week treatment period,patients were encouraged to adhere to the AmericanHeart Association Step I diet; compliance was as-sessed by the Food Record Rating instrument. 5,6 In-clusion criteria for the randomized treatment phaseincluded: fasting LDL cholesterol   4.14 mmol/L(  160 mg/dl) and   5.69 mmol/L (  220 mg/dl) atweeks –1 and –2 before randomization, with the lowervalue being within 15% of the higher value; fastingtriglyceride levels   3.39 mmol/L (  300 mg/dl)throughout the run-in period; and Food Record Ratingscore of   15 at week –2. Exclusion criteria includeduse of cholesterol-lowering drugs within 4 weeks of beginning the run-in period, active arterial disease,history of malignancy, uncontrolled hypertension (di-astolic pressure   95 mm Hg), diabetes mellitus, un-controlled hypothyroidism, homozygous familial hy-percholesterolemia, active liver disease or hepaticdysfunction (defined as alanine aminotransferase[ALT], aspartate aminotransferase,    -glutamyltrans- From the Department of Medicine and Care, University Hospital,Linko¨ping, Sweden; and AstraZeneca, Alderley Park, Cheshire, UnitedKingdom. This study was supported by a grant from AstraZeneca,Alderley Park, Cheshire, United Kingdom. Manuscript received Janu-ary 8, 2001; revised manuscript received and accepted March 29,2001.Address for reprints: Anders G. Olsson, MD, PhD, Department ofMedicine and Care, University Hospital, S-581 85 Linko¨ping, Swe-den. E-mail: andol@kfc.liu.se. 504  ©2001 by Excerpta Medica, Inc. All rights reserved. 0002-9149/01/$–see front matterThe American Journal of Cardiology Vol. 88 September 1, 2001 PII S0002-9149(01)01727-1  ferase, alkaline phosphatase, or bilirubin levels   1.5the upper limit of normal), serum creatinine level  180   mol/L, and serum creatine kinase level   3times the upper limit of normal.In the first study, 142 eligible patients were ran-domized to double-blind placebo or rosuvastatin 1,2.5, 5, 10, 20, or 40 mg or open-label atorvastatin 10or 80 mg once daily for 6 weeks. In the second study,performed after data on clinical exposure to higherrosuvastatin doses became available, 64 patients wererandomized to double-blind, once-daily placebo orrosuvastatin 40 or 80 mg in a 1:1:2 ratio for 6 weeks.All patients were followed for 4 weeks (2 visits) aftercompletion of the treatment phase to monitor clinicaland laboratory safety parameters and lipid variables.These studies were approved by appropriate ethicscommittees. Written informed consent was providedby all patients before participating in these studies.Study populations were combined for analysis of all efficacy outcome measures. The primary objectivewas to estimate the relation between rosuvastatin doseand percent change in LDL cholesterol from baselinewith respect to placebo across the rosuvastatin doserange (1 to 80 mg). Secondary objectives includedestimation of the dose-response relation between ro-suvastatin dose and percent changes in total choles-terol and apolipoprotein (apo) B levels from baselinewith respect to placebo. Other secondary objectiveswere to assess changes from baseline for high-densitylipoprotein (HDL) cholesterol, triglycerides, apo A-I,lipoprotein(a), and lipid ratios (total cholesterol:HDLcholesterol, LDL cholesterol:HDL cholesterol, non-HDL cholesterol:HDL cholesterol, and apo B:apo A-Iratios) versus placebo.Safety analysis included physical examination andcategorization of clinical adverse events according toa dictionary based on coding symbols and thesaurusfor adverse reaction terminology. Laboratory safetyanalyses included liver function tests, clinical bio-chemistry, creatine kinase measurement, hematology,and urinalysis. Liver and muscle toxicity are infre-quent but serious complications of statin therapy 7,8 ;therefore, specific attention was given to clinicallysignificant aspartate amiontransferase and ALT eleva-tions (  3 times the upper limit of normal on 2 sepa-rate occasions 4 to 10 days apart) and creatine kinaseelevations (  10 times the upper limit of normal on 2separate occasions 4 to 10 days apart).Analysis of laboratory samples for fasting lipids,biochemistry, hematology, and urinalysis was per-formed at Covance Central Laboratory Services (Ge-neva, Switzerland). Lipid analysis techniques con-sisted of nephelometry for apo A-I and apo B, color-imetric enzymatic assay for total cholesterol andtriglycerides, and colorimetric enzymatic assay andprecipitation for HDL cholesterol. LDL cholesterolvalues were determined using the Friedewald meth-od. 9 Lipid levels were assessed at weeks –6, –2, and–1 in the dietary run-in period and at weeks 0, 1, 2, 4,and 6 during the treatment phase. Laboratory safetymeasurements were made at weeks –6 and –1 during       T      A      B      L      E      1     L    i   p    i    d    P   a   r   a   m   e   t   e   r    V   a    l   u   e   s   a   t    B   a   s   e    l    i   n   e   a   n    d    P   e   r   c   e   n   t    C    h   a   n   g   e    f   r   o   m    B   a   s   e    l    i   n   e   t   o    W   e   e    k    S    i   x     D   o   u    b    l   e  -    B    l    i   n    d    P    l   a   c   e    b   o    D   o   u    b    l   e  -    B    l    i   n    d    R   o   s   u   v   a   s   t   a   t    i   n    O   p   e   n  -    L   a    b   e    l    A   t   o   r   v   a   s   t   a   t    i   n    *    D   o   s   e    (   m   g    /    d    )    0    1    2 .    5    5    1    0    2    0    4    0    8    0    1    0    8    0   n    2    9    1    3    1    3    1    7    1    6    1    3    3    4    3    1    1    3    1    0    L    D    L    (   m   g    /    d    l    )         †     B   a   s   e    l    i   n   e           S    D    1    9    7 .    2           1    5 .    5    1    8    9 .    4           1    5 .    5    1    8    9 .    4           1    5 .    5    1    9    3 .    4           1    5 .    5    1    8    9 .    4           1    5 .    5    1    8    1 .    7           1    5 .    5    1    8    5 .    6           1    9 .    3    1    8    9 .    4           1    5 .    5    1    8    9 .    4           7 .    7    1    9    3 .    4           1    1 .    6    %                 S    E         3 .    6           1 .    7         3    4 .    3           2 .    6         ‡         4    0 .    7           2 .    6         ‡         4    2 .    5           2 .    4         ‡         5    0 .    5           2 .    4         ‡         5    7 .    0           2 .    7         ‡         6    2 .    6           1 .    5         ‡         6    4 .    8           2 .    0         ‡         4    4 .    2           2 .    5         5    8 .    6           2 .    9    T    C    (   m   g    /    d    l    )    B   a   s   e    l    i   n   e    (    S    D    )    2    7    0 .    7           1    9 .    3    2    6    6 .    8           1    9 .    3    2    6    3 .    0           2    3 .    2    2    7    0 .    7           1    9 .    3    2    6    6 .    8           1    5 .    5    2    6    3 .    0           1    5 .    5    2    5    9 .    1           2    7 .    1    2    6    3 .    0           1    9 .    3    2    6    3 .    0           1    5 .    5    2    6    6 .    8           1    5 .    5    %            (    S    E    )         2 .    2           1 .    3         2    3 .    7           2 .    2         ‡         2    9 .    1           2 .    2         ‡         3    1 .    1           1 .    9         ‡         3    5 .    0           2 .    0         ‡         4    0 .    4           2 .    2         ‡         4    5 .    5           1 .    2         ‡         4    6 .    7           1 .    6         ‡         3    2 .    0           2 .    1         4    6 .    1           2 .    2    H    D    L    (   m   g    /    d    l    )    B   a   s   e    l    i   n   e    (    S    D    )    5    4 .    1           1    1 .    6    5    4 .    1           1    5 .    5    5    0 .    3           1    1 .    6    5    0 .    3           7 .    7    5    0 .    3           1    5 .    5    5    0 .    3           1    1 .    6    5    4 .    1           1    1 .    6    5    0 .    3           1    5 .    5    5    0 .    3           1    5 .    5    4    6 .    4           7 .    7    %            (    S    E    )           3 .    6           2 .    2           1    0 .    0           3 .    6           9 .    3           3 .    6           1    4 .    0           3 .    2           1    4 .    4           3 .    3         §           1    0 .    0           3 .    6           1    0 .    1           2 .    0           1    2 .    9           2 .    7         §           6 .    8           2 .    9         3 .    2           4 .    5    T   r    i   g    l   y   c   e   r    i    d   e   s    (   m   g    /    d    l    )    B   a   s   e    l    i   n   e    (    S    D    )    1    2    4 .    0           4    4 .    3    1    1    5 .    1           5    3 .    1    1    2    4 .    0           5    3 .    1    1    2    4 .    0           5    3 .    1    1    3    2 .    9           5    3 .    1    1    4    1 .    7           5    3 .    1    1    1    5 .    1           5    3 .    1    1    1    5 .    1           3    5 .    4    1    2    4 .    0           5    3 .    1    1    2    4 .    0           3    5 .    4    %            (    S    E    )         1 .    3           4 .    9         1    8 .    8           7 .    9         1    0 .    6           7 .    9         3    4 .    6           7 .    1         §         9 .    8           7 .    3         2    2 .    9           8 .    0         2    8 .    0           4 .    5         ‡         2    2 .    7           5 .    9         §         1    3 .    6           4 .    8         3    0 .    7           6 .    6     *    N   o   s   t   a   t    i   s   t    i   c   a    l   c   o   m   p   a   r    i   s   o   n   s   w   e   r   e   m   a    d   e    b   e   t   w   e   e   n    d   o   u    b    l   e  -    b    l    i   n    d   p    l   a   c   e    b   o   o   r   r   o   s   u   v   a   s   t   a   t    i   n   a   n    d   o   p   e   n  -    l   a    b   e    l   a   t   o   r   v   a   s   t   a   t    i   n .          †     T   o   c   o   n   v   e   r   t    f   r   o   m   m   g    /    d    l   t   o   m   m   o    l    /    L    f   o   r    L    D    L ,    T    C ,   a   n    d    H    D    L ,   m   u    l   t    i   p    l   y    b   y    0 .    0    2    5    8    6   ;    f   o   r   t   r    i   g    l   y   c   e   r    i    d   e   s ,   m   u    l   t    i   p    l   y    b   y    0 .    0    1    1    2    9 .          ‡    p           0 .    0    0    1   c   o   m   p   a   r   e    d   w    i   t    h   p    l   a   c   e    b   o   ;          §    p           0 .    0    5   c   o   m   p   a   r   e    d   w    i   t    h   p    l   a   c   e    b   o .    B   a   s   e    l    i   n   e   v   a    l   u   e   s   a   r   e   m   e   a   n   s           S    D   ;   p   e   r   c   e   n   t   c    h   a   n   g   e    f   r   o   m    b   a   s   e    l    i   n   e    (    %            )   v   a    l   u   e   s    f   o   r   c   o   m    b    i   n   e    d   p    l   a   c   e    b   o   a   n    d   r   o   s   u   v   a   s   t   a   t    i   n   g   r   o   u   p   s   a   r   e    l   e   a   s   t  -   s   q   u   a   r   e   s   m   e   a   n           S    E    f   r   o   m   a   n   a    l   y   s    i   s   o    f   v   a   r    i   a   n   c   e   ;    %           v   a    l   u   e   s    f   o   r   a   t   o   r   v   a   s   t   a   t    i   n   g   r   o   u   p   s   a   r   e   m   e   a   n           S    E .    T    C         t   o   t   a    l   c    h   o    l   e   s   t   e   r   o    l . PREVENTIVE CARDIOLOGY/REDUCTION IN LDL CHOLESTEROL WITH  ROSUVASTATIN   505  the run-in period and at weeks 0, 1, 2, 4, and 6 duringthe treatment phase.The primary statistical analysis was the percentchange from baseline to week 6 in LDL cholesterolusing least-squares means and SEs from analysis of variance in the per-protocol population. The per-pro-tocol population consisted of patients with baselinemeasurements and week 6 measurements who had nomajor protocol violations or deviations; this popula-tion was used for the main analysis because the pri-mary objective was to ascertain dose response, andthis is more accurately achieved in the patient popu-lation complying with the study protocol. BaselineLDL cholesterol value was determined by averagingweek –2, –1, and 0 values. Analysis of variance forchange from baseline included the baseline value as acovariate and factors for treatment group and study.Statistical analyses were performed using the Statisti-cal Analysis System (SAS version 6.12, SAS Institute,Cary, North Carolina). The relation between log-trans-formed dose of rosuvastatin and percent change inbaseline in LDL cholesterol at week 6 was analyzedusing linear regression with a 95% confidence band.All statistical tests were 2-sided at a 5% significancelevel. Total cholesterol changes and apo B changesfrom baseline were analyzed using analysis of vari-ance and logistic regression in a manner similar toanalysis of LDL cholesterol. No statistical compari- FIGURE 1. Relation between log-transformed rosuvastatin doseand percent change in concentrations for LDL cholesterol  (A)  andapo B  (B) . Change indicates change from baseline in least-squares means from analysis of variance. Each doubling of rosu- vastatin resulted in a further 4.5% reduction in LDL cholesterol.       T      A      B      L      E      2     A   p   o    l    i   p   o   p   r   o   t   e    i   n   a   n    d    L    i   p    i    d    R   a   t    i   o    P   a   r   a   m   e   t   e   r   s   a   t    B   a   s   e    l    i   n   e   a   n    d    P   e   r   c   e   n   t    C    h   a   n   g   e   s    f   r   o   m    B   a   s   e    l    i   n   e   t   o    W   e   e    k    S    i   x     D   o   u    b    l   e  -    B    l    i   n    d    P    l   a   c   e    b   o    D   o   u    b    l   e  -    B    l    i   n    d    R   o   s   u   v   a   s   t   a   t    i   n    O   p   e   n  -    L   a    b   e    l    A   t   o   r   v   a   s   t   a   t    i   n    *    D   o   s   e    (   m   g    /    d    )    0    1    2 .    5    5    1    0    2    0    4    0    8    0    1    0    8    0   n    2    9    1    3    1    3    1    7    1    6    1    3    3    4    3    1    1    3    1    0    A   p   o    A  -    I    (   m   g    /    d    l    )         †     B   a   s   e    l    i   n   e           S    D    1    4    6 .    2           2    0 .    5    1    3    9 .    9           1    9 .    1    1    3    2 .    5           1    6 .    5    1    3    8 .    9           1    2 .    2    1    3    5 .    8           2    2 .    3    1    3    9 .    3           1    8 .    9    1    4    1 .    3           2    4 .    7    1    3    9 .    8           2    4 .    8    1    3    2 .    8           2    0 .    1    1    3    2 .    0           1    1 .    4    %                 S    E           3 .    5           2 .    5           5 .    8           4 .    0           9 .    5           4 .    0           6 .    6           3 .    7           6 .    8           3 .    7           7 .    0           4 .    3           1 .    8           2 .    3           6 .    7           3 .    0         1 .    0           2 .    8           0 .    3           4 .    9    A   p   o    B    (   m   g    /    d    l    )    †    B   a   s   e    l    i   n   e           S    D    1    3    9 .    7           1    6 .    3    1    3    0 .    0           1    2 .    6    1    3    3 .    5           1    0 .    8    1    3    8 .    6           1    7 .    7    1    4    2 .    8           1    8 .    8    1    3    2 .    0           1    8 .    6    1    3    3 .    8           1    7 .    6    1    3    7 .    8           1    3 .    3    1    3    6 .    9           1    1 .    4    1    3    5 .    6           1    1 .    1    %                 S    E         2 .    1           1 .    5         2    8 .    5           2 .    5         ‡         3    3 .    7           2 .    5         ‡     3    6 .    3           2 .    3         ‡         4    0 .    7           2 .    3         ‡         4    8 .    8           2 .    6         ‡         5    3 .    9           1 .    4         ‡         5    4 .    7           1 .    8         ‡         3    6 .    4           3 .    1         5    0 .    2           1 .    9    A   p   o    B   :   a   p   o    A  -    I         §     B   a   s   e    l    i   n   e           S    D    1 .    0           0 .    2    1 .    0           0 .    2    1 .    0           0 .    1    1 .    0           0 .    2    1 .    1           0 .    3    1 .    0           0 .    2    1 .    0           0 .    2    1 .    1           0 .    3    1 .    1           0 .    2    1 .    0           0 .    1    E   n    d   o    f   w    k    6           S    E    0 .    9           0 .    0    3    0 .    6           0 .    0    5         ‡     0 .    6           0 .    0    5         ‡     0 .    6           0 .    0    4         ‡     0 .    6           0 .    0    4         ‡     0 .    4           0 .    0    5         ‡     0 .    5           0 .    0    3         ‡     0 .    5           0 .    0    3         ‡     0 .    7           0 .    0    3    0 .    5           0 .    0    3    N   o   n  -    H    D    L   :    H    D    L         §     B   a   s   e    l    i   n   e           S    D    4 .    1           1 .    1    4 .    1           1 .    2    4 .    6           0 .    9    4 .    3           0 .    9    4 .    8           2 .    0    4 .    4           1 .    5    4 .    4           1 .    3    4 .    5           1 .    5    4 .    6           1 .    2    4 .    7           1 .    0    E   n    d   o    f   w    k    6           S    E    4 .    0           0 .    1    2 .    5           0 .    2         ‡     2 .    4           0 .    2         ‡     2 .    1           0 .    2         ‡     2 .    1           0 .    2         ‡     1 .    7           0 .    2         ‡     1 .    6           0 .    1         ‡     1 .    7           0 .    2         ‡     2 .    5           0 .    2    2 .    1           0 .    2     *    N   o   s   t   a   t    i   s   t    i   c   a    l   c   o   m   p   a   r    i   s   o   n   s   w   e   r   e   m   a    d   e    b   e   t   w   e   e   n    d   o   u    b    l   e  -    b    l    i   n    d   p    l   a   c   e    b   o   o   r   r   o   s   u   v   a   s   t   a   t    i   n   a   n    d   o   p   e   n  -    l   a    b   e    l   a   t   o   r   v   a   s   t   a   t    i   n .          †     B   a   s   e    l    i   n   e   v   a    l   u   e   s   a   r   e   m   e   a   n           S    D   ;   p   e   r   c   e   n   t   c    h   a   n   g   e    f   r   o   m    b   a   s   e    l    i   n   e    (    %            )   v   a    l   u   e   s    f   o   r   c   o   m    b    i   n   e    d   p    l   a   c   e    b   o   a   n    d   r   o   s   u   v   a   s   t   a   t    i   n   g   r   o   u   p   s   a   r   e    l   e   a   s   t  -   s   q   u   a   r   e   s   m   e   a   n           S    E    f   r   o   m   a   n   a    l   y   s    i   s   o    f   v   a   r    i   a   n   c   e   ;    %           v   a    l   u   e   s    f   o   r   a   t   o   r   v   a   s   t   a   t    i   n   g   r   o   u   p   s   a   r   e   m   e   a   n           S    E .          ‡    p           0 .    0    0    1   c   o   m   p   a   r   e    d   w    i   t    h   p    l   a   c   e    b   o .          §     B   a   s   e    l    i   n   e   v   a    l   u   e   s   a   r   e   m   e   a   n           S    D   ;   e   n    d  -   p   o    i   n   t    (   w   e   e    k    6    )   v   a    l   u   e   s    f   o   r   c   o   m    b    i   n   e    d   p    l   a   c   e    b   o   a   n    d   r   o   s   u   v   a   s   t   a   t    i   n   g   r   o   u   p   s   a   r   e    l   e   a   s   t  -   s   q   u   a   r   e   s   m   e   a   n           S    E    f   r   o   m   a   n   a    l   y   s    i   s   o    f   v   a   r    i   a   n   c   e   ;   e   n    d  -   p   o    i   n   t   v   a    l   u   e   s    f   o   r   a   t   o   r   v   a   s   t   a   t    i   n   g   r   o   u   p   s   a   r   e   m   e   a   n           S    E . 506  THE AMERICAN JOURNAL OF CARDIOLOGY   VOL. 88 SEPTEMBER 1, 2001  sons were performed between rosuvastatin and ator-vastatin or placebo and atorvastatin.Adverse events were summarized across placeboand active treatments using descriptive statistics andwere evaluated for trends in occurrence rates acrossthe dose range of rosuvastatin. RESULTS Of a total of 594 patients entering the run-in pe-riod, 388 were withdrawn before the treatment phasebecause they failed the screening process. The totalrandomized population was 206, 189 of which pro-vided data for the per-protocol efficacy data set. Sev-enteen patients (8.25%) were excluded from the per-protocol analysis because of major protocol violationsor deviations or withdrawals because of adverseevents.Demographic and baseline characteristics weregenerally similar among study groups receiving ran-domized treatment, although some differences wereapparent. The mean age was 56 years (range 24 to 70)across groups. The mean body mass index was 25.7kg/m 2 (range 24.7 to 26.3). In all, 129 of the 206patients entering randomized treatment were men;male patients accounted for approximately half tomore than three quarters of patients in each group.Compared with placebo, all dose levels of rosuv-astatin produced significant reductions in LDL cho-lesterol (p   0.001), with reductions ranging from34% at rosuvastatin 1 mg to 65% at rosuvastatin 80mg (Table 1). Linear regression analysis demonstrateda dose-response relation for LDL cholesterol reduc-tions (Figure 1A), with modeling indicating an addi-tional 4.5% reduction with each doubling of rosuvas-tatin dose. Approximately 64% and 90% of the LDLcholesterol reduction occurred during the first andsecond weeks of treatment, respectively, across therosuvastatin dose range.Rosuvastatin also produced significant beneficialeffects with respect to other lipid measures (Table 1).Significant, dose-dependent reductions over placebowere observed at all rosuvastatin dose levels for totalcholesterol and apo B (p   0.001; see Figure 1B).Increases in HDL cholesterol and reductions in tri-glycerides were observed at all rosuvastatin dose lev-els. Significant reductions, compared with placebo,were also observed at all rosuvastatin dose levels forall lipid ratios (p  0.001) (Table 2; data are not shownfor total cholesterol:HDL cholesterol and LDL cho-lesterol:HDL cholesterol ratios).The occurrence of adverse events was similar be-tween placebo and active treatments, with no increasein occurrence of adverse events observed with anincreasing rosuvastatin dose. The most common ad-verse events considered to be related to study treat-ment in the rosuvastatin groups were nausea, diarrhea,dry mouth, and abdominal pain (Table 3). Adverseevents leading to treatment withdrawal occurred in 4patients: 1 patient who received placebo, 1 rosuvasta-tin-treated patient (20-mg group), and 2 atorvastatin-treated patients (1 each in the 10- and 80-mg groups).The rosuvastatin-treated patient withdrew because of abdominal pain and nausea considered by the investi-gator to be related to study treatment, and the 2atorvastatin-treated patients withdrew because of pru-ritus and constipation, respectively, that were consid-ered by the investigator to be related to study treat-ment. Serious adverse events occurred in 3 rosuvas-tatin-treated patients during study treatment (1 patientin the 5-mg group and 2 patients in the 80-mg group);none of these events (sepsis, angina and myocardialinfarction, and gastrointestinal neoplasia, respec-tively) was considered by the investigator to be relatedto study treatment. No clinically significant elevationsin ALT, aspartate aminotransferase, or creatine kinasewere observed during treatment in any patient. Myal-gia was reported in 7 patients overall (1 placebo, 4rosuvastatin-treated, and 2 atorvastatin-treated pa-tients). No cases of myopathy were reported. DISCUSSION The current dose-ranging program showed that ro-suvastatin produced clinically and statistically signif-icant dose-dependent reductions in LDL cholesterol TABLE 3  Occurrence of Drug-Related Adverse Events Reported in Two or More Rosuvastatin-Treated Patients During RandomizedTreatment Period by Body System and Treatment Group Double-Blind Placebo Double-Blind RosuvastatinOpen-LabelAtorvastatin*Dose (mg/d) 0 1 2.5 5 10 20 40 80 10 80n 31 15 15 18 17 17 34 31 15 13Whole body, n (%)Abdominal pain 1 (3.2) 0 0 0 0 1 (5.9) 2 (5.9) 2 (6.5) 0 0Headache 0 0 3 (20.0) 0 1 (5.9) 0 1 (2.9) 0 1 (6.7) 1 (7.7)Gastrointestinal, n (%)Nausea 1 (3.2) 1 (6.7) 1 (6.7) 0 2 (11.8) 1 (5.9) 1 (2.9) 1 (3.2) 0 0Diarrhea 1 (3.2) 0 1 (6.7) 1 (5.6) 1 (5.9) 1 (5.9) 2 (5.9) 0 0 2 (15.4)Dry mouth 2 (6.5) 0 0 0 1 (5.9) 0 2 (5.9) 1 (3.2) 0 0Constipation 0 1 (6.7) 0 0 0 1 (5.9) 0 1 (3.2) 2 (13.3) 2 (15.4)Flatulence 0 0 0 0 1 (5.9) 0 2 (5.9) 0 0 3 (23.1)Musculoskeletal, n (%)Myalgia 1 (3.2) 0 0 1 (5.6) 0 1 (5.9) 1 (2.9) 1 (3.2) 1 (6.7) 1 (7.7) *No statistical comparisons were made between double-blind placebo or rosuvastatin and open-label atorvastatin. PREVENTIVE CARDIOLOGY/REDUCTION IN LDL CHOLESTEROL WITH  ROSUVASTATIN   507  across a dose range of 1 to 80 mg/day and was welltolerated in hyperlipidemic patients over a 6-week treatment period. The onset of effect appeared to oc-cur rapidly. Indeed, the reduction in LDL cholesterolachieved with rosuvastatin 80 mg—65%—is greaterthan that reported for any other statin when used asmonotherapy in patients with primary hypercholester-olemia. 4,7,8,10 This agent’s clinically and statisticallysignificant effects in reducing apo B and improvingthe apo B:apo A-I ratio are also notable, particularly inlight of recent findings that this ratio is an accuratepredictor of risk for coronary heart disease duringtherapy for hypercholesterolemia. 11,12 The benefits of rosuvastatin with respect to otherlipid parameters included consistent elevation of HDLcholesterol (9% to 14%) and reduction of triglycerides(–10% to –35%). Given the baseline lipid criteria forthe study patients (i.e., mild to moderate increases inLDL cholesterol, relatively normal triglycerides, anyHDL cholesterol level), dose-related or maximal re-sponses would not be expected for HDL cholesterol ortriglycerides. However, the ability of rosuvastatin toincrease HDL cholesterol across the dose range maybe of potential interest, as some evidence suggests thatsmall increases in HDL cholesterol caused by non-statin agents result in tangible decreases in morbidityand mortality. 13,14 The reductions in triglycerides ob-served across the rosuvastatin dose range are consis-tent with those observed for other available sta-tins. 7,8,10 In addition, the sizable reductions in LDLcholesterol and total cholesterol and the improvementsin HDL cholesterol also resulted in beneficial changesin related lipid ratios.No difference in occurrence of adverse events wasobserved between rosuvastatin at doses up to 80 mgand either placebo or atorvastatin. Few patients dis-continued treatment as a result of adverse events andfew serious adverse events were reported. Hepatotox-icity indicated by increased liver enzymes and myop-athy associated with elevated creatine kinase levelsare relatively infrequent but there are serious effects of statin therapy that appear to be more common athigher statin doses. 7,8 In the current dose-ranging pro-gram, no clinically significant elevations in ALT, as-partate aminotransferase, or creatine kinase were ob-served in any patient.The results of this dose-ranging program indicatethat rosuvastatin exhibits an LDL cholesterol-lower-ing effect of a magnitude that may help patients whorequire lipid-lowering therapy to meet recommendedtarget LDL cholesterol levels. 15,16  Acknowledgment:  We wish to thank GretchenSchmelz, Gregg Truitt, Marlies Winter, and OliverYeh for their assistance in the preparation of thismanuscript.  APPENDIX  In addition to the investigators, the following investigators participated inthese studies: Leiv Ose, Rikshospitalet, Oslo, Norway; Heloe Istad, TheresegateLegesenter, Oslo, Norway; Arne Svilaas, Almenmedisin kostholdesveiledning,Kongsberg, Norway; Elisabeth T.L. Durlinger, Octomed Foundation, Leiden, TheNetherlands; Nicole P.M.W. Thewissen, PreCare Geleen, Geleen, The Nether-lands; Wilko P. Haanstra, Scheperzickenhuis, Emmen, The Netherlands; Olavi J.Luurila, La¨a¨ka¨riasema Koe Oy, Helsinki, Finland; Jaakko Tuomilehto, Kan-santerveyslaitos, Diabetesyksikko and Hakaniemen Poliklinikka Oy, Helsinki,Finland; Mats Eriksson, Huddinge sjukhus, Huddinge, Sweden; Hans Lithell,Geriatriska kliniken, Samariterhemmets sjukhus, Uppsala, Sweden; Bengt R.Widgren, Medicinkliniken, Sahlgrenska sjukhuset, Go¨teborg, Sweden; and HansOlov Victor Wiklund, Sahlgrenska Universitetssjukhuset, Go¨teborg, Sweden. 1.  Smith G, Davidson R, Bloor S, Burns K, Calnan C, McAulay P, Torr N, WardW, McTaggart F. Pharmacological properties of ZD4522—A new HMG-CoAreductase inhibitor (abstr).  Atherosclerosis  2000;151:39. 2.  Buckett L, Ballard P, Davidson R, Dunkley C, Martin L, Stafford J, McTaggartF. Selectivity of ZD4522 for inhibition of cholesterol synthesis in hepatic versusnon-hepatic cells (abstr).  Atherosclerosis  2000;151:41. 3.  Jones P, Kafonek S, Laurora I, Hunninghake D. Comparative dose efficacystudy of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin inpatients with hypercholesterolemia.  Am J Cardiol  1998;81:582–587. 4.  Nawrocki JW, Weiss SR, Davidson MH, Sprecher DL, Schwartz SL, LupienPJ, Jones PH, Haber HE, Black DM. Reduction of LDL cholesterol by 25% to60% in patients with primary hypercholesterolemia by atorvastatin, a new HMG-CoA reductase inhibitor.  Arterioscler Thromb Vasc Biol  1995;15:678–682. 5.  Remmell PS, Gorder DD, Hall Y, Tillotson JL. Assessing dietary adherence inthe Multiple Risk Factor Intervention Trial (MRFIT). I. Use of a dietary moni-toring tool.  J Am Diet Assoc  1980;76:351–356. 6.  Remmell PS, Benfari RC. Assessing dietary adherence in the Multiple Risk Factor Intervention Trial (MRFIT). II. 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