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Lipid-Modifying Effects of Rosuvastatin in Postmenopausal Women With Hypercholesterolemia Who Are Receiving Hormone Replacement Therapy*

Posted on: Saturday, 18 December 2004, 03:00 CST

Key words: Blood lipids - Hormone replacement therapy - Hypercholesterolemia - Postmenopausal women - Rosuvastatin

SUMMARY

Objective: To evaluate the efficacy and safety of rosuvastatin in postmenopausal women with hypercholesterolemia who are receiving hormone replacement therapy (HRT) in a randomized, double-blind, placebo-controlled trial.

Methods: After a 6-week dietary lead-in period, 135 postmenopausal women who had been taking a stable HRT regimen for at least 3 months were randomized to receive rosuvastatin 5 mg, 10 mg or placebo for 12 weeks. Fasting levels of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG) were assessed at weeks 0, 2, 6,10, and 12; apolipoprotein (Apo) B and Apo A-I were measured at weeks 0 and 12.

Results: Rosuvastatin 5 mg and 10 mg significantly reduced LDL-C by 38% (SE = 2.1) and 49% (SE = 2.1), respectively, compared with placebo (1% [SE = 2.1]; p < 0.001). TC, TG, Apo B, and all lipid ratios examined (LDL-C/HDL-C, TC/HDL-C, non-HDL-C/HDL-C, and Apo B/ Apo A-I) were also reduced significantly by both rosuvastatin doses (p < 0.001). HDL-C levels increased significantly in the rosuvastatin groups (11 % and 8% for 5 mg and 10 mg, respectively, vs. -0.5% for placebo; p < 0.001), as did Apo A-I levels (p < 0.05). The combination of rosuvastatin plus HRT was well tolerated with no apparent differences among treatments in the numbers or types of adverse events reported.

Conclusions: Rosuvastatin 5 mg or 10 mg once daily is a well- tolerated and highly efficacious lipid-lowering therapy in postmenopausal women receiving HRT.

Introduction

The changes that occur with menopause include alterations in the blood lipid profile, such as increases in total cholesterol, low- density lipoprotein cholesterol (LDL-C), and triglycerides and decreases in high-density lipoprotein cholesterol (HDL-C)1,2. These lipid changes may increase the risk of cardiovascular disease. The estrogen in hormone replacement therapy (HRT) decreases LDL-C and may increase HDL-C3. However, oral estrogen can also further increase triglyceride levels, and the addition of some forms of progesterone may unfavorably modify the beneficial effects of estrogen on HDL-C3.

Previously, considerable evidence (mostly observational) had supported the benefits of HRT for reducing cardiovascular disease risk. Recently, large-scale, placebocontrolled trials have shown that conjugated estrogens plus medroxyprogesterone acetate do not reduce coronary heart disease events in postmenopausal women with or without established coronary disease4-6. Although HRT is no longer recommended to reduce cardiovascular risk7, many women still receive HRT, however, to reduce symptoms associated with the onset of menopause. Further analysis of the Heart and Estrogen/progestin Replacement Study (HERS) showed that statin (HMG-CoA reductase inhibitor) users had significantly lower risks of myocardial infarction and death due to coronary heart disease or any cause than nonusers8. Furthermore, the significantly increased risk of coronary heart disease observed during the first year of HRT was decreased in women who used statins. Also, large outcome trials have shown significantly reduced risks of cardiovascular disease in women treated with statins9,10. In comparative studies, statins (pravastatin and simvastatin) have been shown to be more effective than HRT in reducing LDL-C, and whereas HRT increases triglycerides, statin therapy decreases this liquid fraction11-15.

Rosuvastatin has been shown to be efficacious in reducing LDL-C and triglycerides and increasing HDL-C in many patient groups with hypercholesterolemia, including postmenopausal women16. However, no previous study with rosuvastatin has specifically enrolled women who were receiving stable HRT. The objective of this trial was to assess the lipid-modifying effects and safety of rosuvastatin in women with hypercholesterolemia who had been receiving HRT for at least 3 months.

Methods

Patients

Women who had their last spontaneous menstrual period at least 1 year before trial entry or who did not have a documented last spontaneous menstrual period but had used HRT for at least 2 years before trial entry were eligible to enroll in this trial. All patients had to have maintained a stable HRT regimen for at least 3 months before enrollment. Oral estrogen (estradiol, conjugated estrogens, or csterified estrogens) with or without progesterone and transdermal combination preparations were allowed.

Exclusion criteria included a history of serious or hypersensitive reactions to other statins, active arterial disease within 3 months of trial entry, a history of malignancy (except if disease free for > 10 years or if the only malignancy was a basal cell or squamous cell skin carcinoma), uncontrolled hypertension, a fasting serum glucose concentration of > 180 mg/dL (> 9.99 mmol/L) or hemoglobin A^sub lc^ > 9%, uncontrolled hypothyroidism, a history of heterozygous or homozygous familial hypercholesterolemia, use of concomitant medications known to affect the lipid profile or present a potential safety concern, a history of alcohol or drug abuse, active liver disease or hepatic dysfunction, serum creatine kinase (CK) > 3 times the upper limit of normal (ULN) during screening, or any serious or unstable medical or psychological condition that could affect the subject's safety or successful trial participation.

Trial Design

This randomized, double-blind, multicenter, parallel-group, placebo-controlled trial (4522IL/0032) was conducted in 31 academic and clinical research centers in the United Kingdom and the United States from November 1999 to January 2001. After discontinuation of all lipid-lowering medications and dietary supplements, patients were instructed to follow the National Cholesterol Education Program (NCEP) Step I diet. This instruction was reinforced throughout the trial. After 6 weeks, women who demonstrated dietary compliance by having an Eating Pattern Assessment Tool section 1 score of ≤ 28(17) and had fasting LDL-C levels ≥ 130mg/dL (≥ 3.4mmol/L) and < 250mg/dL (< 6.5 mmol/L) and triglyceride levels < 400 mg/dL (< 4.5 mmol/L) were eligible for randomization. The randomization scheme was predetermined, and patients were allocated to treatments in blinded balanced blocks at each center. These patients received oral doses of encapsulated rosuvastatin calcium (Crestort) 5 mg or 10mg or matching placebo once daily for 12 weeks.

This trial was designed and conducted in accordance with the Declaration of Helsinki and in compliance with the ethical principles of good clinical practice. Appropriate ethics committees or institutional review boards approved the trial, and all patients gave their written, informed consent before initiation of any trial procedure.

Table 1. Patient characteristics at randomization

Assessments

Plasma lipid levels were measured at randomization (baseline) and at 2, 6, 10, and 12 weeks after randomization. Apolipoprotein (Apo) B and Apo A-I levels were measured at baseline and at 12 weeks. Patients fasted for at least 12 hours before blood samples were taken. All blood samples for efficacy and safety assessments were analyzed in a certified central laboratory (MRL International, Belgium, for European sites and MRL International, Kentucky, for US sites), which maintained Part III standardization as monitored by the Lipid Standardization Program of the Centers for Disease Control and Prevention and the National Heart, Lung, and Blood Institute. Each center used standardized procedures for sample collection and handling. The Friedewald equation was used to calculate LDL-C levels when triglyceride levels were < 400 mg/dL (≤ 4.5 mmol/L)18. When triglyceride levels were > 400 mg/dL (> 4.5 mmol/L), the β- quantification method was used to measure LDL-C10.

Safety evaluations included all patients who received at least one dose of trial medication. Safety was assessed by review of adverse event reports, clinical laboratory data, vital signs, physical examinations, and examination of electrocardiograms. Adverse events recorded by investigators in their own terms were categorized according to the US Food and Drug Administration Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART). Additional clinical chemistry monitoring was performed in patients who had an alanine aminotransferase (ALT) level > 3 ULN or a CK level > 10 χ ULN in two or more consecutive measurements.

Statistics

The primary end point was the percent change from baseline in LDL- C levels at week 12, and was analyzed using analysis of covariance (ANCOVA). First, rosuvastatin 10 mg was compared with placebo, and rosuvastatin 5 mg was compared with placebo if the difference between placebo and rosuvastatin 10 mg was significant (one-sided α = 0.025). Percent change in the secondary end points (other lipid and lipoprotein measurements) was analyzed statistically using an analysis of variance (ANOVA). Statistical analyses included all patients who had a baseline and at least one postbaseline measurement, and the last observation was carried forward if the 12- week value was missing. Safety data were su\mmarized descriptively.

Only a small number of patients (7 patients) were needed to provide at least an 80% power of detecting a 25% difference in change (with a 15% standard deviation) from baseline in LDL-C levels. However, more patients were recruited to acquire more safety data in this patient population.

Results

Patient Characteristics

A total of 689 women entered the dietary lead-in period. Of these, 135 were randomized to treatment (Table 1). The 554 patients who were not randomized into treatment were screen failures (did not meet essential randomization criteria, i.e., had LDL-C or triglyceride values that excluded them from randomization or were not compliant with the NCEP Step I diet) or did not return for follow-up or were withdrawn during the dietary lead-in period. Patient characteristics were similar among treatment groups. According to concomitant medication data, approximately 38% of these women were taking HRT products containing a combination of estrogen and progesterone. Eleven women withdrew from the trial during the randomized treatment period because of adverse events (3 in the placebo group, 7 in the rosuvastatin 5 mg group, and 1 in the rosuvastatin 10mg group).

Table 2. Effect of rosuvastatin 5 mg and 10 mg on plasma lipid and apolipoprotein levels in postmenopausal women with hypercholesterolemia receiving HRT

Effect of Treatment on Lipids

At baseline, mean lipid values were similar among treatment groups (Table 2). After 12 weeks, both rosuvastatin doses reduced LDL-C levels significantly more than placebo (p < 0.001) (Table 7). LDL-C reductions from baseline were 1%, 38%, and 49%, respectively, for the placebo, rosuvastatin 5 mg, and rosuvastatin 10mg groups. Between rosuvastatin 5 mg and placebo, the difference in LDL-C reduction was 36.4% (95% confidence interval = 30.9, 41.9), and between rosuvastatin 10mg and placebo, it was 48.1% (95% confidence interval = 42.6, 53.5). In addition, total cholesterol, triglycerides, and Apo B levels and all lipid ratios were also significantly reduced (p < 0.001), and HDL-C (p < 0.001) and Apo A- I levels (p < 0.05) were significantly increased compared with placebo (Tables 2 and 3). Most of the changes in LDL-C and HDL-C were observed by week 2 and were maintained throughout the 12-week treatment period (Figures IA and 1B). Changes in total cholesterol and triglycerides generally showed a similar pattern over time (data not shown).

Table 3. Effect of rosuvastatin 5 mg and 10mg on lipid and apolipoprotein ratios in postmenopausal women with hypercholesterolemia receiving HRT

Safety

The types of adverse events and numbers of patients who had treatment-emergent adverse events were generally similar in all three groups (Table 4). The percentage of patients with adverse events considered by the investigator to be related to treatment was highest in the placebo group (30%) (14/46) and was 18% in both rosuvastatin groups (8 patients in each group). There were no apparent trends for higher numbers of adverse events in the rosuvastatin groups than in the placebo group. Nearly all of the adverse events were judged to be mild to moderate in intensity. One patient (in the rosuvastatin 10 mg group) suffered a serious adverse event, which was diagnosed as esophagitis and gastritis and considered by the investigator to be unrelated to treatment. Four patients reported myalgia (1 who received placebo, 1 who received rosuvastatin 5 mg, and 2 who received rosuvastatin 10 mg). Symptoms resolved in 3 of the 4 patients while they were still receiving trial treatment. Only 1 patient, who was in the rosuvastatin 10 mg group, still had mild symptoms at the end of the trial, and these symptoms were considered by the investigator to be unrelated to trial treatment. There were no clinically significant elevations in ALT, aspartate aminotransferase (AST), or CK, and no clinically relevant differences among treatment groups were observed in any other biochemical or hmatologie measurements. There was little change in body weight from baseline, and no difference among the three groups.

Discussion

The results of this trial show that rosuvastatin significantly improves the lipid profile and is well tolerated in women receiving HRT who have elevated LDL-C levels. The LDL-C reduction of 49% from baseline observed in the group receiving rosuvastatin 10mg is similar to the 51% reduction with rosuvastatin 10 mg observed previously in pooled data from 267 postmenopausal women16 and the 50% reduction with rosuvastatin 10mg observed in pooled data in all women (n - 303)16.

In previous trials that have compared the combination of a statin (pravastatin or simvastatin) and HRT with HRT or a statin alone in postmenopausal women, the LDL-C reduction with the combination therapy was greater than that with HRT alone and was either similar to11,19 or somewhat greater than13-15,21 that with a statin alone. The LDL-C reduction shown with rosuvastatin 10mg plus HRT in this study was greater than LDL-C reductions shown in these other studies, which is consistent with the greater efficacy of rosuvastatin compared with these statins shown previously16.

In the 3-year Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial3, triglycerides increased approximately 20% to 25% above baseline in women who received unopposed estrogen or estrogen/ progestin regimens. The results of our trial and previous trials suggest that the unfavorable effects of estrogen on triglyceride levels can be reduced when a statin is added. In our trial, triglyceride levels decreased by 9% and 13% when rosuvastatin 10 mg or rosuvastatin 5 mg, respectively, was added to stable HRT, and increased in the group receiving HRT alone. The design of our trial did not allow for an assessment of the overall net effect of the treatments on triglycerides but suggested that the effect of estrogen was at least partially attenuated. In the trial conducted by Lemay et al.14, HRT and statins were sequentially added, and their results also indicated the opposing effects of HRT and a statin (pravastatin) on triglycerides. Crossover studies that compared HRT alone with HRT plus a statin showed that triglycerides increase less with the combination therapy than with HRT alone11,15 A limitation of our study was that there was no careful documentation of the type of HRT being taken by the women in the study.

Figure 1. Percentage change from baseline in (A) LDL-C levels and (B) HDL-C levels over time. LOCF = last observation carried forward

Table 4. Adverse events that occurred in ≥ 3 women in any treatment group

HDL-C and Apo A-I levels increase with either HRT or statin therapy11-15 by variable amounts. Of the treatments studied in the PEPI trial3, unopposed estrogen resulted in the highest increase in HDL-C. When pravastatin was added to HRT (oral estrogen combined with progesterone) or HRT was added to pravastatin, there appeared to be an additive effect14. The women in our trial had mean baseline HDL-C levels well above the level defined as low and associated with coronary heart disease risk (< 40mg/dL [< 1 mmol/L]) by the NCEP Adult Treatment Panel (ATP) III guidelines21. Nevertheless, rosuvastatin added to HRT significantly increased both HDL-C and Apo A-I compared with HRT alone. This increase in HDL-C resulted in group mean levels above the desirable 60mg/dL (1.6 mmol/L) level defined by the ATP III(21).

In conclusion, much research has shown the strong association between elevated LDL-C levels and cardiovascular disease risk, and recent results from large outcome trials support the use of statins in women, including those who receive HRT Our data show that the addition of the statin rosuvastatin to HRT in women with elevated LDL-C levels is well tolerated and has significantly favorable effects on plasma lipid and apolipoprotein levels.

Acknowledgments

This research was supported by AstraZeneca, Macclesfield, Cheshire, UK. We gratefully acknowledge the investigators (see below), their co-investigators and study coordinators, and the patients who participated in this trial. In addition, we wish to thank Eric Justice, BioScience Communications, and Erem Latif and Donna Curtis, AstraZeneca LP, for their assistance in the preparation of this manuscript.

In addition to the authors of this publication, the following investigators participated in this trial.

In the United States: Eli M. Roth, M.D., Cincinnati, Ohio; Phillip D. Toth, M.D., Indianapolis, Indiana; Barbara K. Zedler, M.D., Richmond, Virginia.

In the United Kingdom: Alistair S. Boyd, M.B., Ch.B., Dumbarton; David Blair, M.B., Ch.B., Gourock; Andrew N. Broughton, M.B., B.Chir., Dip. Pharm. Med., Cambridge; Anne Duddy, M.B., Ch.B., Motherwell; Valerie E. Dudgeon, M.B., Ch.B., Glasgow; Elizabeth Duncan, M.B., Ch.B., Bellshill; Lorna Dunlop, M.B., Ch.B., Johnstone; Timothy D. Dunlop, M.B., Ch.B., Linwood; Gordon J. Forrest, M.B., Ch.B., Johnstone and Linwood; Fiona Jarvie, M.B., Ch.B., Airdrie; Alistair S. MacCormick, M.B., Ch.B., East Kilbride; Duncan C. Maclnnes, M.B., Ch.B., Newarthill; Jean G. Masterton, M.B., Ch.B., Bishopton; Margot McLauchlin, M.B., Ch.B., Chapelhall; Ian S. McLellan, M.B., Ch.B., Kilmacolm; Amar N. Mishra, M.B.B.S., Motherwell; Margaret Mitchell, M.B., Ch.B., Johnstone; Gerard A. Murphy, M.B., Ch.B., Bothwell and Uddingston; Susan Murray, M.B., Ch.B., Wishaw; Alison E. Ramage, M.B., Ch.B., Renfrew; Anne Robertson, M.B.B.S., Barrhead; Brian Robson, M.B., Ch.B., Paisley; Brian Shapiro, M.B., Ch.B., Renfrew; Donald B. Winton, M.B., Ch.B., Paisley.

* Information in this manuscript was presented at the 73rd Congress of the European Atherosclerosis Society, Salzburg, Austria, 7-10 July 2002.

[dagger] Crestor is a trade name of AstraZeneca, Macclesfield, UK; licenced from Shionogi & Co., Ltd., Osaka, Japan

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21. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. 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) final report. Circulation 2002;106:3143-421

CrossRcf links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-2706, Accepted for publication: 05 August 2004

Published Online: 24 August 2004

doi:10.1185/030079904X4167

James Shepherd1, Chris Packard1, Thomas W. Littlejohn III2, James Walker3, Evan A. Stein4,5, Karen Smith6, David Kallend6 and James W. Blasetto7

1 Glasgow Royal Infirmary, Glasgow, Scotland, UK

2 Piedmont Medical Research Associates, Winston-Salem, NC, USA

3 Coastal Clinical Research, Mobile, AL, USA

4 Metabolic Atherosclerosis Research Center, Cincinnati, OH, USA

5 Medical Research Laboratories International, Highland Heights, KY, USA

6 AstraZeneca, Macclesfield, Cheshire, UK

7 AstraZeneca, LP, Wilmington, DE, USA

Address for correspondence: Professor James Shepherd, Department of Pathological Biochemistry, Glasgow Royal Infirmary, 84 Castle Street, Glasgow, G4 OSF, Scotland, UK. Tel.: +44-141-211-4628; Fax: +44-141-553-1703; email: jshepherd@gri-biochem.org.uk

Copyright Librapharm Oct 2004

Source: Current Medical Research and Opinion

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