Randomized, controlled study of the effects of raloxifene on high sensitivity C-reactive protein and serum lipids

G E N E R A L G Y N E C O L O G Y

Randomized, controlled study of the effects of raloxifene

on high sensitivity C-reactive protein and serum lipids

Received: 3 October 2009 / Accepted: 10 November 2009 / Published online: 11 December 2009 Ó Springer-Verlag 2009

Abstract

Objective To investigate the effects of raloxifene, on serum lipids and high-sensitivity C-reactive protein (hs-CRP) in healthy postmenopausal women.

Methods We studied the effect of raloxifene, on serum lipids and hs-CRP in 85 healthy postmenopausal women. Participants were randomly assigned to 60 mg daily raloxifene (43 subjects) for 6 months; the rest of the sub-jects were in the control group. Serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, triglyceride and hs-CRP levels were measured at baseline and at the sixth month in both groups.

Results Raloxifene treatment resulted in a 26% reduction in serum hs-CRP concentrations at the sixth month, com-pared with the baseline levels (P \ 0.05). At the sixth month, TC and LDL-C levels were significantly reduced by 60 mg daily raloxifene (6.8 and 5.6%, respectively) when compared with both the baseline levels and the control group.

Conclusion The results of our study showed that raloxifene at a dose of 60 mg daily reduces serum TC, LDL-C and hs-CRP levels significantly in healthy

postmenopausal women. According to the results of the current study, we suggest that raloxifene may have a favorable effect on the prevention of cardiovascular disease in healthy postmenopausal women.

Keywords Menopause
Raloxifene
Lipids
C-reactive protein

Introduction

Cardiovascular disease (CVD) is the most common cause of death in post-menopausal women and the risk of coronary artery disease (CAD) is increased evidently in women above the age of 50. The factor that this group of age is around the onset of menopause, it let the researchers to think, whether it might be related to endogen estrogen deficiency and hormone replacement therapy (HRT) could have favorable effects on cardioprotection [1, 2]. How-ever, today, the evidence for the efficacy of HRT for the prevention of CAD in postmenopausal period has been called into question due to the negative results of the randomized, placebo controlled, prospective studies [3–7]. These results with HRT let the clinical researchers to alternative therapy modalities, that could be recom-mended for long-term use and also have the opportunities to prevent both bone loss and CVD in postmenopausal women.

Atherosclerosis is the main etiological factor in CVD and systemic inflammation is thought to play a key role in pathogenesis [8–10]. Dyslipidemia is one of the established risk factors for CVD. Also in the past decade, it was reported that high-sensitivity C-reactive protein (hs-CRP), one of the inflammatory biomarkers, is a strong, indepen-dent predictor of atherosclerotic diseases, including E. Oztas

Department of Obstetrics and Gynecology,

Faculty of Medicine, Ufuk University, Ankara, Turkey G. Kurtay

Department of Obstetrics and Gynecology, Faculty of Medicine, Ankara University, Ankara, Turkey

E. Oztas (&)

YeniAnkara Sokak 7/7 Cebeci, 06590 Ankara, Turkey e-mail: [email protected]

myocardial infarction, ischemic stroke, and sudden cardiac death [11–14]. Recently, Cook et al. [15] suggested that the relative impact of hs-CRP on the prediction of CVD, is at least important as LDL-C, HDL-C, blood pressure, and smoking, respectively.

Raloxifene, a second-generation non-steroidal benzo-thiophene derivative classified as a selective estrogen receptor modulator (SERM), reproduces the beneficial effects of estrogens on the skeletal system, without neg-ative effects on breast and endometrium [16]. It is evi-dent that, raloxifene improves several CVD risk factors by; improving vascular endothelial function, lowering LDL-C, TC and serum lipoprotein levels without raising triglycerides (TG) and also lowering homocysteine, fibrinogen and pro-inflammatory cytokine levels [17,18]. The Multiple Outcomes of Raloxifene Evaluation (MORE) trial had investigated the effect of raloxifene on cardiovascular events as a secondary end point, and reported that raloxifene therapy for 4 years did not sig-nificantly affect the overall risk of cardiovascular events but did significantly reduce the cardiovascular events in women with increased risk for cardiovascular events [19]. But the investigators of MORE trial, pointed out that this favorable effect of raloxifene in high-risk women could not be explained by the improvement in serum lipid concentrations, just because this improvement of serum lipids in the high-risk group were comparable to those observed for the total cohort. Considering these data, we wondered if the cardioprotective effect of raloxifene could be based on the improvement of another CVD risk factor, namely hs-CRP. There is limited and conflicting data evaluating the effects of raloxifene on serum hs-CRP levels [20, 21].

The aim of the current clinical study was to evaluate the effects of raloxifene on serum lipids and hs-CRP levels, which are established risk factors of CVD, in postmeno-pausal healthy women.

Materials and methods

The procedures used in this study were in accordance with the guidelines of the Helsinki Declaration on human experimentation. The study was approved by Ethical Review Board of the University of Ankara. Before entering the study, the purpose of the study protocol was explained to the patients and their informed consent was obtained. Subjects and study design

This open label, single site, randomized prospective study was conducted at University of Ankara, School of Medi-cine. 85 postmenopausal women with an intact uterus

between 55 and 79 years of age were eligible to participate in the study. Potmenopausal status was confirmed by measurement of serum follicule-stimulating hormone levels, above 40 IU/l and serum estradiol levels, below 20 pg/ml. All participants had amenorrhea for at least 12 months. Body mass index was required to be between 18 and 31 kg/m2. Patients were excluded if they had any history of hypertension (including the patients with, higher than 120 mmHg for systolic and 80 mmHg for diastolic blood pressure), venous thromboembolism, cerebral or coronary events, any endocrinopathy including diabetes mellitus, impaired renal or liver function, breast cancer, or chronic inflammatory disease. Women treated with hypo-lipidemic drugs, systemic corticosteroids, non-steroidal antiinflammatory drugs, drugs affecting the bone turnover, hormone replacement therapy within 6 months of entry, were also excluded.

85 eligible subjects were randomly assigned to two groups: 43 subjects received 60 mg/day raloxifene HCl (study group) (Eli Lilly) and 42 subjects received no medications (control group). Randomization was per-formed using a computer-generated random number table. The follow-up period was 6 months. Subjects were advised not to alter their diets and not to use any kind of medication including analgesics. During the following period, it is formally assessed that, none of the patients started any kind of hormone or lipid-altering therapy.

Measurements

Sample collection and laboratory analysis: after 12-h fast-ing, venous blood sampling was performed at the baseline and at the sixth month. At baseline and at the sixth month, serum TC, high-density lipoprotein cholesterol (HDL-C) and TG levels were measured with enzymatic color test method. LDL-C was calculated by the Friedewald formula. Serum hs-CRP levels were measured by a nephelometric method using ‘‘Beckman Coulter Image Immunochemistry System’’. The sensitivity level of CRP kits was 0.002 mg/dl. Statistical methods

Evaluation of the data was performed using SPSS vs 11.5 (SPSS Inc., IL, USA). The results were expressed as means and medians. To determine whether any changes are present at the parameters at baseline and at the sixth month, paired t test was used when the parameters are homogen-ically distributed and Wilcoxon signed rank test was used when the parameters are nonhomogenically distributed. Comparisons between the raloxifene and the control group were performed using Mann–Whitney U test and Kruskall– Walls test as appropriate. A P \ 0.05 was considered to be statistically significant.

Results

Between September 2003 and January 2004, 85 women were found to be eligible and were randomly assigned into two groups (43–60 mg/day raloxifene, 42 to the control group). Among 85 women participated into the study, 75 (88%) completed the 6 month follow-up period (40 in raloxifene group and 35 in the control group). Subjects were between 55 and 79 years of age with a mean age of

57.66 ± 4.15. At baseline, there were no significant dif-ferences between the groups for age, duration of the post-menopausal period, family history of coronary heart disease, body mass index (BMI), endometrial thickness, serum TC, LDL-C, TG, HDL-C, and hs-CRP concentra-tions (Table1). At the end of the 6 months of the following period, endometrial thickness, BMI, serum TC, LDL-C, TG, HDL-C and hs-CRP levels were re-evaluated (Table2). Compared with the controls, the median hs-CRP

Table 1 Baseline

characteristics of the patients enrolled in the study

SD standard deviation, BMI body mass index, BMD bone mineral densitometry * No statistically significant difference with respect to baseline characteristics among the groups (P [ 0.05)

Characteristic* Raloxifene Control Total

Number (n) 40 35 75

Age

Mean ± SD 57.8 ± 4.3 57.4 ± 3.9 57.6 ± 4.1

Range 55–79 55–70 55–79

Postmenopausal period (year)

Mean ± SD 11.1 ± 4.9 9.9 ± 4.8 10.6 ± 4.9 Range 5–29 5–20 5–29 Family history of CVD (%) 22.5 26.7 24.3 BMI (kg/m2) Mean ± SD 27.3 ± 2.7 27.9 ± 2.3 27.5 ± 2.5 Range 20.4–30.8 23.8–30.8 20.4–30.8 BMD (T score) Mean ± SD -2.88 ± 0.40 -2.80 ± 0.33 -2.85 ± 0.38 Range -3.79/-2.50 -3.78/-2.50 -3.79/-2.50 Endometrial thickness (mm) Mean ± SD 2.87 ± 1.01 2.59 ± 1.11 2.75 ± 1.06 Median 2.95 2.55 2.76 Range 1.1–5.0 1.0–4.5 1.0–5.0 T-cholesterol (mg/dl) Mean ± SD 206.0 ± 29.5 197.7 ± 32.2 202.5 ± 30.7 Median 202 200.5 202 Range 136–268 148–279 136–279 LDL-cholesterol (mg/dl) Mean ± SD 122.3 ± 26.0 113.3 ± 24.8 118.4 ± 25.7 Median 121 114 121 Range 82–196 56–164 56–196 Triglyceride (mg/dl) Mean ± SD 162.6 ± 54.1 151.9 ± 44.8 158.0 ± 50.3 Median 153 143.5 150.5 Range 81–294 75–234 75–294 HDL-cholesterol (mg/dl) Mean ± SD 47.4 ± 10.3 49.2 ± 10.1 48.2 ± 10.2 Median 45.5 49.00 47.5 Range 24–72 27–70 24–72 hs-CRP (mg/L) Mean ± SD 3.6 ± 2.2 3.4 ± 3.2 3.52 ± 2.7 Median 3.18 2.70 3.0 Range 0.54–10.4 0.4–14.2 0.4–14.2

levels were significantly lower in the raloxifene group at the sixth month (median hs-CRP values were 2.22 and 3.65 mg/ l for raloxifene and control groups, respectively, P \ 0.05). All of the parameters were compared with the baseline levels at the sixth month, in both of the groups, respec-tively. Compared with the control group, raloxifene treat-ment for 6 months resulted in significant reductions in total and LDL-C but not significant alterations in TG and HDL-C levels with respect to the baseline [median values were for TC, 202 mg/dl at baseline and 192.5 mg/dl at sixth month (P \ 0.001), for LDL-C, 121 mg/dl at baseline and 113 mg/dl at 6th month P \ 0.05)]. However, the TG levels were decreased in the raloxifene group and this reduction was leaning toward to be significant (P = 0.05). Raloxifene treatment caused a significant reduction in median hs-CRP level compared with the baseline [median

hs-CRP values were 3.18 and 2.22 mg/L, at baseline and at the 6th month respectively (P \ 0.05)] (Table 3). On the other hand, no significant alterations observed in the con-trol group between the baseline and the final levels of the serum lipids and hs-CRP (Table 4).

Table5 shows the percentage changes of median lipid and hs-CRP values in the raloxifene and the control group at the end of the following period. Compared to control group, raloxifene significantly decreased serum TC level by 6.8% (P \ 0.001), LDL-C levels by 5.6% (P \ 0.05), TG levels by 3.2% (P \ 0.05) and hs-CRP levels by 26% (P \ 0.05). In addition, raloxifene significantly increased the serum HDL-C levels [2.2% (P \ 0.05)].

Discussion

The results of the current study showed that 60 mg daily raloxifene reduces serum concentrations of LDL-C (5.6%) and TC (6.8%) in healthy postmenopausal women. These results are in accordance with the previous reports [20, 22–28]. We evaluated the effect of raloxifene at the sixth month of the therapy. In three different studies reported previously, raloxifene has been shown to effect serum lipid levels at the third month of the therapy. Additionally, this effect has been improved to extend constantly until the fourth year of the therapy [22,26,28]. Previous studies evaluating the effects of raloxifene on serum lipid concentrations, have indicated that TG levels are unaffected by raloxifene treatment [27–29]. We Table 2 Comparison of the groups at the sixth month

Characteristic Raloxifene Control P value*

Number (n) 40 35 Endometrial thickness (mm) Mean ± SD 2.67 ± 0.93 2.46 ± 0.77 Median 2.7 2.4 Range 1.0–4.3 1.0–4.0 BMI (kg/m2) Mean ± SD 27.2 ± 2.65 27.8 ± 2.29 Range 20.2–30.4 24.4–31.3 T-cholesterol (mg/dl) Mean ± SD 189.8 ± 30.3 202.3 ± 37.1 Median 192.5 196.0 Range 124–248 142–291 LDL-cholesterol (mg/dl) Mean ± SD 115.6 ± 24.9 114.2 ± 26.0 Median 113 116.5 Range 71–181 52–162 Triglyceride (mg/dl) Mean ± SD 151.6 ± 46.5 160.6 ± 43.3 Median 144.5 155.5 Range 61–261 76–241 HDL-cholesterol (mg/dl) Mean ± SD 48.6 ± 9.9 46.4 ± 9.6 Median 48 46 Range 26–74 25–76 hs-CRP (mg/L) Mean ± SD 2.5 ± 1.4 4.4 ± 3.6 Median 2.22 3.90 <0.05 Range 0.50–7.1 0.8–14.9 SD standard deviation, BMI body mass index

* The change in serum hs-CRP values were statistically significant among the groups at the 6th month

Bold value indicate statistical significance (P \ 0.05)

Table 3 Comparison of the baseline and the sixth month values in raloxifene group

Baseline Sixth month P value* TC (mg/dl) Mean ± SD 206.0 ± 29.5 189.8 ± 30.3 Median 202 (136–268) 192.5 (124–248) <0.001 LDL-C (mg/dl) Mean ± SD 122.3 ± 26.0 115.6 ± 24.9 Median 121 (82–196) 113 (71–181) <0.05 Triglyceride (mg/dl) Mean ± SD 162.6 ± 54.1 151.6 ± 46.5 0.05 Median 153 (81–294) 144.5 (61–261) HDL-C (mg/dl) Mean ± SD 47.4 ± 10.3 48.6 ± 9.9 [0.05 Median 45.5 (24–72) 48 (26–74) hs-CRP (mg/L) Mean ± SD 3.6 ± 2.2 2.5 ± 1.4 Median 3.18 (0.54–10.4) 2.22 (0.50–7.1) <0.05 SD standard deviation

observed a 3.2% reduction in TG levels and this reduction was statistically significant when compared with the alteration in the control group (P \ 0.05). From baseline to the sixth month of raloxifene treatment, a 2.2% increase in the level of HDL-C was observed, a result similar with the results of the Raloxifene Use for The Hearth (RUTH) trial

[30], but this improvement was statistically significant when compared with the alteration in the control group (P \ 0.05).

Hs-CRP is an independent marker for the risk of CVD in men with [31] and without [32] CAD and in postmenopausal women without [33] clinically evident CAD. In the present study, postmenopausal women assigned to use raloxifene showed a decrease (26%) in serum hs-CRP levels after 6 months of the therapy, the result was statistically signifi-cant when compared with both the baseline levels and the control group. The hs-CRP data from the current study are contradictory with the previous prospective, randomized, placebo controlled studies of raloxifene [34,35] that found no or little effect on CRP in postmenopausal women. However, there are some other randomized, placebo-con-trolled studies suggesting that raloxifene lowers serum CRP levels by 2–6%, but this decrease has been shown to be not statistically significant [36,37]. Interestingly, according to the results of the randomized, open-label comparative study by Eilertsen et al. reported in 2008, which the effects of HRT, tibolone and raloxifene on inflammatory markers were compared, raloxifene caused a significant decrease in serum CRP levels [21]. In addition, the most important factor is that in the raloxifene group serum median hs-CRP level was 3.18 mg/l at the baseline and 2.22 mg/l at the end of the study. Based on data from the study of Ridker et al. reported in 2002, in which 27,939 initially healthy women partici-pated, the patients with a CRP level of 1–3 mg/l were established as average and[3 mg/l were as high risk for the first cardiovascular events [14]. When considering the results of Ridker et al. it is evident that, the study group in our study have been in the high risk group for CVD, con-sidering the CRP levels at the baseline (Median 3.18 mg/l) and became to be involved in the average risk group (median 2.22 mg/l) at the sixth month of the raloxifene treatment. In the study mentioned above, it is suggested that CRP was superior to LDL-c in predicting the risk of first CVD, and showed that the relative risk (RR) for the cardiovascular events was 1.0 when both the CRP and LDL-C levels were low. The results of the current study showed that raloxifene causes a significant reduction in both CRP and LDL-C levels, thus in consistent with the study of Ridker et al., we propose that raloxifene decreases the most important car-diovascular risk predictors. However, the results of two, randomized, prospective, controlled studies [23,30] seemed to be conflicting, since those suggested that raloxifene did not affect the risk of CVD. But when the secondary out-comes of MORE were evaluated, it is evident that raloxifene did significantly reduce the cardiovascular events in a subset of women with increased cardiovascular risk. But the results of RUTH trial did not support this hypothesis. In addition, when the results examined in detail it can be seen that the baseline characteristics of the groups in RUTH trial were not Table 4 Comparison of the baseline and the sixth month values of

the control group

Baseline Sixth month P value* TC (mg/dl) Mean ± SD 197.7 ± 32.2 202.3 ± 37.1 [0.05 Median 200.5 (148–279) 196.0 (142–291) LDL-C (mg/dl) Mean ± SD 113.3 ± 24.8 114.2 ± 26.0 [0.05 Median 114 (56–164) 116.5 (52–162) Triglyceride (mg/dl) Mean ± SD 151.9 ± 44.8 160.6 ± 43.3 [0.05 Median 143.5 (75–234) 155.5 (76–241) HDL-C (mg/dl) Mean ± SD 49.2 ± 10.1 46.4 ± 9.6 [0.05 Median 49.0 (27–70) 46 (25–76) hs-CRP (mg/L) Mean ± SD 3.4 ± 3.2 4.4 ± 3.6 [0.05 Median 2.7 (0.4–14.2) 3.9 (0.8–14.9) SD standard deviation

* When P \ 0.05 the result is statistically significant

Table 5 Comparison of the median baseline, the median change, and the median percent change values of the raloxifene and the control group Raloxifene group Control group P value* Median baseline TC (mg/dl) 202 200.5 Median change (mg/dl) -12.5 7.0 <0.001 Median % change -6.8 3.9 <0.001 Median baseline LDL-C (mg/dl) 121 114 Median change (mg/dl) -7.0 -2.0 [0.05 Median % change -5.6 -1.5 <0.05 Median baseline Triglyceride (mg/dl) 153 143.5

Median change (mg/dl) -4.0 4.5 <0.05 Median % change -3.2 3.1 <0.05 Median baseline HDL-C (mg/dl) 45.5 49.0 Median change (mg/dl) 1.0 -1.5 <0.05 Median % change 2.2 -3.5 <0.05 Median baseline CRP (mg/L) 3.18 2.70 Median change -0.83 0.41 <0.05 Median % change -26.0 33.2 <0.05 * Bold values indicate statistical significance (P \ 0.05)

similar since the raloxifene group had a higher cardiovas-cular risk score and patients with established CAD were also more than the ones in placebo group. In our study, the mean age of the participants were 57.66 while the ones in the MORE and RUTH trial were approximately 67, in other words already at increased risk for CVD. This may be another reason leading to different results.

In conclusion, according to our results we suggest that, raloxifene may have favorable effects on some of the cardiovascular disease risk factors. Unfortunately, the limitation of the current study is; not to be placebo con-trolled, double blind, multicenter trial. So, further ran-domized, placebo controlled, multicenter studies are required to determine the effects of raloxifene on serum CRP levels and to comment whether these effects induced by raloxifene, influence cardiovascular outcomes in post-menopausal women without existing CVD.

Conflict of interest statement The authors have no conflict of interest.

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