Influence of a New Oral Contraceptive With Drospirenone on Lipid Metabolism

By Taneepanichskul, Surasak Phupong, Vorapong

Abstract The present study aimed to evaluate the effect of an oral contraception formulation with drospirenone (Yasmin(R)) on lipid metabolism. An open-label, non-comparative clinical trial was conducted. One hundred women, who desired oral contraception for at least 6 months, were recruited. The subjects received a blister pack which contained 21 tablets of 3 mg drospirenone/30 [mu]g ethinyl estradiol for the first four cycles (1 cycle = 28 days). Cycle 5 and 6 blister packs were dispensed during the next visit in cycle 4. Serum from each subject was collected and analyzed for lipid profile levels at baseline and at cycle 6. The mean differences in lipid profile levels at cycle 6 compared with baseline were assessed. Of the total 100 subjects, 92 (92%) completed the study. There was no significant change in total cholesterol. At cycle 6, high-density lipoprotein cholesterol (HDL-C) and triglycerides increased significantly by 25.7% and 42.0%, respectively, compared with baseline. However, low-density lipoprotein cholesterol (LDL-C) decreased significantly by 9.9% at cycle 6 compared with baseline. Our results show that the new oral contraception formulation with drospirenone (Yasmin) is well tolerated and has good contraceptive efficacy. The observed favorable changes in HDL-C and LDL-C suggest a potential cardioprotective benefit.

Keywords: Oral contraception, drospirenone, lipid metabolism, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol

Introduction

Combined oral contraceptives (COCs) have now been in use for more than 40 years and have proved to be a highly efficacious and safe. However, their hormonal components – estrogens (usually ethinyl estradiol, EE) and progestogens – are known to have various metabolic effects. These include effects on lipid and carbohydrate metabolism and hemostasis. The effect on lipid metabolism may represent a risk for cardiovascular disease. Although the specific contributions of the estrogen and the progestogen to the metabolic effects of COCs are not fully understood, it is evident that the dose of EE and the dose and type of the progestogen, particularly when displaying androgenic properties, affect the metabolic influence of COCs [1] . It is well known that androgenic progestins exert an adverse influence on lipid metabolism. This is due, in part, to their ability to counteract the favorable estrogen-induced changes in levels of low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) [2-4] .

Recent reviews have suggested that the ideal pharmacological properties of a synthetic progestin should resemble those of progesterone as closely as possible, while reducing or eliminating the undesirable (mainly androgenic and mineralocorticoid) effects [5,6]. Most currently available progestins are 19-nortestosterone derivatives and as such have inherent androgenic potential. Furthermore, of these progestins, none is able to counteract the mineralocorticoid activity of the estrogen component. In contrast, drospirenone (DSRP), a novel progestogen, has proven antiandrogenic properties and, as an analog of spironolactone, inherent antimineralocorticoid activity [5-7] .

The combination of 3 mg DRSP with 30 [mu]g EE (Yasmin(R)) is characterized by high contraceptive efficacy in combination with excellent cycle control and a low incidence of adverse effects [6,8] . Previous studies have provided evidence of the favorable metabolic effects of this preparation [8-10]. However, more information is needed in order to appreciate its metabolic impact. Thus, the objective of the present study was to evaluate the effects of the combination of 3 mg DSRP and 30 [mu]g EE in an oral contraceptive (OC) (Yasmin) on lipid metabolism.

Methods

This study was conducted at the Family Planning Clinic, Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. Women who were planning to use contraception were enrolled into the study. The inclusion criteria were as follows: (1) age 18-35 years at the time of entry into the study; (2) regular menstrual cycles (25-34 days); (3) no past use of injectable or implant hormonal contraceptives or OCs within 6 months of the study; and (4) willing not to use any other form of hormonal treatment, including other hormonal contraception, for the duration of the study. The exclusion criteria were as follows: (1) pregnancy; (2) breastfeeding; (3) contraindications under World Health Organization categories 2, 3 and 4 [1 1]; and (4) hypersensitivity to the active substances or any of the excipients of Yasmin.

This study was approved by the Ethics Committee of the Faculty of Medicine, Chulalongkorn University. Eligible subjects were required to sign an informed consent form before enrolling in the study. They received a blister pack, which contained 21 tablets of 3 mg DRSP/30 [mu]g EE for the first four cycles (1 cycle = 28 days). They were instructed to take one tablet per day for 21 days followed by a 7- day tablet-free interval. The recommended dosing interval was not longer than 24 h. Compliance was assessed by pill count from the blister packs. Cycle 5 and 6 blister packs were dispensed during the next visit in cycle 4.

Blood samples were taken from each subject to assess lipid parameters at baseline and during the visit in cycle 6, with patients in a fasting state before study drug administration. Analysis of the blood samples was performed at the central laboratory.

The primary measured outcome was change in serum HDL-C levels from baseline to cycle 6. Other measured outcomes were the changes in total cholesterol, LDL-C and triglyceride levels from baseline to cycle 6.

Table I. Lipid profile at baseline and after six cycles of Yasmin” use.

All data were collected, coded and analyzed using SPSS version 12.0 software (SPSS Inc., Chicago, IL, USA). Descriptive statistics (mean, standard deviation (SD), percentage) were used to analyze the data. The Student t test was used to test the differences in mean lipid profile change from baseline to cycle 6. Statistical significance was considered at p values < 0.05.

Results

A total of 100 subjects were recruited, screened and enrolled. All subjects were included in the intention-to-treat analysis. Of these 100 subjects, 92 (92%) completed the study. Of the three subjects who prematurely discontinued before visit 2, two moved their residence and one decided to become pregnant. For the rest of the subjects who did not follow up on visit 3, two subjects moved their residence and three developed adverse events. Adverse events included amenorrhea, cranial nerve VII neuritis and nausea.

The mean ( +- SD) age of the subjects was 27.4 + 4.2 years (range, 19-35 years). The mean ( + SD) weight of subjects was 53.3 +- 7.4 kg (range, 39.5-76.0 kg). Baseline vital signs were all normal. No pregnancies occurred during the study.

Changes in lipid profile levels from baseline to cycle 6 are presented in Table I. HDL-C and triglycerides increased significantly from baseline to cycle 6. LDL-C decreased significantly from baseline to cycle 6.

A total of 29 adverse effects were observed in 18 of 92 subjects, of whom 18.6% (18 of 92) experienced at least one adverse effect during the course of the study. The most common adverse effect reported during the study was nausea, which was reported by four (4.3%) subjects (eight events), followed by irregular bleeding which was reported by three (3.3%) subjects (five events). All reported adverse effects were either of mild (55.2%) or moderate intensity (44.8%). Three subjects discontinued the study prematurely due to adverse effects. They included amenorrhea, nausea and neuritis (cranial nerve VII). No serious adverse effect was reported during the study. Of the 29 reported adverse effects, eight adverse effects were not or unlikely to be related to the study treatment, and 21 adverse effects were probably related to the study treatment.

Discussion

In this study, we investigated the influence of 3 mg DRSP/30 [mu]g EE oral contraception (Yasmin) on lipid profile during 6 cycles of use. Yasmin contains progestogen DRSP, a 17alpha- spirolactone derivative with a unique pharmacological profile that combines potent progestogenic with antiandrogenic and antimineralocorticoid activity. Yasmin significantly increased HDL- C and triglycerides, but decreased LDL-C at cycle 6 compared with baseline.

Alterations in serum lipids during COC intake depend on EE and progestogen doses and on the (anti-)androgenic activity of progestogen. Both constituents have counteracting effects on serum lipids. Progestogens with androgenic activity can shift lipid and lipoprotein metabolism in a potentially unfavorable way [12,13]. Therefore, progestogens with low androgenicity like desogestrel (DSG), or even antiandrogenic properties like DRSP, have been developed to reduce the impact on lipids when used for hormonal contraception [10].

The increase in HDL-C and decrease in LDL-C observed in this study are due to the favorable effects of estrogen. In this study HDL-C rose by 25.7%; this is similar to previous studies (9-17.2%) [8-10,14]. HDL-C may exert positive effects not only on the reverse transport of cholesterol, but also on endothelial function (vasomotion) by inhibiting LDL oxidation (and thus uptake by macrophages), controlling expression of vascular cell adhesion molecule- 1 and by regulating thromboxane and prostacyclin metabolism [12,13]. Since prospective studies have shown that women with high HDL-C levels are less likely to develop cardiovascular disease than those with medium or low levels [15], users of this OC might have a small benefit or a least no clinical disadvantage. LDL- C fell by 9.9% in the present study; again this is similar to earlier reports (15-18%) [9,14], although LDL-C levels were stable in two previous studies [8,10]. This stability or fall in LDL-C is most probably due to the missing androgenic activity of DRSP [10]. Studies with other contraceptives have also shown similar increases in HDL-C and reductions in LDL-C [16-18]. These changes in lipid metabolism appear to reflect a predominance of the effect of the estrogen component [18].

Klipping and colleagues found a greater increase in HDL-C (16% vs. 11%) and a greater decrease in LDL-C (-18% vs. -10%) with EE 20 [mu]g/DRSP 3 mg treatment. This may reflect the lack of androgenic activity with DRSP compared with DSG [14]. In our study, however, the HDL-C/LDL-C ratio increased during DRSP intake by 37.2% as a result of the increased HDL-C and decreased LDL-C level; a pattern that is usually considered beneficial with respect to cardiovascular disease risk reduction.

We found that total cholesterol levels did not change but there was an increase in the levels of triglycerides (+42.0%). A similar rise in triglyceride levels was observed in previous studies (18.1- 78%) [8-10,14]. This rise in triglycerides has also been observed with contraceptives containing EE combined with gestodene or norgestimate (24-100% increase) [16-18]. However, previous studies suggest that an EE-induced rise in triglyceride levels does not appear to increase atherosclerotic risk if LDL-C levels are not increased and HDL-C levels remain high [19].

In conclusion, the new oral contraception formulation with drospirenone (Yasmin) is well tolerated and has good contraceptive efficacy. The observed favorable changes in HDL-C and LDL-C suggest a potential cardioprotective benefit.

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SURASAK TANEEPANICHSKUL & VORAPONG PHUPONG

Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

(Received 28 December 2006; revised 26 February 2007; accepted 5 March 2007)

Correspondence: Vorapong Phupong, Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University, Rama IV Road, Pathumwan, Bangkok 10330, Thailand. Tel: 66 2 256 4241. Fax: 66 2 254 9292. E-mail: vorapong.pluchula.ac.th

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