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Metformin in polycystic ovary syndrome
Moll, E.
Publication date
2013
Link to publication
Citation for published version (APA):
Moll, E. (2013). Metformin in polycystic ovary syndrome.
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Chapter 5
Does metformin treatment in women with polycystic ovary syndrome alter biomarkers associated with metabolic syndrome?
Etelka Moll, Madelon van Wely, Joost C.M. Meijers, Patrick M.M. Bossuyt, Cornelis B. Lambalk, Fulco van der Veen
Abstract
Context: Metabolic syndrome is frequent among women suffering from polycystic
ovary syndrome (PCOS) and these women are thought to be at increased risk for cardiovascular disease. Metformin is claimed to improve biomarkers associated with metabolic syndrome, but evidence about the effectiveness in PCOS is limited.
Objective: To evaluate changes in biomarkers associated with metabolic syndrome -
anthropometric, glucose metabolism, lipid, coagulation and fibrinolytic parameters - in women with polycystic ovary syndrome randomly allocated to metformin or placebo treatment.
Design and Setting: Multicenter randomized controlled trial.
Patients and Methods: 225 treatment-naïve patients were randomly allocated to
receive metformin (n=111) or placebo (n=114). Changes in biomarkers associated with metabolic syndrome over time were investigated using a repeated measurements mixed-effects model.
Results: We found a statistically significant but modest difference between women
treated with metformin and women treated with placebo for one biomarker associated with metabolic syndrome; after treatment the mean endogenous thrombin potential was 8.4% lower in the metformin group (95% confidence interval 13.5% to 3.3%; p<0.001). For all other parameters we found no evidence of a difference between metformin and placebo treatment.
Conclusions: Our findings indicate that metformin on a short term basis does not
lead to major improvement of biomarkers associated with metabolic syndrome in treatment-naive women with polycystic ovary syndrome.
Introduction
Polycystic ovary syndrome (PCOS) affects 5% to 10% of women of reproductive age.1 The syndrome is characterized by oligo-anovulation, clinical or biochemical hyperandrogenism and/or polycystic ovaries.2;3 Insulin resistance accompanied by compensatory hyperinsulinemia often constitutes another major biochemical feature of polycystic ovary syndrome. PCOS can also result in several metabolic abnormalities including impaired glucose tolerance,4 dyslipidemia and hypertension.5 As a consequence, women with PCOS seem to be at increased risk of having metabolic syndrome6 and thereby at risk for cardiovascular disease and diabetes.7-9
There are retrospective studies that claim to have data concerning cardiovascular disease in women with PCOS.10-13 None of these studies included patients with known or proven PCOS defined according to contemporary criteria (Rotterdam, NIH, AES). Recently, data were published concerning cardiovascular disease in 32 postmenopausal women with PCOS. These women did not have a significantly increased risk of cardiovascular disease or diabetes when compared to women without PCOS.14 Despite these data, it is still a matter of debate if women with PCOS suffer more from cardiovascular morbidity and mortality than women without PCOS.15
According to the ESHRE/ASRM PCOS consensus workshop group a woman with PCOS has metabolic syndrome when she suffers from at least three out of the five following criteria: Abdominal obesity (waist circumference), high triglycerides, low HDL, high blood pressure and insulin resistance.2;16 The prevalence of metabolic syndrome in women with PCOS varies largely among various populations and has been reported to range between 16% and 46%.17-22
Since insulin resistance is one of the criteria for the metabolic syndrome, metformin has been suggested to reduce the risk of metabolic syndrome in women with PCOS.19;23;24 In studies where metformin was used to treat patients with diabetes, insulin values as well as lipid profile and coagulation and fibrinolytic factors improved.25;26 Whether metformin also has a positive effect on these parameters in women with PCOS has never been tested in randomized controlled trials with a complete set of biomarkers associated with metabolic syndrome.
We set out to assess the effect of metformin on metabolic syndrome markers by analysing data in a previously conducted randomised controlled trial,27 in which
women were randomly allocated to treatment with clomifene and metformin or to treatment with clomifene and placebo.
Methods
Subjects and experimental protocol
The data for this analysis were collected in randomized controlled trial published in detail elsewhere.27 In this double blinded, multicenter trial we recruited treatment-naïve infertile women with polycystic ovary syndrome and randomly assigned them to clomifene plus metformin (500 mg 4/day) or to clomifene plus placebo. This trial took place from June 2001 till May 2004 in twenty Dutch hospitals. Polycystic ovary syndrome was defined according to present guidelines.2 Primary exclusion criteria were other causes of anovulation, age over 40 years and liver-, kidney or heart disease/failure (i.e. abnormal results on liver function tests, serum creatinine concentration > 95 μmol/l or a history of heart disease/failure) and sperm quality indicating male subfertility (Total Motile Count < 10 x 106).
Randomization was performed in the coordinating centre (AMC, Amsterdam), using computer generated blocks of four. The containers with study medication were prepared by Merck Santé, France. The randomization was stratified per centre, and the centers received blinded, numbered containers with medication. Each included patient received the container with the next number in their own hospital.
Women continued to take the study medication until a positive pregnancy test (four weeks after the first day of menstruation) or during a maximum of six ovulatory cycles or when clomifene resistance occurred. Women were advised to discontinue their medication as soon as they had a positive pregnancy test.
Ongoing pregnancy was defined as a viable pregnancy at 12 weeks of gestation. The study was approved by the Institutional Review Boards of all hospitals. Written informed consent was obtained from all participants.
Biomarkers associated with metabolic syndrome
The following 17 biomarkers were evaluated: anthropometric parameters (waist circumference, diastolic and systolic blood pressure), metabolic parameters (glucose at 2 hours, glucose insulin ratio, total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, triglycerides) and coagulation and fibrinolytic parameters (prothrombin time, activated partial thromboplastin time,
d-dimers, plasminogen activator inhibitor 1 activity, von Willebrand factor antigen, prothrombin fragment F1+2, activated protein C resistance and endogenous thrombin potential). Waist circumference and blood pressure were measured at the beginning of the trial and at the start of every cycle.
Before women started taking the study medication venous blood samples were obtained, after an overnight fast, in tubes with an anticoagulant (heparin and citrate) and the biomarkers were analysed. With the results of the glucose tolerance test we calculated homeostatic model assessment (HOMA) and the quantitative insulin sensitivity check index (QUICKI).
During the course of the study we planned to evaluate glucose, insulin and the lipid profile in every cycle; the coagulation and fibrinolytic profile was evaluated over maximally three cycles. Lipid profile and coagulation and fibrinolytic parameters were tested only in the women recruited in the Academic Medical Centre, Amsterdam.
Laboratory methods
Coagulation assays PT and APTT, and PAI-1 activity were performed on an automated coagulation analyzer (Behring Coagulation System, BCS) with reagents and protocols from the manufacturer (Dade Behring, Marburg, Germany). Von Willebrand factor antigen levels were determined with an ELISA developed in our laboratory using antibodies from Dako (Glostrup, Denmark). The plasma concentrations of prothrombin fragment F1+2 were measured by ELISA (Dade Behring, Marburg, Germany). Resistance to activated protein C was determined with an endogenous thrombin potential (ETP)-based test. The ETP-based test was carried out as described by Rosing et al.28 The activated protein C sensitivity (APCsr) is defined as the ratio of time integrals of thrombin formation, determined in the presence and absence of activated protein C, divided by the same ratio of normal plasma.29 Resistance to activated protein C results in an increase in APCsr.
Plasma TC, LDL, HDL, and TG were determined using commercially available kits (Boehringer Mannheim, Mannheim, Germany).
Statistical Analysis
We compared the 17 anthropometric, metabolic and coagulation parameters between the metformin group and the placebo group using linear mixed-effects models with repeated measures. We built models investigating the effect of treatment
over time, accounting for female age and ovulation, including all available measurements for each marker (Table 2). We used a Bonferroni correction of P = 0.0029, equivalent to a 5% significance level, to correct for multiple testing. Data are presented as model-based estimated means before and after treatment, with 95% confidence intervals. To perform the statistical analysis, we used PASW statistics 18.
Results
Baseline characteristics of all women included in the randomised controlled trial are shown in Table 1. We were able to collect biomarkers associated with metabolic syndrome in a selection only. An oral glucose tolerance test was performed in 182 patients (91 patients from the metformin group, 91 from the placebo group), a lipid profile was determined in 37 patients (17 from the metformin group, 20 from the placebo group), and coagulation and fibrinolysis parameters were determined in 39 women (19 from the metformin group, 20 from the placebo group). Women were followed up until a maximum of eight cycles.
The baseline parameters in women in whom an oral glucose tolerance test was performed were comparable with those in the study group. The women in whom we determined a lipid profile and coagulation and fibrinolysis parameters differed slightly; they had a longer duration of infertility (0.69 years, p=0.00), higher diastolic blood pressure (4 mm Hg, p=0.01) and higher testosterone level (1.28 nmol/l, p=0.04). Within these women, there were no statistically significant differences in baseline characteristics in women receiving metformin or placebo (data not shown).
The number of women available for the analysis in each cycle is shown in Table 2. Patients conceived, became clomifene resistant or had six ovulations. All were endpoints of the study protocol. The only women that completed eight cycles are the ones who ovulated six cycles with 150mg clomifene (after anovulation with 50 and 100mg clomifene) but failed to conceive.
The results of the analyses are expressed in Tables 3a – 3d. For 16 of the 17 biomarkers associated with metabolic syndrome, metformin treatment did not result in a significant effect compared to placebo. We found a statistically significant but modest difference between women treated with metformin and women treated with placebo in the change over time in endogenous thrombin potential; the estimated mean after treatment, adjusted for female age and ovulation, was 8.4% lower in the metformin group (95% confidence interval 13.5% to 3.3%; p<0.001).
Discussion
This study is the first to compare extensively and directly the effect of metformin on a large series of known biomarkers associated with the metabolic syndrome in the setting of a randomized controlled trial. All women were treatment-naïve prior to entering our study. We found that out of the 17 biomarkers associated with metabolic syndrome that were analysed, only endogenous thrombin potential changed in a statistically significant way after eight months of metformin treatment. The effect of metformin on the value of this parameter was very small, and most likely clinically not significant, while all values were still within the normal range.
A weakness of our study is that we analyzed biomarkers associated with metabolic syndrome in a subset of women that entered our study. This reduced sample size means that subtle effects may have been missed. In addition, the mean duration of treatment with metformin was only eight months. We cannot exclude that more substantial effects exist in specific subgroups of women, possibly those at increased risk for metabolic syndrome, or with longer duration of treatment. Our trial was designed and powered to determine whether metformin improved pregnancy chances, and biomarkers associated with metabolic syndrome were not among the primary outcome measures.
In addition to metformin or placebo all women in our study also received clomifene 50-150 mg per day for five consecutive days in the beginning of a cycle. Clomifene is an ovulation inducer, which adheres to hypothalamic estrogen receptors in order to block the estrogen negative feedback system. While we know that estrogen from the oral contraceptive pill (OCP) is not associated with clinically significant adverse metabolic consequences, the effect of clomifene on the studied biomarkers has never been studied.30 We assume that clomifene has little or no effect on the biomarkers that were investigated in our study. Furthermore, the randomized comparison of clomifene with metformin and clomifene with placebo eliminated the effects of clomifene alone on these biomarkers.
Although the recently updated Cochrane review found a limited benefit of metformin on weight loss, insulin sensitivity or lipid profile,31 it is possible that longer treatment with metformin results in a more pronounced effect on metabolic parameters, as was shown in a study that treated patients for over 36 months.32 The Cochrane review did not find studies investigating a complete set of metabolic
parameters as we did. There were no data about the coagulation and fibrinolytic parameters.
Studies in patients suffering from diabetes mellitus have shown that life style interventions are more effective in lowering risk factors for cardiovascular disease than drug-intervention with metformin.33;34 A recent Cochrane review concluded that lifestyle treatment also improves several aspects of the metabolic syndrome seen in patients with PCOS.35 Data on prevalence and incidence of type 2 diabetes mellitus and cardiovascular disease in women with PCOS are limited. We do not know of any studies that demonstrated a direct effect of life style adjustments or metformin on the incidence of these diseases in these women36 Up till now only one randomized controlled trial has been performed, in which women with PCOS were assigned to metformin or to life style adjustments.37 The small study showed a significant decrease in waist circumference in the life style group, but one third of the included patients did not finish the study and there was no intention to treat analysis. This limited evidence precludes firm conclusions.
In conclusion, our findings indicate that metformin on a short term basis does not lead to clinical improvement of biomarkers associated with metabolic syndrome in treatment-naive women with polycystic ovary syndrome. At this moment in time, there is insufficient evidence to recommend metformin to ameliorate biomarkers associated with metabolic syndrome in an unselected population of women with the polycystic ovary syndrome.
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Table 1. Baseline characteristics.
Characteristics Treatment n Baseline
*
(SD) Age (years) metformin 104 28.1 (3.8)
placebo 109 28.7 (3.8)
Duration of desire to conceive (years) metformin 98 1.6 (1.2)
placebo 105 1.4 (1.1)
Body mass index (kg/m2) metformin 103 28.4 (7.1)
placebo 109 27.8 (6.7)
Volume ovaries (ml) metformin 71 9.1 (6.1)
placebo 65 10.1 (4.9) LH/FSH ratio metformin 105 1.9 (1.3) placebo 109 2.1 (1.4) LH (U/l) metformin 105 9.9 (5.1) placebo 109 10.8 (5.9) FSH (U/l) metformin 105 5.6 (1.9) placebo 109 5.4 (2.0)
Testosterone (nmol/l) metformin 104 3.5 (3.7)
placebo 108 3.6 (3.5)
Free androgen index metformin 70 12.9 (17.9)
placebo 69 11.7 (11.9)
Table 2. Number of patients per cycle per variable.
Characteristics 0 1 2 3 4 5 6 7 8 Waist circumference 205 129 100 77 47 25 19 10 5
Diastolic blood pressure 197 127 100 73 47 25 17 8 3
Systolic blood pressure 197 127 100 73 47 25 17 8 3
Glucose 2 hours 182 18
Glucose insulin ratio 113 76 57 50 28 19 11 6 4
HOMA 113 76 57 50 28 19 11 6 4 QUICKI 113 76 57 50 28 19 11 6 4 TC 59 36 27 22 9 9 5 3 2 LDL 55 33 25 22 9 9 5 3 2 HDL 55 33 25 22 9 9 5 3 2 TG 59 36 27 22 9 9 5 3 2 PT 39 28 23 13 1 1 APTT 39 28 23 13 1 1 D-dimer 39 28 23 13 1 1 PAI-1 39 28 23 13 1 1
von Willebrand factor 39 28 23 13 1 1
Prothrombin fragment 1 + 2 39 28 23 13 1 1
APC-SR 39 28 23 13 1 1
102 Table 3a . Ch an ge s i n an th ro pom e tric b iom arke rs assoc ia ted with metab o lic s y ndr ome af ter treatm ent with m e tf o rmi n or p la c ebo. Ch a ract eri s tic s Treatment n Baseline * (SD) Aft e r tre a tmen t Mean di ffere n c e betw een me tformi n and p lac ebo (95 % CI ) † p-va lu e ‡ W a ist c irc umfe re n c e (cm) metformin 102 90 .1 ( 1 6 .3) 8 9 .6 (1 5.1) 1 .0 (-3.8 to 4.8) 0.5 p lace bo 103 88 .4 ( 1 6 .9) 8 5 .3 (1 4.7) D iastoli c blood pre ssure (mm H g ) metformin 98 75 .0 ( 1 0 .4) 74 .3 ( 8 .2 ) -0.3 (-2 .5 to 1 .9) 0.8 p lace bo 99 76.2 (9 .0 ) 74 .6 ( 9 .1 ) S y stoli c bloo d pre s sure (mm H g) metformin 98 120 ( 15.2) 119 ( 16.4) 1 .0 (-2.3 to 4.3) 0.5 p lace bo 99 1 21 5.5) 11 8 (6 .8 ) * Da ta ar e pres ente d as mea n s w it h sta n d a rd de v ia tio n , † L ine ar m ix e d mod e ls we re us ed to estimate d if fer e n c e s b e twee n grou ps over tim e , co n tr o lle d for fem a le ag e and o c c u rr enc e of o v ulati o n, ‡ after Bon fe rroni correction
103 Table 3b. Ch an g e s in g lu c os e bi omark e rs associ ate d with m e ta b o lic syn d ro me a fter tre a tm e n t wit h metform in or p lac e b o. Ch a ract eri s tic s Treatm e nt n Ba seli n e * (SD) Afte r trea tmen t M e a n dif fe re nc e b e tw ee n me tformi n and plac ebo (9 5 % CI ) † p -value ‡ Glu c ose 2 hours (mm o l/l ) metformin 91 5.0 ( 1 .4 ) 5.1 ( 1 .4 ) -0 .4 ( -2. 8 to 2.0 ) 0. 7 plac ebo 91 5.1 ( 1 .4 ) 5.6 ( 1 .6 ) Glu c ose insuli n ra ti o metformin 56 1.0 ( 0 .6 ) 0.8 ( 0 .6 ) -0 .3 ( -0. 3 to 0.2 ) 0. 8 plac ebo 57 1.2 ( 0 .9 ) 0.8 ( 0 .8 ) HO MA metformin 56 4.6 ( 8 .3 ) 6.0 ( 7 .5 ) -0 .3 ( -3. 2 to 2.6 ) 0. 8 plac ebo 57 3.8 ( 4 .6 ) 6.3 ( 5 .3 ) QUIC KI metformin 56 0.6 ( 0 .1 ) 0.6 ( 0 .2 ) 0.1 (-0.0 to 11) 0. 1 plac ebo 57 0.6 ( 0 .2 ) 0.5 ( 0 .2 ) * Da ta ar e pres ente d as mea n s w it h sta n d a rd de v ia tio n , † L ine ar m ix e d mod e ls we re us ed to estimate d if ferenc e s b e twee n grou ps over tim e , co n tr o lle d for fem a le ag e and o c c u rr enc e of o v ulati o n, ‡ after Bon fe rroni correction
104 Table 3c . Ch an ge s i n lip id bi oma rke rs ass o c ia ted w ith meta bo lic s y n d ro m e af ter t re a tm ent with m e tf or mi n or p laceb o . Ch a ract eri s tic s Treatment n Ba seli n e * (SD) Afte r trea tmen t M e a n dif fe re nc e b e tw ee n me tformi n and plac ebo (9 5 % CI ) † p -value ‡ TC (mm o l/l ) me tf ormi n 17 4.8 ( 0 .9 ) 4.8 ( 0 .9 ) -0 .1 ( -0. 5 to 0.4 ) 0. 8 p la c eb o 20 5.0 ( 0 .9 ) 4.8 ( 1 .0 ) LDL (mm o l/ l) me tf ormi n 17 2.8 ( 0 .8 ) 2.7 ( 0 .9 ) -0 .2 ( -0. 5 to 0.0 ) 0. 1 p la c eb o 20 3.1 ( 0 .9 ) 3.0 ( 1 .0 ) HD L (m m o l/ l) me tf ormi n 17 1.7 ( 0 .9 ) 1.5 ( 1 .0 ) 0 .0 (-0.2 to 0.3) 0. 5 p la c eb o 20 1.5 ( 0 .5 ) 1.4 ( 1 .0 ) TG (mmol/l) me tf ormi n 17 0.8 ( 0 .4 ) 0.9 ( 0 .5 ) -0 .1 ( -0. 3 to 0.1 ) 0. 3 p la c eb o 20 0.9 ( 0 .7 ) 1.0 ( 0 .6 ) * Da ta ar e pres ente d as mea n s w it h sta n d a rd de v ia tio n , † L ine ar m ix e d mod e ls we re us ed to estimate d if fer e n c e s b e twee n grou ps over tim e , co n tr o lle d for fem a le ag e and o c c u rr enc e of o v ulati o n, ‡ after Bon fe rroni correction
105 Table 3d. Ch an g e s i n co a gul a ti o n a n d f ibr inolyt ic bi o m arkers ass o ci a ted w it h met abo lic synd ro m e a ft e r treatme n t with me tformin or plac ebo . Ch a ract eri s tic s Treatment n Ba seli n e * (SD) Afte r trea tmen t Mea n differen ce between me tformin and plac ebo (9 5 % CI) † p-va lu e ‡ PT (s) me tf ormi n 19 11.6 (0. 7 ) 12 (0.7 ) -0 .2 ( -0 .6 to 0. 2 ) 0.3 p la c eb o 20 11.8 (0. 6 ) 12 (0.5 ) AP T T (s) me tf ormi n 19 36.1 (3. 7 ) 34.2 (3. 7 ) 0.3 (-0.8 to 1 .4 ) 0.5 p la c eb o 20 36.2 (3. 3 ) 33.9 (3. 0 ) D-d imer ( ug/l) me tf ormi n 19 21 4 (76 ) 31 9 (89 ) -8 .2 (-73.5 to 5 7 .1) 0.8 p la c eb o 20 213 ( 112 ) 327 ( 111) PA I-1 (U/m l) me tf ormi n 19 8.2 ( 6 .1 ) 5.3 ( 4 .4 ) -1.4 (-3. 6 t o 0 .8) 0.2 p la c eb o 20 5.9 ( 5 .6 ) 6.7 ( 5 .2 ) v o n Wil le b ra nd f a c tor (%) me tf ormi n 19 11 5 (33 ) 12 4 (43 ) -2 .5 (-18.1 to 1 3 .1) 0.7 p la c eb o 20 11 4 (39 ) 12 6 (42 ) Pro thro m bi n fra g men t 1 + 2 (nmo l/l ) me tf ormi n 19 0.8 ( 0 .4 ) 1.0 ( 0 .5 ) -0 .0 ( -0 .2 to 0. 1 ) 0.8 p la c eb o 20 0.8 ( 0 .5 ) 1.1 ( 0 .6 ) AP C -S R me tf ormi n 19 1.0 ( 1 .1 ) 0.9 ( 1 .5 ) -0.2 (-0. 4 t o -0 .1 ) 0.01 p la c eb o 20 0.8 ( 0 .6 ) 1.2 ( 0 .7 ) Endog e nous Thrombin Potential (% ) me tf ormi n 19 10 0 (21 ) 9 6 (28) -8.4 (-13.5 to -3.3) 0.00 p la c eb o 20 10 1 (22 ) 10 4 (25 ) * Da ta ar e pres ente d as mea n s w ith sta n d a rd de v ia tio n , † L ine ar m ix e d mod e ls we re us ed to estimate d if ferenc e s b e twee n grou ps over tim e , co n tr o lle d for fem a le ag e and o c c u rr enc e of o v ulati o n, ‡ after Bon fe rroni correction
