Trial Information

Effect of Diet Plus Sibutramine on Hormonal and Metabolic Features in Overweight and Obese Women With PCOS: a Randomized, 24-Week Study

The Polycystic Ovary Syndrome (PCOS) is one of the most common hormonal disorders in women
of reproductive age. As a syndrome it has multiple components, such as reproductive (chronic
anovulation and infertility), metabolic and cardiovascular. Although lean women present
PCOS, obesity is one of the main manifestations of the syndrome. Androgen excess and insulin
resistance underline much of the clinical and metabolic features of the syndrome.

Recent evidence suggests that PCOS patients have a substantial risk for the development of
metabolic and cardiovascular abnormalities similar to those presented in the metabolic
syndrome. Obesity, particularly of the abdominal type, is presented in approximately half
of the women with PCOS, although several studies have shown that percentage can vary from
30% to 75%. Several studies have demonstrated that obesity in women with PCOS enhances the
clinical and metabolic abnormalities of the syndrome, since obese women with PCOS have more
profound insulin resistance or type 2 DM,dyslipidemia and cardiovascular disease’s risk, and
greater level of androgens due to low SHBG levels.

A modest weight loss (<5% or even 5-10% of initial body weight) has been shown to improve
ovulation frequency and conception, to reduce miscarriage, hyperlipidemia, hypertension,
hyperglycemia and insulin resistance in women with PCOS. There are only a few studies on the
effect of anti-obesity drug administration in obese and overweight women with PCOS. To the
authors’ best knowledge, the effect of sibutramine, a serotonin and noradrenaline reuptake
inhibitor (SNRI) approved as antiobesity drug, has been studied in only one study with obese
women with PCOS. Given this lack of information, the aim of the present study was to
investigate any additional effect of sibutramine combined with a hypocaloric diet on body
composition, hormonal and lipids parameters and insulin resistance in obese women with PCOS.

Study's design The study was prospective, open label, randomized, comparative trial. The
study design included 3 periods; a screening period in order to confirm the diagnosis of
PCOS, a lead-in period (4 weeks duration) that all patients were prescribed 10mg/day
sibutramine plus a 600 kcal deficient diet, and a treatment period (for the subsequent 6
months) that subjects were randomized in a 2:1 ratio to the S group (10 mg/day of
Sibutramine plus hypocaloric diet) and the D group (hypocaloric diet only). Diet was based
on the individualized basal metabolic rate as defined by the Harris-Benedict’s equation
adjusted for moderate physical activity. Before entering the lead-in period all subjects
were prescribed an energy-restricted diet containing 50% as carbohydrate, 30% as fat (10%
saturated), and 20% as protein. After randomization, subjects were advised not to modify
their eating habits throughout the study period.

The randomization was performed using sealed envelopes prepared in advance of the study by a
research associate not involved in the study. A randomisation table was created using blocks
of 3 numbers with all possible combinations. A random number generator has been used to
create balance between the treatment groups.

Clinical measures Body weight, waist circumference and fasting blood samples for total
testosterone (T), Sex Hormone Binding Globulin (SHBG), dehydroepiandrosterone sulfate
(DHEAS), androstenedione (Δ4Α), 17a-hydroxyprogesterone, follicle stimulating hormone (FSH),
luteinising hormone (LH), thyroid stimulating hormone (TSH), total cholesterol (TC),
triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein
cholesterol (HDL-C), glucose, and insulin were taken at baseline as well as at 3 and 6
months of treatment. At the same period, an Oral Glucose Tolerance Test (OGGT) with 75-g
glucose was performed.

Blood samples were collected between 08:30 and 09:00 a.m., after an overnight fast, and
during the follicular phase of women’s menstrual cycle. Monthly, subjects’ body weight was
measured, adverse events, heart rate, blood pressure, and study drug compliance were
determined and a pregnancy urine test was performed. Body weight was always determined at
morning hours with subjects in light clothes.