Polycystic ovary syndrome (PCOS) is the most common endocrinological disorder affecting 4-12% of women. It has also been the most controversial medical condition and every aspect has received a lot of attention from the nomenclature to the management. Metformin treatment of women with polycystic ovary syndrome (PCOS) is widespread, as determined by studies with diverse patient populations. Metformin, a commonly used drug in type 2 diabetes mellitus (T2DM), has garnered attention for its potential role in weight management, particularly in individuals with PCOS. This article aims to provide a comprehensive review of the evidence surrounding metformin's impact on weight loss in the context of PCOS, while also addressing its mechanisms of action, safety profile, and clinical considerations.
Understanding PCOS and Insulin Resistance
PCOS refers to a disorder with a combination of reproductive and metabolic characteristics. Several descriptions of similar conditions took place in the 20th century and it was named Stein-Leventhal Syndrome in 1935 after the authors who described polycystic ovarian morphology in patients suffering from hirsutism, amenorrhoea and infertility [Leventhal, 1958; Stein and Leventhal, 1935]. Currently, PCOS refers to a disorder with a combination of reproductive and metabolic characteristics. This has evolved over time with controversy over the definition culminating in the latest consensus [ESHRE/ASRM, 2004] which instead of solving the issue created more controversy [Azziz et al. 2006]. In the European Society of Human Reproduction and Embryology/American Society of Reproductive Medicine (ESHRE/ASRM) consensus, at least two of the following features are needed to make the diagnosis; oligo/anovulation, hyperandrogenism, and polycystic features on ultrasound scan [ESHRE/ASRM, 2004].
Failure of the target cells to respond to normal or ordinary levels of insulin is regarded as insulin resistance (IR) [Le Roith and Zick, 2001]. The presence of IR, however, leads to a compensatory increased production of insulin by the pancreatic beta cells to control the hyperglycaemia which ultimately fails leading to T2DM. In PCOS, hyperinsulinaemia has been thought to increase hyperandrogenaemia via a central role [Barbieri et al. 1986] or by decreasing the circulating levels of sex hormone binding globulin [Nestler et al. IR is not considered a diagnostic criterion in PCOS [ESHRE/ASRM, 2004]. However, it is recognized by many as a common feature in PCOS independent of obesity [Dunaif et al. 1987; Chang et al. 1983; Burghen et al. 1980]. An estimated prevalence of IR among PCOS patients of 60-70% has been reported [DeUgarte et al. 2005]. However, being overweight or obese is common among PCOS women, affecting up to 88% of these women [Holte et al. 1995; Pasquali and Casimirri, 1993; Kiddy et al. 1992], therefore casting doubt on the role IR plays in the pathogenesis of PCOS. Further, clinical quantification of IR is not accurate enough [Legro et al. 2004; Gennarelli et al. 2000] to enable a better understanding of the role of IR in PCOS pathogenesis or to incorporate it into the work up programme of PCOS patients.
Metformin: An Insulin-Sensitizing Agent
Metformin is the only remaining member of the biguanide family that has been used for the treatment of diabetes for a long time. It is the most commonly used drug in T2DM. Metformin works by improving the sensitivity of peripheral tissues to insulin [Bailey and Turner, 1996; Bailey, 1992], which results in a reduction of circulating insulin levels. Metformin inhibits hepatic gluconeogenesis and it also increases the glucose uptake by peripheral tissues and reduces fatty acid oxidation [Kirpichnikov et al. 2002]. Metformin has a positive effect on the endothelium and adipose tissue independent of its action on insulin and glucose levels [Diamanti-Kandarakis et al.
Evidence for Weight Loss with Metformin
Clinical Trials and Meta-Analyses
Evidence supports the weight-loss effects of metformin in adults with obesity and without type 2 diabetes. The main sources of evidence for weight loss with metformin in people without type 2 diabetes come from the Diabetes Prevention Program trial (DPP)2 and its long-term follow-up, the Diabetes Prevention Program Outcomes Study (DPPOS).1 The DPP, a 3-arm randomized controlled trial, compared the effects of intensive lifestyle intervention, metformin 1,700 mg/day, and placebo in 3,234 participants with prediabetes. The primary outcome measure was prevention or delayed onset of type 2 diabetes, with weight loss reported as a secondary outcome.2 The mean weight and body mass index (BMI) of the overall population in the study was 94.2 ± 20.3 kg and 34 ± 6.7 kg/m2, respectively. During the initial 2.8-year follow-up, the metformin group experienced an average weight loss of 2.1 kg, compared with 5.6 kg in the lifestyle intervention group, and 0.1 kg in the placebo group.2
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Weight loss is a feature of protracted metformin therapy in obese women with PCOS, with greater weight reduction potentially achievable with higher doses. Intention to treat analyses showed significant weight loss in both dose groups. Only the obese subgroup showed a dose relationship (1.5 and 3.6 kg in 1500- and 2550-mg groups, respectively; P = 0.04). The morbidly obese group showed similar reductions (3.9 and 3.8 kg) in both groups.
A meta-analysis that included 21 trials and 1,004 participants analyzed the effect of metformin on BMI in different populations and found that in patients with obesity, BMI was reduced by 1.3 units (weighted mean difference [WMD] 1.31; 95% CI −2.07 to −0.54).6 A subanalysis found that metformin had the most pronounced effect in the population with BMI greater than 35 kg/m2 (WMD −1.12; 95% CI −1.84 to −0.39), at doses higher than 1,500 mg/day (WMD −1.01; 95% CI −1.29 to −0.73) for at least 6 months (WMD −1.09; 95% CI −1.71 to −0.47).
Long-Term Weight Management
The magnitude of metformin-induced weight loss is modest but clinically significant, and it is achievable at low cost with an agent that has proven long-term safety, few serious adverse effects, and well-documented favorable non-glycemic effects. Unlike the weight loss experienced in the intensive lifestyle intervention group, weight loss in the metformin group was maintained throughout the DPP and DPPOS follow-up periods (N = 2,766 participants). Those on metformin had an average 2.5-kg weight loss over time, while the lifestyle intervention group progressively regained weight, with a final average weight loss of 2.0 kg after 10 years of follow-up.3 Approximately 30% of participants randomized to metformin lost more than 5% of their body weight in the first year, and a post hoc analysis demonstrated that their mean weight loss relative to baseline was 6.2% after 15 years of follow-up, compared with 3.7% in the lifestyle intervention arm. Adherence and weight loss during the first year of treatment with metformin were relevant predictors of long-term weight-loss maintenance.1
Real-World Evidence
A more recent nonrandomized, real-world study assessed the efficacy of metformin for weight loss in 154 patients with obesity and no diabetes compared with 45 control participants.5 The mean weight loss in the metformin group was 5.8 kg (± 7.0), whereas controls gained 0.8 kg (± 3.5 kg) on average (P < 0.0001).5 Both absolute and relative weight loss increased with higher degrees of insulin resistance, as measured by the Matsuda index and HOMA index.5 The study provides good real-world evidence on the use of metformin in patients with obesity and no diabetes, but the control group comprised patients who chose not to use medication as a means of reducing weight. Consequently, the possibility of innate bias should be considered when interpreting the results.
Metformin in Specific PCOS Populations
Women with Prediabetes
In the DPP trial, the incidence of diabetes was 58% lower (95% CI 48% to 66%) in the lifestyle intervention group and 31% lower (95% CI 17% to 43%) in the metformin group compared with placebo.2 However, metformin proved to be particularly effective for preventing or delaying diabetes in the subgroups of participants with higher BMI (≥ 35), younger age (< 60), and higher baseline fasting blood glucose and hemoglobin A1c, and in women with a history of gestational diabetes.2,9,10 This particular effect has been shown to be durable after 15 years of follow-up.9 In these populations, the role of metformin goes beyond its weight loss effects, and its use should be encouraged with the dual goal of promoting weight loss and preventing or delaying the onset of type 2 diabetes.
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Patients Treated with Antipsychotic Drugs
Most antipsychotic drugs are associated with weight gain. It has been reported that 75% of patients receiving antipsychotic agents increased their baseline weight by more than 7%. Atypical antipsychotics have greater potential for inducing weight gain, and among them, clozapine and olanzapine are the agents most associated with weight gain, followed by risperidone and quetiapine.11 These are also the agents for which the literature on metformin’s weight-attenuating and weight-loss effects is more abundant. However, there does not appear to be an antipsychotic drug-specific beneficial effect of metformin, and it is rather the magnitude of weight gain that drives metformin efficacy. Several trials have demonstrated beneficial effects of metformin in reversing or preventing weight gain associated with antipsychotic drug therapy. A meta-analysis including 12 studies and 743 participants confirmed that metformin is effective in treatment of weight gain associated with these agents. The mean weight loss was 3.27 kg (95% CI −4.66 to −1.89; Z = 4.64; P < .001), and metformin resulted in significant reduction in BMI (−1.13; 95% CI −1.61 to −0.66) compared with placebo.12
Weight gain can be associated with other medications, including some anticonvulsants, antidepressants, and systemic glucocorticoids, but evidence regarding the utility of metformin in those groups of patients is lacking.
Women with Polycystic Ovary Syndrome
In women with polycystic ovary syndrome, metformin therapy has been shown to increase ovulation, menstrual frequency, fertility, and rates of live birth. A meta-analysis comparing orlistat with metformin in women with polycystic ovary syndrome found that both had similar favorable effects on BMI, with a mean decrease in BMI of 3.4 to 4.55 with metformin, and 4.48 to 5.7 with orlistat (difference −0.65%, 95% CI −2.03 to 0.73).13
Potential Mechanisms of Action
Some evidence suggests that the mechanisms underlying metformin’s effects on body weight are much broader than its insulin-sensitizing effects. These include:
- Appetite suppression through increased secretion of glucagon-like peptide 1 and peptide YY, and increased hypothalamic leptin sensitivity
- Alteration of the gut microbiome
- Induced expression and secretion of growth-differentiating factor 15, which reduces food intake, body mass, fasting insulin, and glucose intolerance.14,15
Although most studies have used metformin in its immediate-release formulation, there is sufficient evidence to suggest no differences between immediate-release and extended-release formulations in terms of their weight-loss properties or the secretion of substances that potentially underlie this effect.16
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Safety and Side Effects
The main side effects associated with metformin treatment are the gastrointestinal symptoms of nausea, diarrhoea, flatulence, bloating, anorexia, metallic taste and abdominal pain. These symptoms occur with variable degrees in patients and in most cases resolve spontaneously. The severity of side effects can be reduced by gradual administration of metformin and titrating the dose increase guided by the severity of symptoms. A start dose of 500 mg daily during the main meal of the day for 1-2 weeks can lessen the side effects and allow tolerance to develop. A weekly or biweekly increase by 500 mg a day can then be pursued as required until a maximum dose of 2500-2550 mg/day is reached depending on the clinical benefit and side effects. If the dose increase results in worsening of the side effects, the current dose can be maintained for 2-4 weeks until tolerance is developed [Nestler, 2008]. Slow release metformin can be associated with fewer side effects.
When metformin is used and prescribed appropriately, serious adverse events are extremely rare. The most common side effects are gastrointestinal-diarrhea, nausea, flatulence, vomiting, and abdominal discomfort. These are less frequent with postprandial use and with extended-release than immediate-release formulations. Given the lack of prospective data on the effect of metformin on weight loss, it is unclear whether weight loss is associated with gastrointestinal side effects. Since the magnitude of weight loss during the DPP (and its maintenance during the DPPOS) was directly related to adherence to metformin therapy,17 such an association seems unlikely.
The main contraindication associated with metformin is severe renal impairment, defined as an estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m2. The following guidelines should be considered when prescribing metformin based on eGFR:
- eGFR less than 45 mL/min/1.73 m2: refrain from starting metformin
- eGFR 45 to 60 mL/min/1.73 m2: prescribe a maximum total daily dose of 1,500 mg (or 1,700 mg if prescribing an immediate-release formulation)
- eGFR 30 to 45 mL/min/1.73 m2 and already on metformin therapy: adjust to a maximum daily dose of 1,000 mg.
Metformin can also lead to vitamin B12 malabsorption in the distal ileum in approximately 10-30% of patients which is an effect dependent on age, dose and duration of treatment [Ting et al. 2006]. Rarely, lactic acidosis can occur, mainly in diabetic patients, which is a serious condition that can potentially be fatal. However, unless there is a contraindication to taking metformin such as renal disease the risk of lactic acidosis is negligible [Salpeter et al.
Chronic metformin use has been associated with a decrease in serum vitamin B12 levels without clinical manifestations. Reported in approximately 7% of patients, it is attributed to interference with vitamin B12 absorption. It is rarely associated with anemia and appears to be reversible with discontinuation of metformin or with vitamin B12 supplementation, or both.19
Cost-Effectiveness
Metformin is widely available, with an average price of about $10 for a 90-day supply. There are no studies of the cost-effectiveness of metformin as a weight-loss intervention. However, cost-effectiveness analysis of metformin as a diabetes prevention strategy in the DPP concluded that, compared with placebo, it was “extremely cost-effective (that is, improved outcomes at a low incremental cost) or even cost-saving (improved outcomes and reduced total costs).”20
Long-Term Effects of Metformin Withdrawal
Collectively, present study implies some metabolic and endocrine treatment legacy in both groups as well as some group-specific deteriorations in clinical parameters 6 months after metformin withdrawal. At baseline and after 6 months of follow up, all patients underwent history check-up and standard anthropometric measurements: height, weight, waist circumference, blood pressure (BP). A fasting blood was drawn for determination of glucose, insulin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), androstenedione, total and free testosterone followed by a standard 75 g oral glucose tolerance test (OGTT). At the entry point and at the end of the study they completed The Three-Factor Eating Questionnaire-R18 (TFEQ-R18) for assessment of eating behavior [16]. After 3 months of withdrawal from metformin all women came for a safety check-up visit to determine glucose homeostasis with standard OGTT.
After metformin withdrawal, short-term (ST) group gained significant amount of weight (from 92 (75.5-107.3) kg to 96 (76-116) kg; p = 0.019). Weight tended to increase also in long-term (LT) users (from 87 (75-103) to 87 (73-105) kg; p = 0.058). More women in LT group maintained stable weight (27% in LT group vs 15% in ST group). Eating behavior deteriorated in both groups. Withdrawal of metformin resulted in a decrease of menstrual frequency (6 (6-6) to 6 (4-6) menstrual bleeds per 6 months; p = 0.027) and in borderline increase of androstenedione (6.4 (4.6-7.6) to 7.8 (4.8-9.6) nmol/L; p = 0.053) in LT group. Waist circumference, HOMA and glucose homeostasis remained stable in both groups. There were no differences between groups at 6-month follow up.