What is the recommended treatment approach for a female patient with Polycystic Ovary Syndrome (PCOS) using metformin (biguanide oral hypoglycemic), considering her insulin resistance and risk of developing type 2 diabetes?

Metformin for PCOS

Metformin is recommended for women with PCOS who have cardiometabolic features such as abdominal obesity, insulin resistance, or metabolic syndrome, regardless of whether they are attempting conception. 1

Primary Indications for Metformin in PCOS

• Prescribe metformin specifically for PCOS patients demonstrating insulin resistance or metabolic syndrome features, even with normal HbA1c values 1
• The American College of Cardiology emphasizes metformin use particularly for women with cardiometabolic features like abdominal obesity and insulin resistance 2, 1
• Metformin improves menstrual regularity, metabolic parameters, and may enhance fertility when combined with other treatments 1

Metabolic and Cardiovascular Benefits

• Metformin decreases LDL cholesterol and triglyceride levels, providing cardiovascular protection 1
• Metformin maintains or decreases weight, unlike thiazolidinediones which cause weight gain 1
• Metformin maintains or improves glucose tolerance over time, even with normal baseline HbA1c 1
• The drug reduces ovarian androgen production by lowering insulin levels, which subsequently decreases testosterone 1

Screening Requirements Before Initiating Therapy

• All women with PCOS should be screened for type 2 diabetes and glucose intolerance with a fasting glucose level followed by a two-hour glucose level obtained after a 75-gram glucose load 2
• Screen for dyslipidemia with a fasting lipoprotein profile including total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride measurements 2
• Calculate body mass index and waist-hip ratio 2
• International guidelines recommend screening for cardiovascular risk with weight monitoring every 6-12 months, at least annual blood pressure checks, fasting lipid panels, and glycemic control assessments 2

Dosing and Administration

• Start with lower doses and titrate up to minimize gastrointestinal side effects 1
• Typical effective dosing is 1500-2000 mg daily, which can be divided as 1000 mg twice daily with extended-release formulation 1
• The FDA-approved starting dose is 500 mg orally twice daily or 850 mg once daily, given with meals 3
• Increase the dose in increments of 500 mg weekly or 850 mg every 2 weeks based on glycemic control and tolerability, up to a maximum dose of 2550 mg per day 3

Absolute Contraindications

• Do not use metformin in patients with impaired renal function (eGFR below 30 mL/min/1.73 m²), known hepatic disease, hypoxemic conditions, severe infections, alcohol abuse, or acute illness with dehydration or hypoxemia 1, 3
• Metformin is contraindicated in patients with an estimated glomerular filtration rate below 30 mL/minute/1.73 m² 3
• Initiation is not recommended in patients with an eGFR between 30 to 45 mL/minute/1.73 m² 3

Renal Function Monitoring

• Assess renal function prior to initiation and periodically thereafter 3
• In patients taking metformin whose eGFR later falls below 45 mL/min/1.73 m², assess the benefit-risk of continuing therapy 3
• Discontinue if the patient's eGFR later falls below 30 mL/minute/1.73 m² 3

Special Considerations for Pregnancy

• Metformin appears to be safe during pregnancy according to ACOG guidelines, though documentation on its effects in early pregnancy is limited 4
• Women with hypertension, preeclampsia, or at risk for intrauterine growth restriction during pregnancy should not use metformin 1
• Long-term offspring data show concerning trends: 9-year-old children exposed to metformin had higher BMI, increased waist-to-height ratio, and greater waist circumference in some cohorts 1
• Provide preconception counseling due to increased risk of unplanned pregnancy with restored ovulation 1

Lifestyle Modification as Essential Adjunct

• Even modest weight loss of 5% of initial body weight significantly enhances metformin's effects on both metabolic and reproductive abnormalities 1
• Combining lifestyle modification with metformin produces superior outcomes compared to medication alone 1
• ACOG recommends weight loss and exercise as the first-line approach to improve insulin sensitivity, ovulation rates, and metabolic outcomes 4
• Before drug therapy is used, regular exercise and weight control measures should be tried 2

Fertility Considerations

• For women attempting conception, start with lifestyle modification and clomiphene citrate as first-line ovulation induction, with metformin as a potential adjunctive treatment 4
• Clomiphene citrate has an 80% ovulation rate and 50% conception rate among ovulators 4
• Pretreatment with metformin may favor ovulatory response to clomiphene citrate 5

Common Pitfalls to Avoid

• Do not use metformin as monotherapy without addressing lifestyle modification - the combination is superior to medication alone 1
• Discontinue metformin at the time of, or prior to, iodinated contrast imaging procedures in patients with eGFR between 30-60 mL/min/1.73 m², or in patients with liver disease, alcoholism, or heart failure 3
• Re-evaluate eGFR 48 hours after imaging procedures before restarting 3
• Be aware that metformin should not be used as first-line treatment for ovulatory dysfunctions in adult women with PCOS, but rather as adjunctive therapy 5

Pharmacokinetic Considerations

• Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism 3
• Approximately 90% of absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours 3
• Food decreases the extent of absorption by approximately 40% for peak concentration and 25% for AUC 3
• Cationic drugs eliminated by renal tubular secretion (such as cimetidine) may reduce metformin elimination and increase exposure 3