What are the primary medical indications for metformin, particularly in adults with type 2 diabetes or polycystic ovary syndrome (PCOS)?

Metformin Medical Indications

Metformin is FDA-approved as an adjunct to diet and exercise for improving glycemic control in adults and children ≥10 years old with type 2 diabetes mellitus, and is widely used off-label for diabetes prevention in high-risk individuals, polycystic ovary syndrome (PCOS), and obesity management. 1

FDA-Approved Indication

• Type 2 diabetes mellitus in adults and pediatric patients aged 10 years and older, used alongside diet and exercise to improve glycemic control 1
• Metformin is not approved for type 1 diabetes or diabetic ketoacidosis 1

Diabetes Prevention (Off-Label but Guideline-Recommended)

Metformin should be considered for prevention of type 2 diabetes in adults at high risk, particularly those aged 25-59 years with BMI ≥35 kg/m², and in individuals with prior gestational diabetes mellitus. 2

• Most effective in younger adults (25-44 years), those with BMI ≥35 kg/m², baseline fasting glucose ≥110 mg/dL, A1C 6.0-6.4%, or history of gestational diabetes 2
• Achieved 6.2% weight loss at 15-year follow-up in the Diabetes Prevention Program, compared to 2.8% with placebo 2
• In women with prior gestational diabetes, metformin and intensive lifestyle modification both reduced diabetes risk by 50% 2
• Long-term use requires periodic vitamin B12 monitoring due to risk of deficiency, especially in those with anemia or peripheral neuropathy 2

Pediatric Type 2 Diabetes

In metabolically stable children and adolescents with type 2 diabetes (A1C <8.5% and asymptomatic), metformin is the initial pharmacologic treatment of choice if renal function is >30 mL/min/1.73 m². 2

• Pharmacologic therapy should be initiated at diagnosis alongside lifestyle therapy 2
• Youth with marked hyperglycemia (blood glucose ≥250 mg/dL or A1C ≥8.5%) without ketoacidosis should be treated initially with basal insulin while metformin is initiated and titrated 2
• Metformin and insulin are the only two FDA-approved drugs for youth-onset type 2 diabetes 2
• The TODAY study found metformin alone provided durable glycemic control in approximately half of pediatric subjects 2

Polycystic Ovary Syndrome (PCOS) - Off-Label

Metformin improves insulin resistance, menstrual regularity, and androgen levels in women with PCOS, particularly those with obesity or insulin resistance, but is not effective as first-line therapy for weight loss, ovulation induction, or treatment of hirsutism or acne. 3

• Reduces hyperinsulinemia, which contributes to disordered ovarian function and androgen excess 4, 5
• Improves ovulation rates and may reduce early spontaneous miscarriage risk in women with PCOS 5
• During pregnancy, may reduce early pregnancy loss, miscarriage, and preterm birth, though effects on gestational diabetes and preeclampsia are inconsistent 3
• Critical counseling point: Treatment may normalize ovulatory function and increase risk of unplanned pregnancy in premenopausal anovulatory women 2, 1
• Metformin is frequently offered to patients with PCOS although it is not FDA approved for this diagnosis 2

Obesity Management - Off-Label

Metformin is associated with approximately 3% weight loss in clinical trials, with 25-50% of participants achieving at least 5% weight loss, making it a commonly used off-label option for obesity management. 2

• Doses >1500 mg are associated with greatest weight loss 2
• Pleiotropic effects include decreased inflammation, increased insulin and leptin sensitivity, and decreased hunger and ghrelin levels, especially with twice-daily dosing 2
• Widely available and inexpensive compared to FDA-approved anti-obesity medications 2
• Also used off-label to mitigate weight gain from antipsychotic medications 2

Other Off-Label Uses Under Investigation

• Prevention of cancer (including Li Fraumeni syndrome) 6
• Renal protection 6
• Alzheimer's disease 6
• Metabolic dysfunction-associated steatotic liver disease 6
• Promotion of healthy ageing 6

Critical Safety Considerations

Metformin is contraindicated when eGFR falls below 30 mL/min/1.73 m² due to increased risk of metformin-associated lactic acidosis (MALA). 7, 8

• Can be used with standard dosing when eGFR ≥45 mL/min/1.73 m² 7, 9
• For eGFR 30-44 mL/min/1.73 m², metformin can be continued but requires dose reduction to maximum 1,000 mg/day 7, 9
• Should not be initiated when eGFR is 30-45 mL/min/1.73 m² 7
• Must be temporarily discontinued during acute illness, contrast procedures, hospitalization, or surgery 7, 9
• Monitor eGFR every 3-6 months in patients at risk for declining kidney function 7, 9
• Additional contraindications include decompensated heart failure, hepatic impairment, and alcohol abuse 8, 1