What are the indications for metformin (biguanide) beyond diabetes?

Indications for Metformin Beyond Diabetes

Metformin should be considered for prevention of type 2 diabetes in high-risk adults (especially those aged 25-59 years with BMI ≥35 kg/m² or with prior gestational diabetes), and as adjunctive therapy in polycystic ovary syndrome (PCOS) for metabolic and reproductive benefits. 1

Primary Non-Diabetic Indication: Type 2 Diabetes Prevention

Metformin is recommended for diabetes prevention in specific high-risk populations, particularly those who meet criteria from the Diabetes Prevention Program (DPP):

• Adults aged 25-59 years with BMI ≥35 kg/m² show effectiveness equivalent to intensive lifestyle modification 1
• Women with prior gestational diabetes mellitus (GDM) achieve a 50% reduction in diabetes risk, maintained over 10-15 years 1
• Individuals with higher baseline fasting glucose (≥110 mg/dL) or A1C (6.0-6.4%) experience greater risk reductions 1

The evidence demonstrates that metformin reduces diabetes incidence by approximately 23-25% overall in high-risk adults, with effectiveness particularly pronounced in younger individuals and those with higher BMI 2. Metformin combined with lifestyle interventions reduces diabetes incidence by 52% compared to standard care alone in patients with prediabetes 2.

Dosing for Diabetes Prevention

• Target dose: 1700 mg daily for optimal effectiveness 2
• Start with 500 mg once or twice daily and titrate gradually to minimize gastrointestinal side effects 3
• Effectiveness is maintained with continuous use but weakens after discontinuation 2

Polycystic Ovary Syndrome (PCOS)

Metformin improves insulin resistance, menstrual regularity, and androgen levels in women with PCOS, particularly those with obesity or documented insulin resistance 4, 5.

Specific Benefits in PCOS:

• Metabolic improvements: Reduces insulin resistance and may prevent progression to metabolic syndrome and type 2 diabetes 5
• Reproductive benefits: Restores menstrual cyclicity and may enhance fertility when combined with other treatments 4, 5
• Pregnancy outcomes: May reduce early pregnancy loss, miscarriage, and preterm birth; reduces risk of gestational diabetes, eclampsia, and hypertension 4, 5

Important Limitations in PCOS:

• Not effective as first-line therapy for weight loss, ovulation induction, or treatment of hirsutism/acne 4
• Works best when combined with other treatments rather than as monotherapy 4

Gestational Diabetes and Pregnancy

Metformin is used as second-line therapy for diabetes during pregnancy when dietary modifications are insufficient 3. However, important caveats exist:

• Metformin crosses the placenta, raising concerns about long-term safety for children 3
• Follow-up studies show children exposed to metformin in utero have higher BMI and increased obesity rates in childhood 3
• Not recommended as first-line treatment for gestational diabetes in the US due to these safety concerns 3

Weight Management (Off-Label)

Metformin is NOT FDA-approved for weight loss and should not be used as a primary weight loss agent, though it produces modest weight effects as a secondary benefit 3.

• Typical weight loss: approximately 3%, with 25-50% achieving ≥5% weight loss 3
• Most effective in individuals with BMI ≥35 kg/m², adults under 60 years, and women with prior GDM 3
• Requires doses >1500 mg daily for greatest weight effect 3

Safety Monitoring for Long-Term Use

All patients on chronic metformin therapy require periodic vitamin B12 monitoring, especially after 4-5 years of use 1, 3:

• Monitor annually in patients on metformin >4 years 1
• Higher risk groups: vegans, previous gastric/small bowel surgery, those with anemia or peripheral neuropathy 1
• Vitamin B12 deficiency risk increases with duration of therapy 1

Contraindications Across All Indications:

• eGFR <30 mL/min/1.73 m² (absolute contraindication) 1, 3
• Hepatic dysfunction, severe infection, or hypoxia 3
• Consider dose reduction to half maximum if eGFR 30-44 mL/min/1.73 m² 3

Investigational Uses (Not Yet Established)

Current research is exploring metformin for cancer prevention, renal protection, Alzheimer's disease, metabolic dysfunction-associated steatotic liver disease, and healthy aging, but these remain investigational without sufficient evidence for clinical recommendation 6.