What are the other uses of metformin (Metformin) besides type 2 diabetes mellitus (Type II DM)?

Other Uses of Metformin Beyond Type 2 Diabetes

Metformin has established clinical uses beyond type 2 diabetes, most notably for polycystic ovary syndrome (PCOS), diabetes prevention in high-risk prediabetes, and gestational diabetes, with emerging evidence for metabolic dysfunction-associated liver disease and cancer prevention. 1, 2, 3

Established Clinical Uses

Polycystic Ovary Syndrome (PCOS)

• Metformin improves insulin sensitivity and may normalize menstrual cycles in females with PCOS. 1
• It reduces circulating androgens and insulin resistance, thereby improving ovulation rates. 4
• Critical caveat: Because metformin may improve fertility in patients with PCOS, contraception is indicated for sexually active patients who wish to avoid pregnancy. 1

Diabetes Prevention in Prediabetes

• The American Diabetes Association recommends metformin as adjunctive therapy for specific high-risk populations with prediabetes: 2
  • BMI ≥35 kg/m²
  • Age 25-59 years
  • History of gestational diabetes
• Long-term data from the Diabetes Prevention Program showed 6.2% mean weight loss at 15-year follow-up compared to 2.8% with placebo. 2
• In adults with prediabetes and BMI ≥35 kg/m², metformin was as effective as lifestyle modification. 2

Gestational Diabetes and Pregnancy

• The FDA label states that metformin is present in human milk, with infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage. 3
• Published data have not reported a clear association with major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. 3
• Women with prior gestational diabetes showed equivalent 50% reduction in diabetes risk with metformin compared to intensive lifestyle modification. 2

Adjunct Therapy in Type 1 Diabetes

• Adding metformin to insulin therapy may reduce insulin requirements (6.6 U/day reduction) and improve metabolic control in overweight/obese patients with poorly controlled type 1 diabetes. 1
• Metformin led to small reductions in weight and total and LDL cholesterol but not to improved glycemic control (absolute A1C reduction 0.11%, P = 0.42). 1

Emerging and Investigational Uses

Metabolic Dysfunction-Associated Liver Disease (MASLD/MASH)

• The evidence is contradictory regarding metformin's role in fatty liver disease: 5, 6
  • Metformin suppresses hepatic glucose production, improves hepatic steatosis, and suppresses liver inflammation according to human and animal studies. 6
  • However, recent research suggests metformin worsens inflammation in non-alcoholic fatty liver disease (NAFLD) and should not be used for this purpose. 5
• Metformin decreased the risk of death in patients with liver cirrhosis. 5

Cancer Prevention and Treatment

• Metformin is being investigated for cancer prevention, including in Li Fraumeni syndrome. 7
• Evidence suggests beneficial effects in colorectal cancer, early-stage prostate cancer, breast cancer, urothelial cancer, blood cancer, melanoma, and bone cancer. 5
• Metformin is effective in the prevention and improvement of survival in patients with hepatocellular carcinoma. 5

Neuroprotection and Cognitive Function

• Metformin shows neuroprotective effects and provides potential therapeutic benefit for mild cognitive impairment and Alzheimer's disease. 5
• It has been shown to improve mental function and reduce the incidence of dementia. 5

Renal Protection

• Daily oral administration of metformin could ameliorate kidney fibrosis and normalize kidney structure and function. 5

Weight Management in Non-Diabetic Individuals

• Metformin typically produces approximately 3% weight loss, with only 25-50% of patients achieving the clinically meaningful threshold of ≥5% weight loss. 2
• Doses greater than 1500 mg daily are associated with greater weight loss effects. 2
• Important caveat: Metformin is not effective as first-line therapy for weight loss compared to newer agents like GLP-1 receptor agonists, which produce substantially greater weight loss. 2

Critical Safety Considerations Across All Uses

Contraindications

• Severe renal impairment (eGFR <30 mL/min/1.73 m²) 1, 3
• Hepatic impairment 1, 3
• Risk for lactic acidosis (sepsis, hypoxia, shock, acute kidney injury) 1, 3
• Before iodinated contrast imaging procedures in patients with reduced eGFR (<60 mL/min/1.73 m²) 1

Dose Adjustments

• Dose reduction is recommended if eGFR is 30-45 mL/min/1.73 m². 1
• Metformin should be discontinued if eGFR is less than 30 mL/min/1.73 m². 1

Long-Term Monitoring

• Periodic testing of vitamin B12 levels is essential, as metformin use is associated with increased risk of vitamin B12 deficiency and worsening of symptoms of neuropathy. 1
• Lactate concentrations should be measured in fragile patients, and metformin should be withdrawn if increased lactate concentrations are apparent. 1

Reproductive Considerations

• Premenopausal women should be counseled that metformin therapy may result in ovulation in some anovulatory women, which may lead to unintended pregnancy. 3