Metformin (Glucophage) for Type 2 Diabetes & Metabolic Health — Weight & Metabolism
First-line oral biguanide for type 2 diabetes that decreases hepatic glucose production and improves insulin sensitivity, with emerging longevity and cancer-prevention properties.
Overview
Metformin is the most widely prescribed oral antidiabetic and first-line therapy for type 2 diabetes per ADA/EASD guidelines. A biguanide that primarily decreases hepatic glucose production and improves peripheral insulin sensitivity. The UKPDS trial demonstrated HbA1c reduction of 1.3% vs placebo, with dose-response studies showing reductions of 0.9% (500mg), 1.5% (1500mg), and 2.0% (2000mg daily). Beyond glycemic control, metformin has cardiovascular benefits, modest weight neutrality/loss, and emerging evidence for anti-aging properties (TAME trial ongoing). Used as first-line monotherapy when HbA1c <9% at diagnosis, or in combination with any other diabetes medication class. Extremely well-established safety profile with >60 years of clinical use. PMID: 9428832, 10359389.
Indications
- First-line pharmacotherapy for type 2 diabetes mellitus
- Prediabetes prevention (off-label; DPP trial showed 31% diabetes risk reduction)
- Polycystic ovary syndrome (PCOS) - insulin resistance and ovulatory dysfunction
- Gestational diabetes mellitus (adjunct to insulin in some guidelines)
- Anti-aging and longevity research (TAME trial - Targeting Aging with Metformin)
Mechanism of Action
Insulin resistance in the liver leads to excessive gluconeogenesis and glycogenolysis, driving fasting hyperglycemia
Dosing
| Compound | Dose | Frequency | Notes |
|---|---|---|---|
| Metformin IR | 500 mg | Once daily with dinner for 1 week | Starting dose to minimize GI side effects |
| Metformin IR | 500 mg | Twice daily (breakfast & dinner) | Increase after 1 week if tolerated |
| Metformin IR | 1000 mg | Twice daily (2000mg/day total) | Maximum effective dose; additional benefit minimal above this |
| Metformin XR | 500-2000 mg | Once daily with evening meal | Better GI tolerability; equivalent efficacy to IR at same total daily dose |
Evidence Grade
GRADE A
Safety & Contraindications
- Well-established safety profile with >60 years of clinical experience
- GI side effects most common: nausea, diarrhea, abdominal pain - mitigated with slow titration and extended-release formulation
- Rare but serious: lactic acidosis (2-9 per 100,000 person-years); risk increases with renal impairment, hepatic disease, sepsis, dehydration
- Contraindicated if eGFR <30 mL/min/1.73m2; reduce dose if eGFR 30-45; hold before iodinated contrast procedures
- Long-term use associated with vitamin B12 deficiency (5-10% of patients) - monitor B12 levels after 4+ years
- Does NOT cause hypoglycemia as monotherapy (glucose-dependent mechanism)