Generic Name

Metformin

Mechanism

Metformin exerts its antihyperglycemic effect primarily through multiple, complementary mechanisms:
• ↓ Hepatic gluconeogenesis – Inhibits mitochondrial respiratory chain complex I, reducing ATP production and activating AMP‑activated protein kinase (AMPK). AMPK phosphorylates and inactivates phosphoenolpyruvate carboxykinase (PEPCK) and glucose‑6‑phosphatase, suppressing gluconeogenesis.
• ↑ Peripheral glucose uptake – Enhances GLUT‑4 translocation in skeletal muscle and adipose tissue, improving insulin sensitivity.
• ↓ Intestinal glucose absorption – Modulates intestinal glucose transporters, contributing modestly to glycemic control.
• Metabolic shift – Promotes fatty acid oxidation and reduces lipolysis, indirectly lowering insulin resistance.

The synergistic reduction of hepatic glucose output and increased peripheral utilization underlies its effectiveness as a first‑line therapy in type 2 diabetes.

Pharmacokinetics

• Absorption – Oral bioavailability ~50 %; peak plasma concentration 1–3 h post‑dose. Absorption is concentration‑dependent; higher doses saturate transporters.
• Distribution – Widely distributed in tissues; plasma protein binding <10 %. Accumulates in the small intestine and kidney.
• Metabolism – Not metabolized; eliminated unchanged.
• Elimination – Renal excretion via glomerular filtration and active tubular secretion (OAT1, OCT2). Half‑life 4.5–8.7 h in normal renal function; prolonged in renal impairment.
• Drug interactions – Cimetidine, spironolactone, or other drugs inhibiting renal transporters can increase plasma levels; concomitant use with contrast agents may elevate lactic acidosis risk.

Indications

• Primary treatment of type 2 diabetes mellitus (HbA1c 7–10 %, BMI >25 kg/m²).
• Prevention of diabetes in high‑risk individuals (e.g., impaired glucose tolerance, pre‑diabetes).
• Polycystic ovary syndrome (PCOS) – Improves ovulatory function and insulin sensitivity.
• Gestational diabetes – Low‑dose metformin is an adjunct to lifestyle changes (off‑label in many regions).
• Weight management adjuncts – In obese, non‑diabetic patients under clinical trials.

Contraindications

• Absolute contraindications
• Known hypersensitivity to metformin.
• Acute or chronic renal impairment (eGFR <30 mL/min/1.73 m²).
• Severe hepatic disease or cirrhosis.
• Current use of iodinated contrast agents without adequate renal function monitoring.
• Relative cautions
• Heart failure (NYHA Class III/IV).
• Alcohol dependence (risk of lactic acidosis).
• Use during pregnancy (Category D; limited data).
• Severe infections or sepsis – avoid due to lactic acidosis risk.
• Warnings
• Lactic acidosis – Rare (≤1:10 000) but potentially fatal; patients with renal or hepatic dysfunction, heart failure, or hypoxia require monitoring.
• Vitamin B12 deficiency – Chronic use may impair absorption; screen annually.

Dosing

• Initiate with low dose, increase gradually to minimize gastrointestinal upset.
• Administer with food to reduce nausea.
• Swallow tablets whole; do not crush XR formulation.

Adverse Effects

Common (≥5 %)
• Nausea
• Diarrhea
• Dry mouth
• Headache
• Metallic taste

Serious (rare)
• Metformin‑associated lactic acidosis (MALA) – ↑ lactate, ↓ pH, ↑ β‑hydroxybutyrate.
• Severe vitamin B12 deficiency → peripheral neuropathy, anemia.
• Rare cases of hypoglycemia (usually with concomitant sulfonylureas or insulin).

Monitoring

| eGFR / Serum creatinine | Every 6 months (or 3 months if eGFR <60 mL/min) | Adjust dose at eGFR ↓10 %

Clinical Pearls

• Use the XR formulation whenever possible: it maintains plasma levels, lessens GI adverse effects, and allows once‑daily dosing, improving adherence.
• Pre‑treatment eGFR check is mandatory; if eGFR 30–59 mL/min, start at 500 mg BID and titrate only if tolerated, never exceeding 1500 mg BID.
• Avoid contrast imaging within 48 h of starting therapy, especially in CKD; consider alternative contrast or ensure adequate hydration.
• B12 monitoring: A simple serum B12 test every 12 months in patients on metformin >2 years; supplement with cyanocobalamin if <200 pg/mL.
• Pregnancy: Off‑label use in gestational diabetes can reduce insulin needs; counsel patient on weight monitoring and bleeding risk.
• Caffeine sensitivity: Some patients report jitteriness or palpitations; modestly lower caffeine intake to differentiate side effects.
• Exercise synergy: Metformin’s AMPK activation amplifies the benefits of aerobic training—encourage combined lifestyle modification.

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• Key take‑away: Metformin remains the cornerstone of type 2 diabetes management, offering robust glycemic control with a favorable safety profile when appropriately dosed, monitored, and individualized.