Metformin

Metformin is a biguanide antihyperglycemic agent that improves glucose tolerance in patients with type 2 diabetes by lowering both basal and postprandial plasma glucose. It is considered the first-line pharmacological treatment for type 2 diabetes.

Mechanism of Action

Metformin works through several complementary mechanisms:

• Mitochondrial complex I / ETFDH inhibition: metformin’s primary molecular target is the mitochondrial respiratory chain — it inhibits NADH-ubiquinone oxidoreductase (complex I) and electron transfer flavoprotein dehydrogenase (ETFDH). This raises the intracellular AMP:ATP ratio, activating AMP-activated protein kinase (AMPK, encoded by PRKAB1). AMPK activation suppresses hepatic gluconeogenesis by phosphorylating CREB-regulated transcriptional coactivator 2 (CRTC2) and other transcriptional mediators.
• Hepatic glucose production: decreases hepatic gluconeogenesis and glycogenolysis; improves hepatic insulin sensitivity. This is the primary mechanism accounting for fasting glucose reduction.
• Peripheral: enhances insulin-mediated glucose uptake in skeletal muscle and improves peripheral insulin sensitivity.
• Intestinal: delays glucose absorption, may increase GLP-1 secretion, and modulates the gut microbiome.
• Transporter profile: metformin entry into hepatocytes is mediated by organic cation transporter 1 (OCT1, SLC22A1) — reduced OCT1 expression is a recognized cause of inter-patient variability in response. In the kidney, metformin is a substrate and inhibitor of OCT2 (SLC22A2) and is excreted via MATE1 (SLC47A1) and MATE2 (SLC47A2) transporters; inhibition of these by co-medications (e.g., cimetidine) increases metformin exposure.

Metformin does not stimulate insulin secretion and therefore does not cause hypoglycemia when used as monotherapy. It is generally weight-neutral or associated with modest weight loss.

Pharmacokinetics

• Absorption: from the small intestine; bioavailability approximately 50–60%. Peak plasma concentration 2–3 hours after oral administration.
• Volume of distribution: 654 ± 358 L — very large, reflecting extensive distribution into tissues (particularly erythrocytes and intestinal wall).
• Plasma protein binding: negligible; metformin does not bind plasma proteins.
• Metabolism: not metabolized by the liver or kidneys; excreted unchanged.
• Plasma half-life: approximately 6.2 hours.
• Blood (whole-blood) half-life: approximately 17.6 hours — substantially longer than plasma half-life due to accumulation in erythrocytes. This erythrocyte compartment is clinically relevant: in renal failure, prolonged blood half-life increases lactic acidosis risk even when plasma concentrations appear moderate.
• Clearance: renal tubular secretion is the dominant elimination pathway; metformin renal clearance is approximately 3.5 times creatinine clearance, confirming active secretion via OCT2/MATE transporters (not just glomerular filtration).
• Excretion: primarily renal — approximately 90% of absorbed dose excreted unchanged in urine via tubular secretion.

Metformin is the most extensively studied oral antidiabetic medication, with decades of clinical evidence supporting its efficacy and safety.

• HbA1c reduction: typically 1–2% from baseline.
• Fasting plasma glucose: significant reductions of 50–70 mg/dL.
• Cardiovascular outcomes: in the UK Prospective Diabetes Study (UKPDS), metformin reduced diabetes-related deaths by 32%, myocardial infarction by 39%, and stroke by 41% in overweight patients with type 2 diabetes — benefits that extend beyond glycemic control alone.
• Weight effects: weight-neutral or modest weight loss (1–4 kg); preferred in overweight/obese patients.
• Other benefits: reduces progression from prediabetes to type 2 diabetes; useful in polycystic ovary syndrome (PCOS).

• Type 2 diabetes mellitus: first-line therapy as an adjunct to diet and exercise, as monotherapy in adults, adolescents, and children ≥10 years, or in combination with other oral antidiabetic agents, GLP-1 receptor agonists, or insulin.

Off-label uses (region-dependent): prediabetes prevention, polycystic ovary syndrome, gestational diabetes, weight management in patients with insulin resistance.

• Hypersensitivity to metformin or any of the excipients.
• Renal impairment with eGFR <30 mL/min/1.73 m².
• Acute conditions that may alter renal function (dehydration, severe infection, shock, intravascular iodinated contrast administration).
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis.
• Severe hepatic impairment.
• Acute alcohol intoxication, alcoholism.
• Hypoxic states (cardiac failure, respiratory failure, recent myocardial infarction).

Temporary discontinuation required: 48 hours before elective surgery; before and 48 hours after radiological procedures with iodinated contrast.

Very Common (>10%): nausea, vomiting, diarrhea, abdominal pain, loss of appetite, metallic taste. These gastrointestinal effects typically occur at the start of treatment and resolve spontaneously in most cases.

Common (1–10%): vitamin B12 deficiency with long-term use.

Rare (<0.1%): hepatitis, urticaria, erythema, lactic acidosis (very rare but serious).

Laboratory findings: decreased vitamin B12 levels in 7–30% of patients with long-term use.

• Insulin and insulin secretagogues: increased risk of hypoglycemia.
• Alcohol: increases risk of lactic acidosis and hypoglycemia.
• Iodinated contrast media: increases risk of lactic acidosis.
• Cationic drugs (amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, vancomycin): may compete for renal tubular transport and increase metformin exposure.
• Drugs that may decrease metformin effect: thiazide and other diuretics, corticosteroids, thyroid hormones, estrogens and oral contraceptives, phenytoin, high-dose nicotinic acid, sympathomimetics, calcium channel blockers.
• May affect warfarin (monitor INR).

Metformin should be taken with or immediately after meals to reduce gastrointestinal side effects.

Adults and Adolescents ≥10 Years

• Initial dose: 500 mg twice daily or 850 mg once daily with meals.
• Titration: increase by 500 mg every 1–2 weeks (or 850 mg every 2 weeks) based on glycemic response and tolerability. Slow titration improves gastrointestinal tolerance.
• Maintenance: usually 1500–2000 mg/day.
• Maximum: 2550 mg/day (3000 mg/day in some regions), divided into 2–3 doses with meals.

Children 10–17 Years

• Initial: 500 mg once or twice daily.
• Maximum: 2000 mg/day in divided doses.
• Not established in children under 10 years.

Renal Impairment Dosing

• eGFR 45–59: maximum 2000 mg/day; monitor renal function every 3–6 months.
• eGFR 30–44: maximum 1000 mg/day; monitor every 3 months.
• eGFR <30: contraindicated.

Elderly

Start at lower doses due to potential decline in renal function. Monitor renal function regularly. Maximum doses are generally not recommended.

Missed Dose

Take as soon as remembered with food. If almost time for the next dose, skip the missed dose. Do not double the dose.

Lactic Acidosis Warning

Lactic acidosis is a rare but serious metabolic complication (approximately 0.03 cases per 1000 patient-years). Risk factors include renal impairment, acute illness or dehydration, excessive alcohol intake, hepatic impairment, and hypoxic conditions.

Patients should seek immediate medical attention for symptoms such as muscle pain or cramping, unusual tiredness or weakness, dizziness, stomach discomfort, nausea or vomiting, slow or irregular heartbeat, difficulty breathing, or feeling cold.

Vitamin B12 Monitoring

Long-term metformin use may reduce vitamin B12 absorption. Monitor levels annually, especially in patients with anemia or peripheral neuropathy. Consider supplementation if deficiency is confirmed. Higher risk in elderly patients, vegetarians/vegans, and those with gastrointestinal disorders.

Renal Function Monitoring

Assess eGFR before initiating, then at least annually (more frequently in at-risk patients). Adjust dose or discontinue based on renal function.

Iodinated Contrast and Surgery

Discontinue metformin before or at the time of any iodinated contrast procedure and withhold for 48 hours after; restart only once renal function is confirmed normal. Discontinue 48 hours before elective surgery and resume when oral intake and renal function are restored.

Alcohol

Avoid excessive acute or chronic alcohol intake.

Pregnancy and Lactation

• Pregnancy: insulin is generally preferred. Metformin may be used in selected indications (PCOS, gestational diabetes) in some regions.
• Breastfeeding: excreted in small amounts in breast milk; benefit-risk should be assessed.

Effect on Driving

Metformin alone does not cause hypoglycemia and does not impair the ability to drive or operate machinery. Patients combining metformin with insulin or insulin secretagogues should be aware of hypoglycemia risk.

Store below 25°C in the original package to protect from moisture. Store out of reach of children.

3 years. Do not use after the expiry date.

Prescription required.