Introduction
Metformin is a biguanide antihyperglycemic agent that has served as a cornerstone therapy for type 2 diabetes mellitus since its FDA approval in 1994. As the first-line pharmacological treatment recommended by major guidelines worldwide, metformin effectively lowers blood glucose with a favorable safety profile and minimal risk of hypoglycemia when used as monotherapy.
Mechanism of Action
Metformin's primary mechanism involves activation of AMP-activated protein kinase (AMPK), a key cellular energy sensor. Its glucose-lowering effects are achieved through multiple pathways:
- Decreases hepatic glucose production via gluconeogenesis suppression
- Enhances peripheral glucose uptake and utilization in muscle tissue
- Improves insulin sensitivity by reducing insulin resistance
- Delays intestinal glucose absorption
Unlike sulfonylureas, metformin does not stimulate insulin secretion and therefore does not cause hypoglycemia when used alone.
Indications
- First-line treatment for type 2 diabetes mellitus as monotherapy or in combination with other antidiabetic agents
- Prevention of type 2 diabetes in high-risk individuals (off-label)
- Polycystic ovary syndrome (PCOS) for metabolic improvements (off-label)
- Gestational diabetes (off-label in some guidelines)
Dosage and Administration
Standard dosing:- Initial dose: 500 mg once daily or 500 mg twice daily with meals
- Maintenance dose: 500-850 mg two to three times daily
- Maximum dose: 2550 mg/day (850 mg three times daily) or 2000 mg/day for extended-release formulation
- Renal impairment: Not recommended if eGFR <30 mL/min/1.73m²; use caution with eGFR 30-45 mL/min/1.73m²
- Hepatic impairment: Contraindicated in severe impairment
- Elderly: Monitor renal function regularly
- Pediatrics: FDA-approved for children ≥10 years
- Immediate-release tablets: 500 mg, 850 mg, 1000 mg
- Extended-release tablets: 500 mg, 750 mg, 1000 mg
Pharmacokinetics
- Absorption: Bioavailability 50-60%; food decreases extent but not overall absorption
- Distribution: Volume of distribution 63-276 L; minimal plasma protein binding
- Metabolism: Not metabolized hepatically; no cytochrome P450 involvement
- Elimination: Renal excretion unchanged via tubular secretion; elimination half-life 6.2 hours
- Steady-state: Reached within 24-48 hours
Contraindications
- Severe renal impairment (eGFR <30 mL/min/1.73m²)
- Metabolic acidosis, including diabetic ketoacidosis
- History of hypersensitivity to metformin
- Acute or chronic metabolic acidosis
- Conditions predisposing to renal dysfunction including:
- Cardiovascular collapse - Acute myocardial infarction - Sepsis
Warnings and Precautions
Lactic acidosis: Rare but serious complication (approximately 6 cases per 100,000 patient-years) requiring immediate medical attention. Risk factors include:- Renal impairment
- Congestive heart failure requiring pharmacologic treatment
- Age >65 years
- Radiographic contrast administration
- Surgery requiring restricted food and fluid intake
- Excessive alcohol intake
- Hepatic impairment
Drug Interactions
Major interactions:- Cationic drugs (amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, vancomycin): Compete for renal tubular secretion
- Alcohol: Increases risk of lactic acidosis
- Iodinated contrast media: Increases risk of contrast-induced nephropathy and lactic acidosis
- Carbonic anhydrase inhibitors (topiramate, zonisamide): May increase lactic acidosis risk
Adverse Effects
Common (≥5%):- Gastrointestinal: Diarrhea (53%), nausea/vomiting (26%), abdominal discomfort (25%)
- Metallic taste (3%)
- Decreased appetite
- Lactic acidosis (0.03 cases per 1000 patient-years)
- Vitamin B12 deficiency (7% after 5 years of use)
- Hepatitis (rare)
Monitoring Parameters
- Baseline: Renal function (eGFR), hepatic function, vitamin B12 level, hemoglobin A1c
- Ongoing:
- Hemoglobin A1c every 3 months until stable, then every 6 months - Renal function annually (more frequently if impaired) - Vitamin B12 levels every 2-3 years - Signs/symptoms of lactic acidosis (myalgias, respiratory distress, malaise) - Gastrointestinal tolerance
Patient Education
- Take with meals to minimize gastrointestinal upset
- Do not crush or chew extended-release tablets
- Report unusual muscle pain, trouble breathing, stomach pain, nausea, or dizziness
- Inform all healthcare providers about metformin use before procedures
- Avoid excessive alcohol consumption
- Be aware of potential vitamin B12 deficiency symptoms (fatigue, neuropathy)
- Understand that metformin does not typically cause hypoglycemia when used alone
- Never discontinue without consulting healthcare provider
References
1. American Diabetes Association. Standards of Medical Care in Diabetes—2023. Diabetes Care. 2023;46(Suppl 1):S1-S291. 2. Foretz M, Guigas B, Viollet B. Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus. Nat Rev Endocrinol. 2019;15(10):569-589. 3. FDA Prescribing Information: Metformin Hydrochloride Tablets. Revised 2022. 4. McCreight LJ, Bailey CJ, Pearson ER. Metformin and the gastrointestinal tract. Diabetologia. 2016;59(3):426-435. 5. de Jager J, Kooy A, Lehert P, et al. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ. 2010;340:c2181. 6. Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA. 2014;312(24):2668-2675.