Introduction
Glucophage (metformin hydrochloride) is an oral antihyperglycemic agent belonging to the biguanide class, widely recognized as first-line pharmacotherapy for type 2 diabetes mellitus. Originally derived from French lilac (Galega officinalis), metformin has been used clinically since the 1950s and received FDA approval in the United States in 1994. It remains one of the most prescribed medications worldwide due to its efficacy, favorable safety profile, and potential cardiovascular benefits.
Mechanism of Action
Metformin's primary mechanism involves activation of adenosine monophosphate-activated protein kinase (AMPK), a cellular energy sensor. Its glucose-lowering effects are achieved through multiple pathways:
- Decreased hepatic glucose production via inhibition of gluconeogenesis and glycogenolysis
- Enhanced peripheral glucose uptake and utilization in muscle tissue
- Improved insulin sensitivity by reducing insulin resistance
- Delayed intestinal glucose absorption
Unlike many other antidiabetic agents, metformin does not stimulate insulin secretion and therefore does not typically cause hypoglycemia when used as monotherapy.
Indications
FDA-approved indications:- Type 2 diabetes mellitus as monotherapy or in combination with other oral antidiabetic agents or insulin
- Pediatric type 2 diabetes (ages 10 years and older)
- Polycystic ovary syndrome (PCOS)
- Prediabetes/impaired glucose tolerance
- Gestational diabetes (in some clinical scenarios)
- Weight management in certain metabolic conditions
- Prevention of type 2 diabetes in high-risk individuals
Dosage and Administration
Initial dosing: 500 mg once or twice daily, or 850 mg once daily with meals Maintenance dosing: 500-850 mg twice daily or 1000 mg twice daily (maximum 2550 mg/day) Extended-release formulation: 500-2000 mg once daily with evening meal Special populations:- Elderly: Use lower end of dosing range; monitor renal function carefully
- Renal impairment: Contraindicated if eGFR <30 mL/min/1.73m²; use caution with eGFR 30-45 mL/min/1.73m²
- Hepatic impairment: Use with caution due to increased lactic acidosis risk
- Pediatrics: 500 mg twice daily, maximum 2000 mg daily
Pharmacokinetics
Absorption: Bioavailability 50-60%; food decreases extent and slightly delays absorption Distribution: Volume of distribution 63-276 L; minimal plasma protein binding Metabolism: Not metabolized hepatically; no cytochrome P450 involvement Elimination: Renal excretion unchanged (90%); half-life 6.2 hours Steady-state: Achieved within 24-48 hoursContraindications
- Renal impairment (eGFR <30 mL/min/1.73m²)
- Metabolic acidosis, including diabetic ketoacidosis
- Acute or chronic metabolic acidosis
- History of hypersensitivity to metformin
- Acute conditions that may affect renal function (sepsis, dehydration, acute heart failure)
- Hepatic disease
- Alcohol abuse
Warnings and Precautions
Boxed Warning: Lactic acidosis - rare but serious metabolic complication with mortality rate up to 50%. Risk factors include renal impairment, congestive heart failure, advanced age, dehydration, and concomitant use of certain medications. Additional precautions:- Vitamin B12 deficiency (monitor periodically)
- Gastrointestinal adverse effects (usually transient)
- Surgical procedures (withhold 48 hours before and after)
- Radiological studies with contrast media (withhold prior to procedure)
- Hypoxic states (cardiac or respiratory failure, sepsis)
Drug Interactions
Significant interactions:- Cationic drugs: Cimetidine, ranitidine, trimethoprim - compete for renal tubular secretion
- Alcohol: Increased risk of lactic acidosis
- Carbonic anhydrase inhibitors: Topiramate, zonisamide - may increase acidosis risk
- Contrast media: Increased risk of contrast-induced nephropathy
- Other hypoglycemic agents: Additive glucose-lowering effects
Adverse Effects
Common (>10%):- Gastrointestinal: diarrhea, nausea, vomiting, abdominal discomfort, flatulence
- Metallic taste
- Anorexia
- Vitamin B12 deficiency (with long-term use)
- Lactic acidosis
- Hepatitis
- Skin reactions (urticaria, erythema)
- Hemolytic anemia
Monitoring Parameters
- Glycemic control: HbA1c every 3 months until stable, then every 6 months
- Renal function: Serum creatinine/eGFR at baseline and annually (more frequently if impaired)
- Vitamin B12 levels: Annually in high-risk patients or with long-term use
- Hepatic function: Periodically in patients with liver disease
- Signs of lactic acidosis: Unexplained hyperventilation, myalgia, malaise, respiratory distress
- Electrolytes: In patients at risk for acidosis
Patient Education
- Take with meals to minimize gastrointestinal upset
- Do not crush or chew extended-release tablets
- Report unusual muscle pain, breathing difficulties, or unexplained malaise immediately
- Maintain regular meal patterns and avoid excessive alcohol consumption
- Inform all healthcare providers about metformin use before procedures
- Recognize symptoms of hypoglycemia when used with other antidiabetic agents
- Continue dietary modifications, exercise, and regular blood glucose monitoring
- Report persistent gastrointestinal symptoms that don't resolve after few weeks
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. Metformin: update on mechanisms of action and repurposing potential. Nat Rev Endocrinol. 2023;19(8):460-476. 3. Glucophage® (metformin hydrochloride) prescribing information. Bristol-Myers Squibb Company. 4. Inzucchi SE, et al. Management of hyperglycemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2022;45(11):2753-2786. 5. Lipska KJ, et al. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA. 2021;325(22):2264-2275. 6. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes. Lancet. 1998;352(9131):854-865.