Metformin (Glucophage)

• Core dose: PO only — IR: 500 mg once or twice daily with food, titrated every 5–7 days as tolerated; usual max 2,000–2,550 mg/day. ER: 500–750 mg once daily with evening meal; usual max 2,000 mg/day
• Onset/duration: IR peaks 2–3 hours; ER peaks 6–8 hours; half-life ~4–9 hours (longer in renal impairment); duration of effect 12–24 hours depending on formulation
• Key danger: Metformin-associated lactic acidosis (MALA) in renal impairment, AKI, sepsis, shock, or overdose; GI intolerance; vitamin B12 deficiency with chronic use; hold in severe illness, eGFR <30, or before/after contrast in at-risk patients
• Special: First-line oral agent for type 2 diabetes; does not cause hypoglycemia when used alone; improves insulin sensitivity and reduces hepatic glucose output without stimulating insulin secretion; requires dose adjustment or discontinuation based on renal function

• Generic Name: Metformin
• Brand Names: Glucophage (IR), Glucophage XR, Fortamet, Glumetza, Riomet (oral solution), plus many generics and combination products with sulfonylureas, DPP-4 inhibitors, SGLT2 inhibitors, and other antihyperglycemics

Biguanide antihyperglycemic agent. Metformin primarily reduces hepatic gluconeogenesis, improves peripheral insulin sensitivity, and modestly decreases intestinal glucose absorption, leading to lower fasting and postprandial glucose levels without stimulating insulin secretion.

Mechanism of Action:

• Decreases hepatic gluconeogenesis by inhibiting mitochondrial respiratory-chain complex I and altering cellular energy state (↑AMP/ATP ratio), which activates AMP-activated protein kinase (AMPK)
• AMPK activation leads to reduced expression of gluconeogenic enzymes and decreased hepatic glucose output
• Improves insulin sensitivity in skeletal muscle and adipose tissue, enhancing peripheral glucose uptake and utilization
• May delay intestinal glucose absorption and alter gut microbiome/GLP-1 signaling, contributing to postprandial glucose control
• Does not stimulate pancreatic insulin secretion, so hypoglycemia is rare when used as monotherapy

Pharmacokinetics:

• Absorption: Oral bioavailability ~50–60%; IR peaks in 2–3 hours; ER peaks in 6–8 hours. Food may slow absorption and reduce GI side effects
• Distribution: Not protein bound; large volume of distribution; accumulates in intestinal wall, liver, and kidneys
• Metabolism: Not significantly metabolized; excreted unchanged
• Elimination: Primarily renal via active tubular secretion; half-life ~4–9 hours, longer in renal impairment. Renal function is the key determinant of clearance; accumulation in severe CKD or AKI increases risk of lactic acidosis

Available Forms:

• Immediate-release (IR) tablets: commonly 500 mg, 850 mg, 1,000 mg
• Extended-release (ER/XR) tablets: commonly 500 mg, 750 mg, 1,000 mg (varies by brand)
• Oral solution: 500 mg/5 mL (100 mg/mL) in some formulations
• Multiple fixed-dose combination products with other antihyperglycemics (sulfonylureas, DPP-4 inhibitors, SGLT2 inhibitors, TZDs, etc.)

Adult Dosing (Outpatient-Oriented):

Absolute Contraindications:

• Severe renal impairment (eGFR <30 mL/min/1.73 m²)
• Known hypersensitivity to metformin
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis (with or without coma)
• Situations associated with hypoxia or significant hemodynamic compromise where lactic acidosis risk is high (e.g., acute MI with shock, severe heart failure exacerbation, severe sepsis) — functionally contraindicated until stabilized

Precautions:

• Moderate renal impairment (eGFR 30–44) — avoid initiation; if continued, use lower doses and more frequent monitoring
• Hepatic impairment, chronic alcohol use, or conditions predisposing to hypoxia (COPD, heart failure, shock) — higher lactic acidosis risk; individualize risk/benefit
• Iodinated contrast exposure: Hold at or just before contrast in at-risk patients and restart only after verifying stable renal function
• Older adults (≥65) with borderline renal function — more frequent renal monitoring and lower maximum doses
• Prolonged fasting, severe dehydration, or surgery — consider temporary discontinuation during periods of restricted intake or hemodynamic instability
• Concomitant nephrotoxic agents or drugs that may reduce renal function (e.g., NSAIDs, ACEI/ARB plus diuretics, contrast) — monitor kidney function more closely

Common:

• Gastrointestinal: Nausea, vomiting, diarrhea, abdominal cramping, metallic taste — often dose-related and improved by slow titration and ER formulations
• Mild weight loss or weight neutrality (often a benefit compared with other agents)
• Decreased vitamin B12 levels with chronic use, which can contribute to neuropathy or anemia

Serious (ED/ICU-Relevant):

• Metformin-associated lactic acidosis (MALA): Rare but potentially fatal; presents with high anion gap metabolic acidosis, elevated lactate, GI symptoms, malaise, tachypnea, hypotension, and altered mental status
• Severe hypoglycemia is uncommon with metformin alone but can occur when combined with insulin or insulin secretagogues (e.g., sulfonylureas)
• Acute kidney injury in the setting of dehydration, contrast exposure, or nephrotoxic drugs leading to drug accumulation and increased MALA risk

• Insulin & insulin secretagogues (sulfonylureas, meglitinides): Increased hypoglycemia risk when combined — monitor glucose closely
• Contrast dye (iodinated): Increased risk of contrast-induced nephropathy and MALA; hold metformin before/after contrast in at-risk patients
• Alcohol: Increased lactic acidosis risk, especially with chronic heavy use or acute intoxication — counsel patients to avoid excessive alcohol
• Cationic drugs (cimetidine, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, vancomycin): May compete for renal tubular secretion, increasing metformin levels — monitor
• Carbonic anhydrase inhibitors (topiramate, zonisamide, acetazolamide): May increase risk of lactic acidosis — use with caution
• Nephrotoxic agents (NSAIDs, aminoglycosides, contrast): Increased AKI risk and metformin accumulation — monitor renal function closely

Renal Impairment:

• eGFR ≥60: Full dose permitted; monitor renal function at least annually
• eGFR 45–59: Use with caution; monitor renal function every 3–6 months
• eGFR 30–44: Avoid initiating; if already on metformin, consider dose reduction (e.g., max 1,000 mg/day) and close monitoring; many guidelines recommend discontinuation if risks are high
• eGFR <30: Contraindicated — stop metformin

Hepatic Impairment:

• Avoid in severe hepatic disease due to increased lactic acidosis risk
• Use with caution in mild-moderate hepatic impairment

Elderly Patients:

• More frequent renal monitoring required
• Consider lower maximum doses
• Increased risk of lactic acidosis with age-related decline in renal function

Pregnancy & Lactation:

• Pregnancy: Category B; insulin is preferred for managing diabetes in pregnancy, though metformin is increasingly used off-label for gestational diabetes and PCOS
• Lactation: Excreted in breast milk in small amounts; generally considered compatible with breastfeeding but discuss with patient

Clinical Monitoring:

• Blood glucose monitoring (fasting glucose, A1c every 3 months while adjusting, then every 6 months once stable)
• Self-monitoring of blood glucose (SMBG) or continuous glucose monitoring (CGM) as appropriate
• Watch for hypoglycemia when combined with insulin or secretagogues
• GI tolerance and adherence

Laboratory Monitoring:

• Renal function (serum creatinine/eGFR) at baseline and at least annually; every 3–6 months in patients with CKD, elderly, or high-risk comorbidities
• A1c every 3 months while adjusting therapy, then every 6 months once stable
• Vitamin B12 levels periodically (e.g., every 2–3 years) in long-term metformin users, or sooner if neuropathy or macrocytic anemia is suspected
• Lactate, blood gas, and anion gap in patients with suspected MALA (shock, AKI, overdose)

Before/After Contrast Exposure:

• Verify stable renal function before restarting metformin in at-risk patients

Metformin-Associated Lactic Acidosis (MALA):

• Presentation: High anion gap metabolic acidosis, elevated lactate (often >5 mmol/L), GI symptoms (nausea, vomiting, abdominal pain), malaise, tachypnea, hypotension, altered mental status, hypothermia
• Risk factors: Metformin overdose, severe renal impairment, AKI, sepsis, shock, tissue hypoperfusion, chronic liver disease, chronic alcoholism
• Treatment:
  • Supportive care and source control (treat sepsis, shock, hypoxia)
  • Discontinue metformin immediately
  • IV fluids and vasopressors as needed for hemodynamic support
  • Sodium bicarbonate for severe acidosis (pH <7.1) — controversial but often used
  • Hemodialysis: Indicated for severe acidosis (pH <7.0), lactate >20 mmol/L, refractory shock, or significant metformin levels; metformin is dialyzable
• Prognosis: Mortality can be high (up to 30–50%) in severe cases; early recognition and aggressive supportive care improve outcomes

• Type 2 diabetes mellitus (first-line oral therapy in most patients)
• Prediabetes in selected high-risk patients to delay progression to type 2 diabetes (e.g., younger than 60, BMI ≥35, history of gestational diabetes)
• Polycystic ovary syndrome (PCOS) with insulin resistance or impaired glucose tolerance (often adjunct to lifestyle and fertility treatments)
• Adjunct to insulin therapy in type 2 diabetes to lower total insulin requirement and improve glycemic control
• Off-label uses: Antipsychotic-induced weight gain/insulin resistance, NAFLD/NASH (data evolving)
• ED/ICU relevance: Recognition and management of metformin-associated lactic acidosis (MALA) in overdose or severe comorbid illness, and adjustment/holding of home metformin in AKI, sepsis, or contrast exposure

• 1. American Diabetes Association. (2024). Standards of medical care in diabetes. Diabetes Care, 47(Suppl. 1). https://doi.org/10.2337/dc24-SINT
• 2. Inzucchi, S. E., et al. (2015). Management of hyperglycemia in type 2 diabetes, 2015: A patient-centered approach. Diabetes Care, 38(1), 140–149. https://doi.org/10.2337/dc14-2441
• 3. U.S. Food and Drug Administration. (2024). Glucophage (metformin hydrochloride) tablets [Prescribing information]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/020357s044lbl.pdf
• 4. DeFronzo, R., Fleming, G. A., Chen, K., & Bicsak, T. A. (2016). Metformin-associated lactic acidosis: Current perspectives on causes and risk. Metabolism, 65(2), 20–29. https://doi.org/10.1016/j.metabol.2015.10.014
• 5. UpToDate. (2024). Metformin in the treatment of adults with type 2 diabetes mellitus. Wolters Kluwer. Retrieved November 24, 2025, from https://www.uptodate.com