II. History
- Other Biguanides removed from U.S. market in 1960's
- Toxicity limited prior use (Lactic Acidosis)
- Metformin has not demonstrated increased Lactic Acidosis risk
- Oldest Diabetes Mellitus agent
- Derivative of Goat's Rue (French Lily)
- Used in medieval Europe for Diabetes Mellitus
III. Indications
- First line agent in Type II Diabetes Mellitus
- Obese patients
- Hyperlipidemia
- Children over age 10 with Type II Diabetes
- Metabolic Syndrome
- Polycystic Ovary Syndrome (PCOS)
- Induces Ovulation (with or without Hyperandrogenism)
- Other indicators
- Hemoglobin A1C <9%
- High Fasting Blood Glucose 160-250 mg/dl
- Dyslipidemia
IV. Contraindications
- Risk of Lactic Acidosis (theoretical based on older Biguanides)
- Avoid if GFR <30 ml/min (previously contraindicated in GFR <60 ml/min)
- Reduce Metformin dose to half if GFR 30-45 ml/min (max 1000 mg/day)
- (2012) Presc Lett 19(11): 64
- Avoid with Alcohol Abuse
- Avoid concurrent IV Iodinated Contrast Dye use
- Allow 48 hour wash-out of dye or
- Confirm normal Renal Function tests after dye
- Avoid in combination with carbonic anhydrase inhibitors
- Large review found no associated increased risk of Lactic Acidosis at standard dosing
- Avoid if GFR <30 ml/min (previously contraindicated in GFR <60 ml/min)
- Avoid in hepatic insufficiency
- Also avoid if excessive Alcohol
- Hold prior to Iodinated Contrast Dye or surgery
- Avoid in Proteinuria
- Avoid in Peripheral Vascular Disease
- Avoid in Coronary Artery Disease
- Not contraindicated in stable Congestive Heart Failure
V. Mechanism
- Decreases hepatic Glucose production (Gluconeogenesis)
- Increases peripheral Glucose uptake (sensitizes peripheral tissue to Insulin)
- Slows intestinal Glucose absorption
- Decreases Fatty Acid oxidation
VI. Pharmacokinetics
- Peak activity: 2 hours
- Half-Life: 3-6 hours (assuming normal Renal Function)
- Minimal metabolism
- Renal excretion: 90%
- Toxic dose: >100 mg/kg (children) up to >5 grams (adults)
VII. Medications
- Metformin Tablets: 500 mg, 850 mg, 1000 mg
- Metformin XR Tablets: 500 mg, 750 mg, 1000 mg
- Metformin Oral Solution: 500 mg/5 ml
- Glumetza: 500 mg, 1000 mg
VIII. Dosing: General
- Maximum daily dose of Metformin is 2500 mg (for either regular or XR or ER)
- Effective maximum dose is 2000 mg daily (effect drops off above 2000 mg)
- Limit dose to 1000 mg/day for GFR 30-45 ml/min
- Dose related drop in Fasting Blood Glucose
- Metformin 500 mg decreases Fasting Blood Glucose by 19 mg/dl
- Metformin 1000 mg decreases Fasting Blood Glucose by 31 mg/dl
- Metformin 1500 mg decreases Fasting Blood Glucose by 41 mg/dl
- Metformin 2000 mg decreases Fasting Blood Glucose by 78 mg/dl
- Metformin 2500 mg decreases Fasting Blood Glucose by 62 mg/dl
- Cost
- Most formulations (except Glumetza and Fortamet) are generic and very affordable
- Avoid Glumetza ($1600/month) and Fortamet ($360/month) in 2024
- Metformin is the most cost-effective agent in the Type II Diabetes Mellitus arsenal of medications
- Metformin extended release preparations are generic and typically $10/month in U.S.
- Most formulations (except Glumetza and Fortamet) are generic and very affordable
- References
IX. Dosing: Metformin Immediate Release (Short acting)
- FDA approved for ages >=10 years old
- Week 1: 500 mg orally twice daily (or 850 mg orally daily)
- Week 2
- Example 1: 1000 mg orally qAM and 500 mg orally qPM
- Example 2: 850 mg orally twice daily
- Week 3: 1000 mg orally twice daily
X. Dosing: Metformin Extended Release (Long Acting)
- FDA approved for ages >=17 years old
- Start: Metformin XR 500 mg daily
- Increase by 500 mg weekly until at 2000 mg or at goal Blood Sugar
- May divide dosing to twice daily
XI. Adverse Effects
- Gastrointestinal side effects (up to one third of patients)
- Symptoms
- Abdominal discomfort
- Abdominal Bloating
- Diarrhea
- Metallic Taste
- Nausea or Vomiting
- Anorexia
- Prevention (improving compliance)
- Expect gastrointestinal adverse effects to be transient (days to weeks)
- Slow titration from 500 mg daily (or 250 mg) up to 2000 mg over 1-2 months
- Extended release formulations have less adverse effects
- Consider divided dosing (e.g. twice daily) for XR or ER if GI side effects
- Take during or after a large meal
- If GI side effects, decrease dose back to prior, and retrial higher dose after 2 weeks
- Symptoms
-
Folic Acid Deficiency
- Decreased Folic Acid absorption
-
Vitamin B12 Deficiency (due to decreased absorption)
- See Vitamin B12 Deficiency for management
- Consider periodic screening every 2-3 years in higher risk patients
- Proton Pump Inhibitor use
- Vegetarians
- Elderly
- Check serum B12 when Peripheral Neuropathy occurs (do not assume Diabetic Nephropathy only)
- Recheck serum B12 if new numbness or Paresthesias occur
- Ting (2007) Arch Intern Med 166:1975-9 [PubMed]
-
Lactic Acidosis Risk
- See contraindications above
- Severe Lactic Acidosis may occur with acute Overdose or in significantly reduced Renal Function
- Despite theoretical risk, no evidence that Lactic Acidosis occurs with Metformin at standard doses
XII. Safety
- Pregnancy Category B
- Unknown safety in Lactation
XIII. Management: Overdose
- Toxic dose: >100 mg/kg (children) up to >5 grams (adults)
- Labs
- See Medication Overdose
- Serum Glucose
- Serum lactate
- Venous Blood Gas
- Basic metabolic panel
- Consider Activated Charcoal if large ingestion and presentation within 1 hour
- Supportive care (Vasopressors may be needed)
-
Hemodialysis Indications
- Lactic Acid >20 mmol/L
- Metabolic Acidosis with pH <7.0
- Very low serum bicarbonate <5 mEq/L
- Refractory to supportive care
- Disposition
- Indications for discharge at 6 hours (8 hours if Metformin XR)
- No Metabolic Acidosis
- Asymptomatic
- Indications for hospital observation
- Symptomatic
- Worsening Metabolic Acidosis
- Indications for discharge at 6 hours (8 hours if Metformin XR)
XIV. Drug Interactions
- Carbonic anhydrase inhibitors
- Increased risk of Lactic Acidosis
- IV Iodinated Contrast Dye
- Increased risk of Lactic Acidosis
XV. Resources
XVI. References
- (2015) Presc Lett 22(12): 67
- (2022) Presc Lett 29(2): 8
- Tomaszewksi (2019) Crit Dec Emerg Med 33(8): 32
- Bailey (1996) N Engl J Med 334:574-9 [PubMed]
- Defronzo (1995) N Engl J Med 333:541-9, 550-4 [PubMed]
- Hermann (1994) Diabetes Care 17:1100-9 [PubMed]
- Stumvoll (1995) N Engl J Med 333:550-4 [PubMed]
- Luna (2001) Am Fam Physician 63(9):1747-56 [PubMed]
- Vaughan (2024) Am Fam Physician 109(4): 333-42 [PubMed]
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