II. History

  1. Other Biguanides removed from U.S. market in 1960's
    1. Toxicity limited prior use (Lactic Acidosis)
    2. Metformin has not demonstrated increased Lactic Acidosis risk
  2. Oldest Diabetes Mellitus agent
    1. Derivative of Goat's Rue (French Lily)
    2. Used in medieval Europe for Diabetes Mellitus

III. Mechanism

  1. Decreases hepatic Glucose production (Gluconeogenesis)
  2. Increases peripheral Glucose uptake (sensitizes peripheral tissue to Insulin)
  3. Slows intestinal Glucose absorption
  4. Decreases Fatty Acid oxidation

IV. Pharmacokinetics

  1. Peak activity: 2 hours
  2. Half-Life: 3-6 hours (assuming normal Renal Function)
  3. Minimal metabolism
  4. Renal excretion: 90%
  5. Toxic dose: >100 mg/kg (children) up to >5 grams (adults)

V. Indications

  1. First line agent in Type II Diabetes Mellitus
    1. Obese patients
    2. Hyperlipidemia
    3. Children over age 10 with Type II Diabetes
  2. Metabolic Syndrome
  3. Polycystic Ovary Syndrome (PCOS)
  4. Induces Ovulation (with or without Hyperandrogenism)
    1. Carmina (2004) Am J Obstet Gynecol 191:1580-4 [PubMed]
  5. Other indicators
    1. Hemoglobin A1C <9%
    2. High Fasting Blood Glucose 160-250 mg/dl
    3. Dyslipidemia

VI. Contraindications

  1. Risk of Lactic Acidosis (theoretical based on older Biguanides)
    1. Avoid in Renal Insufficiency
      1. Current guidelines as of 2012
        1. Avoid if GFR <30 ml/min
        2. Reduce Metformin dose to half if GFR 30-50 ml/min
        3. (2012) Presc Lett 19(11): 64
      2. Older guidelines
        1. Avoid if GFR <60 ml/min
        2. Avoid if Serum Creatinine >1.5 mg/dl in men and >1.4 mg/dl in women
    2. Avoid with Alcohol Abuse
    3. Avoid concurrent IV Iodinated Contrast Dye use
      1. Allow 48 hour wash-out of dye or
      2. Confirm normal Renal Function tests after dye
    4. Large review found no associated increased risk of Lactic Acidosis at standard dosing
      1. Salpeter (2003) Arch Intern Med 163(21): 2594-602 [PubMed]
      2. Salpeter (2010) Cochrane Database Syst Rev (4):CD002967 [PubMed]
  2. Avoid in hepatic insufficiency
    1. Also avoid if excessive Alcohol
  3. Hold prior to Iodinated Contrast Dye or surgery
  4. Avoid in Proteinuria
  5. Avoid in Peripheral Vascular Disease
  6. Avoid in Coronary Artery Disease
  7. Not contraindicated in stable Congestive Heart Failure
    1. Eurich (2007) BMJ 335(7618):497 [PubMed]

VII. Dosing: General

  1. Maximum daily dose of Metformin is 2500 mg (for either regular or XR or ER)
  2. Effective maximum dose is 2000 mg daily
    1. Effect drops off above 2000 mg
  3. Dose related drop in Fasting Blood Glucose
    1. Metformin 500 mg decreases Fasting Blood Glucose by 19 mg/dl
    2. Metformin 1000 mg decreases Fasting Blood Glucose by 31 mg/dl
    3. Metformin 1500 mg decreases Fasting Blood Glucose by 41 mg/dl
    4. Metformin 2000 mg decreases Fasting Blood Glucose by 78 mg/dl
    5. Metformin 2500 mg decreases Fasting Blood Glucose by 62 mg/dl
  4. References
    1. Garber (1997) Am J Med 103(6):491-7 +PMID: 9428832 [PubMed]

VIII. Dosing: Short acting

  1. Week 1: 500 mg orally twice daily
  2. Week 2
    1. Example 1: 1000 mg orally qAM and 500 mg orally qPM
    2. Example 2: 850 mg orally twice daily
  3. Week 3: 1000 mg orally twice daily

IX. Dosing: Long Acting

  1. Start: Metformin XR 500 mg daily
  2. Increase by 500 mg weekly until at 2000 mg or at goal Blood Sugar
    1. May divide dosing to twice daily

X. Cost

  1. Most formulations (except Glumetza and Fortamet) are generic and very affordable
  2. Most cost-effective agent in the Type II Diabetes Mellitus arsenal of medications
    1. Metformin extended release preparations are generic and typically $10/month in U.S.
    2. Avoid Glumetza ($1600/month) and Fortamet ($360/month)

XI. Adverse effects

  1. Gastrointestinal side effects (up to one third of patients)
    1. Symptoms
      1. Abdominal discomfort
      2. Diarrhea
      3. Metallic Taste
      4. Nausea or Vomiting
      5. Anorexia
    2. Prevention (improving compliance)
      1. Expect gastrointestinal adverse effects to be transient (days to weeks)
      2. Slow titration from 500 mg daily (or 250 mg) up to 2000 mg over 1-2 months
      3. Extended release formulations have less adverse effects
        1. Consider divided dosing (e.g. twice daily) for XR or ER if GI side effects
      4. Take during or after a large meal
      5. If GI side effects, decrease dose back to prior, and retrial higher dose after 2 weeks
  2. Folic Acid Deficiency
    1. Decreased Folic Acid absorption
  3. Vitamin B12 Deficiency (due to decreased absorption)
    1. See Vitamin B12 Deficiency for management
    2. Consider periodic screening every 2-3 years in higher risk patients
      1. Proton Pump Inhibitor use
      2. Vegetarians
      3. Elderly
    3. Check serum B12 when Peripheral Neuropathy occurs (do not assume Diabetic Nephropathy only)
      1. Recheck serum B12 if new numbness or Paresthesias occur
    4. Ting (2007) Arch Intern Med 166:1975-9 [PubMed]
  4. Lactic Acidosis Risk
    1. See contraindications above
    2. Severe Lactic Acidosis may occur with acute Overdose or in significantly reduced Renal Function
    3. Despite theoretical risk, no evidence that Lactic Acidosis occurs with Metformin at standard doses
      1. Salpeter (2003) Arch Intern Med 163:2594-602 [PubMed]

XII. Management: Overdose

  1. Toxic dose: >100 mg/kg (children) up to >5 grams (adults)
  2. Labs
    1. See Medication Overdose
    2. Serum Glucose
    3. Serum lactate
    4. Venous Blood Gas
    5. Basic metabolic panel
  3. Consider Activated Charcoal if large ingestion and presentation within 1 hour
  4. Supportive care (Vasopressors may be needed)
  5. Hemodialysis Indications
    1. Lactic Acid >20 mmol/L
    2. Metabolic Acidosis with pH <7.0
    3. Very low serum bicarbonate <5 mEq/L
    4. Refractory to supportive care
  6. Disposition
    1. Indications for discharge at 6 hours (8 hours if Metformin XR)
      1. No Metabolic Acidosis
      2. Asymptomatic
    2. Indications for hospital observation
      1. Symptomatic
      2. Worsening Metabolic Acidosis

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Cost: Medications

metformin (on 12/21/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
METFORMIN ER 1,000 MG GASTR-TB Generic $3.76 each
METFORMIN ER 1,000 MG OSM-TAB Generic $0.51 each
METFORMIN ER 500 MG GASTRC-TB Generic $2.70 each
METFORMIN ER 500 MG OSMOTIC TB Generic $0.63 each
METFORMIN HCL 1,000 MG TABLET Generic $0.03 each
METFORMIN HCL 500 MG TABLET Generic $0.02 each
METFORMIN HCL 500 MG/5 ML SOLN Generic $0.89 per ml
METFORMIN HCL 850 MG TABLET Generic $0.03 each
METFORMIN HCL ER 500 MG TABLET Generic $0.04 each
METFORMIN HCL ER 750 MG TABLET Generic $0.06 each
glumetza (on 2/22/2023 at Medicaid.Gov Survey of pharmacy drug pricing)
GLUMETZA ER 500 MG TABLET Generic $2.70 each