Metformin

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
Oldest Diabetes Mellitus agent
1. Derivative of Goat's Rue (French Lily)
2. Used in medieval Europe for Diabetes Mellitus

Risk of Lactic Acidosis (theoretical based on older Biguanides)
1. Avoid if GFR <30 ml/min (previously contraindicated in GFR <60 ml/min)
  1. Reduce Metformin dose to half if GFR 30-45 ml/min (max 1000 mg/day)
  2. (2012) Presc Lett 19(11): 64
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. Avoid in combination with carbonic anhydrase inhibitors
5. 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]
Avoid in hepatic insufficiency
1. 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
1. Eurich (2007) BMJ 335(7618):497 [PubMed]

Maximum daily dose of Metformin is 2500 mg (for either regular or XR or ER)
1. Effective maximum dose is 2000 mg daily (effect drops off above 2000 mg)
2. Limit dose to 1000 mg/day for GFR 30-45 ml/min
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
Cost
1. Most formulations (except Glumetza and Fortamet) are generic and very affordable
  1. Avoid Glumetza ($1600/month) and Fortamet ($360/month) in 2024
2. Metformin is the 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.
References
1. Garber (1997) Am J Med 103(6):491-7 +PMID: 9428832 [PubMed]

FDA approved for ages >=10 years old
Week 1: 500 mg orally twice daily (or 850 mg orally daily)
Week 2
1. Example 1: 1000 mg orally qAM and 500 mg orally qPM
2. Example 2: 850 mg orally twice daily
Week 3: 1000 mg orally twice daily

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
1. May divide dosing to twice daily

Gastrointestinal side effects (up to one third of patients)
1. Symptoms
  1. Abdominal discomfort
  2. Abdominal Bloating
  3. Diarrhea
  4. Metallic Taste
  5. Nausea or Vomiting
  6. 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
Folic Acid Deficiency
1. Decreased Folic Acid absorption
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]
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]

Toxic dose: >100 mg/kg (children) up to >5 grams (adults)
Labs
1. See Medication Overdose
2. Serum Glucose
3. Serum lactate
4. Venous Blood Gas
5. Basic metabolic panel
Consider Activated Charcoal if large ingestion and presentation within 1 hour
Supportive care (Vasopressors may be needed)
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
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