Glucophage

Aka: Glucophage, Metformin, Biguanide

1. See Also
   1. Oral Hypoglycemic Agents
2. Mechanism
   1. Primary mechanism: Inhibits hepatic gluconeogenesis
   2. Secondary mechanism: Sensitize peripheral tissue to Insulin
3. History
   1. Other Biguanides removed from U.S. market in 1960's
      1. Toxicity limited prior use
   2. Oldest Diabetes Mellitus agent
      1. Derivative of Goat's Rue (French Lily)
      2. Used in medieval Europe for Diabetes Mellitus
4. Pathophysiology
   1. Decreases hepatic Glucose production
   2. Increases peripheral Glucose uptake
   3. Slows intestinal Glucose absorption
5. 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
   5. Other indicators
      1. Hemoglobin A1C <9%
      2. High fasting Blood Glucose 160-250 mg/dl
      3. Dyslipidemia
6. Contraindications
   1. Risk of Lactic Acidosis (theoretical based on older Biguanides)
      1. Avoid in Renal Insufficiency (GFR <60 ml/min)
         1. 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
         1. Salpeter (2003) Arch Intern Med 163(21): 2594-602
   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
7. Dosing: General
   1. Maximum daily dose of Metformin is 2500 mg (for either regular or XR)
   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
8. Dosing: Short acting
   1. Week 1: 500 mg PO bid
   2. Week 2
      1. Example 1: 1000 mg PO qAM and 500 mg PO qPM
      2. Example 2: 850 mg PO bid
   3. Week 3: 1000 mg PO bid
9. 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
10. Cost
    1. More expensive than Sulfonylureas (except generic Metformin)
    2. Less expensive than Thiazolidinediones
11. Adverse effects
    1. Abdominal discomfort
    2. Diarrhea
    3. Metallic Taste
    4. Nausea or Vomiting
    5. Anorexia
    6. Decreased absorption of Folic Acid
    7. Vitamin B12 Deficiency (due to decreased absorption)
       1. Consider periodic screening
       2. Check serum B12 when Peripheral Neuropathy occurs (do not assume Diabetic Nephropathy only)
       3. Ting (2007) Arch Intern Med 166:1975-9
    8. Lactic Acidosis Risk
       1. See contraindications above
       2. Despite theoretical risk, no evidence that Lactic Acidosis occurs with Metformin
          1. Salpeter (2003) Arch Intern Med 163:2594-602
12. References
    1. Bailey (1996) N Engl J Med 334:574-9
    2. Defronzo (1995) N Engl J Med 333:541-9, 550-4
    3. Hermann (1994) Diabetes Care 17:1100-9
    4. Stumvoll (1995) N Engl J Med 333:550-4
    5. Luna (2001) Am Fam Physician 63(9):1747-56