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. Pathophysiology

  1. Decreases hepatic Glucose production (gluconeogenesis)
  2. Increases peripheral Glucose uptake (sensitizes peripheral tissue to Insulin)
  3. Slows intestinal Glucose absorption

IV. 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

V. Contraindications

  1. Risk of Lactic Acidosis (theoretical based on older Biguanides)
    1. Avoid in Renal Insufficiency
      1. Newer guidelines (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
      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]

VI. 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 103(6):491-7 +PMID: 9428832 [PubMed]

VII. 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

VIII. 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

IX. Cost

  1. Most formulations (except Glumetza) are generic and very affordable
  2. Most cost-effective agent in the Type II Diabetes Mellitus arsenal of medications
  3. Avoid Glumetza (nearly $7000 extended release Metformin)

X. 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 (and may be divided twice daily)
      4. Take during after a large meal
  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. Despite theoretical risk, no evidence that Lactic Acidosis occurs with Metformin
      1. Salpeter (2003) Arch Intern Med 163:2594-602 [PubMed]

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Cost: Medications

METFORMIN (on 2/19/2015 at Target.com)
METFORMIN 1000 MG* Tablet #90 for $10.00 $0.11 each
METFORMIN 500 MG Tablet #90 for $10.00 $0.11 each
METFORMIN 850 MG Tablet #90 for $10.00 $0.11 each
METFORMIN ER (on 2/19/2015 at Target.com)
METFORMIN ER 500 MG* Tablet #90 for $10.00 $0.11 each
glucophage (on 4/20/2016 at Medicaid.Gov Survey of pharmacy drug pricing)
GLUCOPHAGE 1,000 MG TABLET Generic $0.03 each
GLUCOPHAGE 500 MG TABLET Generic $0.02 each
GLUCOPHAGE XR 500 MG TAB Generic $0.04 each
metformin (on 8/17/2016 at Medicaid.Gov Survey of pharmacy drug pricing)
METFORMIN ER 1,000 MG OSM-TAB Generic $12.37 each
METFORMIN HCL 1,000 MG TABLET Generic $0.03 each
METFORMIN HCL 500 MG TABLET Generic $0.02 each
METFORMIN HCL 850 MG TABLET Generic $0.03 each
METFORMIN HCL ER 1,000 MG TAB Generic $90.21 each
METFORMIN HCL ER 500 MG OSM-TB Generic $6.84 each
METFORMIN HCL ER 500 MG TABLET Generic $0.04 each
METFORMIN HCL ER 750 MG TABLET Generic $0.11 each
glumetza (on 5/18/2016 at Medicaid.Gov Survey of pharmacy drug pricing)
GLUMETZA ER 1,000 MG TABLET Generic $90.21 each
GLUMETZA ER 500 MG TABLET Generic $45.79 each

Ontology: Biguanides (C0005382)

Concepts Organic Chemical (T109) , Pharmacologic Substance (T121)
MSH D001645
SnomedCT 109082004, 373306007
Swedish Biguanider
Czech biguanidy
Finnish Biguanidit
Russian BIGUANIDY, БИГУАНИДЫ
Croatian BIGVANIDI, BIGUANIDI
English Biguanides [Chemical/Ingredient], biguanide, biguanides, Biguanides, Biguanide, Biguanide (product), Biguanide (substance)
Polish Biguanidu pochodne
Norwegian Not Translated[Biguanides]
Spanish biguanida (producto), biguanida (sustancia), biguanida, Biguanidas
French Biguanides
German Biguanide
Italian Biguanidi
Portuguese Biguanidas

Ontology: Metformin (C0025598)

Definition (CHV) a kind of diabetes treatment drug
Definition (NCI_NCI-GLOSS) The active ingredient in a drug used to treat diabetes mellitus (a condition in which the body cannot control the level of sugar in the blood). It is also being studied in the treatment of cancer. It decreases the amount of glucose (a type of sugar) released into the bloodstream from the liver and increases the body's use of the glucose. Metformin is a type of antidiabetic agent.
Definition (NCI) An agent belonging to the biguanide class of antidiabetics with antihyperglycemic activity. Metformin is associated with a very low incidence of lactic acidosis. This agent helps reduce LDL cholesterol and triglyceride levels, and is not associated with weight gain, and prevents the cardiovascular complications of diabetes. Metformin is not metabolized and is excreted unchanged by the kidneys.
Definition (MSH) A biguanide hypoglycemic agent used in the treatment of non-insulin-dependent diabetes mellitus not responding to dietary modification. Metformin improves glycemic control by improving insulin sensitivity and decreasing intestinal absorption of glucose. (From Martindale, The Extra Pharmacopoeia, 30th ed, p289)
Definition (CSP) N,N-dimethylimidodicarbonimidic diamide; an oral hypogylcemic agent.
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH D008687
SnomedCT 109081006, 372567009
LNC LP33332-5, MTHU016062
English Dimethylbiguanidine, Dimethylguanylguanidine, Metformin, Imidodicarbonimidic diamide, N,N-dimethyl-, 1,1-Dimethylbiguanide, N,N-Dimethylimidodicarbonimidic Diamide, Metformin [Chemical/Ingredient], METFORMIN, metFORMIN, metformin, Metformin (product), Metformin (substance)
Swedish Metformin
Czech metformin
Finnish Metformiini
Russian METFORMIN, DIMETILGUANILGUANIDIN, ДИМЕТИЛГУАНИЛГУАНИДИН, МЕТФОРМИН
Japanese ジメチルグアニルグアニジン, 1,1-ジメチルビグアニド, メトホルミン塩酸塩, ネルビス, 塩酸メトホルミン, グリコラン, メデット, メトホルミン, メルビン, メトフォルミン
Italian Dimetilbiguanide, Dimetil guanil guanidina, Metoformina
Croatian METFORMIN
Polish Metformina
Spanish metformina (producto), metformina (sustancia), metformina, Dimetilguanilguanidina, Metformina
French Diméthylbiguanide, Metformine
German Dimethylguanylguanidin, Metformin
Portuguese Dimetil Guanil Guanidina, Metformina

Ontology: Glucophage (C0591573)

Definition (CHV) brand name of metformin an anti-diabetic drug
Definition (CHV) brand name of metformin an anti-diabetic drug
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH D008687
English glucophage, Glucophage [brand name], Glucophage

Ontology: Glumetza (C1724447)

Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
English Glumetza