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]
Images: Related links to external sites (from Bing)
Related Studies
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 |
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 |