Metformin

Aka: Metformin, Glucophage, Biguanide, Glumetza, Fortamet, Metformin Toxicity

advertisement

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. 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

IV. Contraindications

  1. 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]
  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]

V. Mechanism

  1. Metformin is 1-1-dimethylbiguanide, derived from guanidine (via the plant French Lilac)
    1. Structurally similar to Phenformin, buformin and to antimalarials (proguanil, chlorproguanil)
  2. Therapeutic effects (at standard dosing)
    1. Increases hepatic Insulin sensitivity
      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
  3. Toxicity (massive Overdose or severe renal Impairment)
    1. Inhibits Electron Transport Chain complex 1 (ETC1)
      1. Mitochondrial dysfunction
      2. Hyperlactinemia
    2. Hepatic cytosolic redox state increased
      1. Decreased Gluconeogenesis
      2. Hypoglycemia

VI. Pharmacokinetics

  1. Oral Bioavailability: 50%
    1. Standard formulations fully absorbed within 6 hours
  2. Peak concentration: 4-8 hours
    1. Peak activity as early as 2 hours after ingestion
  3. Half-Life: 3-6 hours up to 8 hours (assuming normal Renal Function)
  4. Minimal metabolism
  5. Renal excretion: 90% (unchanged)
  6. Toxic dose: >100 mg/kg (children) up to >5 grams (adults)

VII. Medications

  1. Metformin Tablets: 500 mg, 850 mg, 1000 mg
  2. Metformin XR Tablets: 500 mg, 750 mg, 1000 mg
  3. Metformin Oral Solution: 500 mg/5 ml
  4. Glumetza: 500 mg, 1000 mg

VIII. Dosing: General

  1. 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
  2. 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
  3. 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.
  4. References
    1. Garber (1997) Am J Med 103(6):491-7 +PMID: 9428832 [PubMed]

IX. Dosing: Metformin Immediate Release (Short acting)

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

X. Dosing: Metformin Extended Release (Long Acting)

  1. FDA approved for ages >=17 years old
  2. Start: Metformin XR 500 mg daily
  3. Increase by 500 mg weekly until at 2000 mg or at goal Blood Sugar
    1. May divide dosing to twice daily

XI. Adverse Effects

  1. 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
  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
    1. See contraindications above
    2. Metabolic Acidosis with Anion Gap
    3. Severe Lactic Acidosis risk factors
      1. Acute massive Overdose (toxic at >5 g, and severe at >=20-30 grams)
      2. Significantly reduced Renal Function (drug accumulation)
    4. Despite theoretical risk, no evidence that Lactic Acidosis occurs with Metformin at standard doses
      1. Salpeter (2003) Arch Intern Med 163:2594-602 [PubMed]
  5. Hemolytic Anemia
    1. Rare, case reports
    2. Kirkiz (2014) Med Princ Pract 23(2):183-5 +PMID: 24296614 [PubMed]

XII. Safety

  1. Pregnancy Category B
  2. Unknown safety in Lactation

XIII. Management: Overdose

  1. Toxic dose: >100 mg/kg (children) up to >5 grams (adults)
    1. Acute massive Overdose (>=20-30 grams) results in severe Lactic Acidosis and higher mortality (see below)
    2. Toxicity may also occur with significant renal Impairment
  2. Findings
    1. Severe Lactic Acidosis (Metabolic Acidosis with Anion Gap)
    2. Shock state
    3. Acute Kidney Injury
  3. Labs
    1. See Medication Overdose
    2. Serum Glucose
    3. Serum lactate
    4. Venous Blood Gas
    5. Basic metabolic panel
  4. Acute management
    1. Consider Activated Charcoal if large ingestion and presentation within 1 hour
    2. Consider Insulin and dextrose infusion for Metabolic Acidosis
    3. Supportive care (Vasopressors may be needed)
    4. Shock management
      1. Intravenous FluidResuscitation
      2. Vasopressors (e.g. Norepinephrine)
      3. Bicarbonate IV (or Tromethamine) for shock with pH<6.9
      4. Methylene Blue for Catecholamine-resistant shock
  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. Prognosis: Factors associated with higher mortality
    1. pH <=7.2
    2. Lactic Acid >=15 mmol/L
    3. INR increased
    4. Acute massive Overdose (>=20-30 grams)
  7. Disposition
    1. Indications for discharge at 6 hours (8 hours if Metformin XR, 12 hours for high risk ingestion)
      1. No Metabolic Acidosis
      2. Asymptomatic
    2. Indications for hospital observation
      1. Symptomatic
      2. Lactic Acidosis or Metabolic Acidosis

XIV. Drug Interactions

  1. Carbonic anhydrase inhibitors
    1. Increased risk of Lactic Acidosis
  2. IV Iodinated Contrast Dye
    1. Increased risk of Lactic Acidosis

XV. Efficacy

  1. Type 2 Diabetes Mellitus
    1. Lowers HBA1C by 1.5%
  2. Prediabetes
    1. Reduces progression to Diabetes Mellitus
    2. Does not decrease overall mortality or cardiovascular deaths
    3. Lee (2021) Diabetes Care 44(12): 2775-82 [PubMed]
    4. Goldberg (2022) Circulation 145(22): 1632-41 [PubMed]

XVI. Resources

  1. Metformin Tablets
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=56d13a1c-b289-4528-b23c-60f5427b4552
  2. Metformin XR Tablets
    1. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=d09a2eda-fdd8-44ed-8e2f-ea91ddfd3c68

XVII. References

  1. (2015) Presc Lett 22(12): 67
  2. (2022) Presc Lett 29(2): 8
  3. Tomaszewksi (2019) Crit Dec Emerg Med 33(8): 32
  4. Carroll and Yakey (2026) Crit Dec Emerg Med 40(2): 36
  5. Bailey (1996) N Engl J Med 334:574-9 [PubMed]
  6. Defronzo (1995) N Engl J Med 333:541-9, 550-4 [PubMed]
  7. Hermann (1994) Diabetes Care 17:1100-9 [PubMed]
  8. Stumvoll (1995) N Engl J Med 333:550-4 [PubMed]
  9. Luna (2001) Am Fam Physician 63(9):1747-56 [PubMed]
  10. Vaughan (2024) Am Fam Physician 109(4): 333-42 [PubMed]

Images: Related links to external sites (from Bing)

These images are a random sampling from a Bing search on the term "Metformin." Click on the image (or right click) to open the source website in a new browser window. Search Bing for all related images

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
FPNotebook does not benefit financially from showing this medication data or their pharmacy links. This information is provided only to help medical providers and their patients see relative costs. Insurance plans negotiate lower medication prices with suppliers. Prices shown here are out of pocket, non-negotiated rates. See Needy Meds for financial assistance information. GoodRx is another tool for finding lower drug prices.

Related Topics in Pharmacology

advertisement