Pharm
Glucophage
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Glucophage
, Metformin, Biguanide, Glumetza, Fortamet
See Also
Oral Hypoglycemic
Agents
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
Mechanism
Decreases hepatic
Glucose
production (
Gluconeogenesis
)
Increases peripheral
Glucose
uptake (sensitizes peripheral tissue to
Insulin
)
Slows intestinal
Glucose
absorption
Decreases
Fatty Acid
oxidation
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)
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
)
Carmina (2004) Am J Obstet Gynecol 191:1580-4 [PubMed]
Other indicators
Hemoglobin A1C
<9%
High
Fastin
g
Blood Glucose
160-250 mg/dl
Dyslipidemia
Contraindications
Risk of
Lactic Acidosis
(theoretical based on older Biguanides)
Avoid in
Renal Insufficiency
Current guidelines as of 2012
Avoid if GFR <30 ml/min
Reduce Metformin dose to half if GFR 30-50 ml/min
(2012) Presc Lett 19(11): 64
Older guidelines
Avoid if GFR <60 ml/min
Avoid if
Serum Creatinine
>1.5 mg/dl in men and >1.4 mg/dl in women
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
Large review found no associated increased risk of
Lactic Acidosis
at standard dosing
Salpeter (2003) Arch Intern Med 163(21): 2594-602 [PubMed]
Salpeter (2010) Cochrane Database Syst Rev (4):CD002967 [PubMed]
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
Eurich (2007) BMJ 335(7618):497 [PubMed]
Dosing
Gene
ral
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
Dose related drop in
Fastin
g
Blood Glucose
Metformin 500 mg decreases
Fastin
g
Blood Glucose
by 19 mg/dl
Metformin 1000 mg decreases
Fastin
g
Blood Glucose
by 31 mg/dl
Metformin 1500 mg decreases
Fastin
g
Blood Glucose
by 41 mg/dl
Metformin 2000 mg decreases
Fastin
g
Blood Glucose
by 78 mg/dl
Metformin 2500 mg decreases
Fastin
g
Blood Glucose
by 62 mg/dl
References
Garber (1997) Am J Med 103(6):491-7 +PMID: 9428832 [PubMed]
Dosing
Short acting
Week 1: 500 mg orally twice 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
Dosing
Long Acting
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
Cost
Most formulations (except Glumetza and Fortamet) are generic and very affordable
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.
Avoid Glumetza ($1600/month) and Fortamet ($360/month)
Adverse effects
Gastrointestinal side effects (up to one third of patients)
Symptoms
Abdominal discomfort
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
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
Vegetarian
s
Elderly
Check serum B12 when
Peripheral Neuropathy
occurs (do not assume
Diabetic Nephropathy
only)
Recheck serum B12 if new numbness or
Paresthesia
s 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
Salpeter (2003) Arch Intern Med 163:2594-602 [PubMed]
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 (
Vasopressor
s 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
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]
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