Medications> Glucose-lowering>

INDICATIONS

• Type 2 diabetes mellitus

• Polycystic ovarian syndrome (PCOS)
• Prevention of type 2 diabetes mellitus in selected patients with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) ("pre-diabetes")
• Prevention against gestational diabetes mellitus

MECHANISM

• Decreases hepatic glucose production
• Decreases intestinal absorption of glucose
• Increases peripheral glucose uptake and utilization

USUAL ADULT DOSING

• Immediate release tablet: "start low, go slow," and take with or after meals to reduce risk of GI upset.
• Up to 20% of patients will experience GI upset if metformin is not initiated at a low dose, not titrated upwards slowly, or given on an empty stomach.
• Recommend initiation with 500 mg with dinner x 2 weeks, then 500 mg with breakfast and 500 mg with dinner x 2 weeks, then 500 mg with breakfast and 1 gm with dinner x 2 weeks, then 1 gm twice a day with breakfast and dinner if no side effects.
• Usual maintenance dose for immediate release: 1000 mg to 2550 mg daily, split among 2 to 3 divided doses. Maximum total daily dose 2550 mg.
• Extended release tablet: 500 mg XR once daily, then increase dosage by 500 mg weekly. Maximum total daily dose 2500 mg (Fortamet), or 2000 mg (Glucophage XR and Glumetza).

FORMS

*Prices represent cost per unit specified and are representative of "Average Wholesale Price" (AWP). AWP Prices were obtained and gathered by Lakshmi Vasist Pharm D using the Red Book, manufacturer's information, and the McKesson database.

^Dosage is indicated in mg unless otherwise noted.

DOSING IN SPECIAL POPULATIONS

• Contraindicated if creatinine > 1.4 mg/dL in women, or > 1.5 mg/dL in men, due to increased risk of lactic acidosis

• Avoid due to increased risk of lactic acidosis

• FDA Category B

• Thomson Lactation Ratings: infant risk is minimal.
• In a study by Glueck et al (2006), the use of metformin (2550 mg total daily dose) by mothers breastfeeding their infants for 6 months did not affect growth, motor, or social development; the effects beyond 6 months were not studied.

ADVERSE DRUG REACTIONS

• Generally well tolerated if taken with or after meals (reduces GI upset)
• Contraindicated in renal impairment (creatinine > 1.4 mg/dL for women, and creatinine > 1.5 mg/dL for men) due to increased risk of lactic acidosis
• If patients are having radiologic studies requiring intravenous iodinated contrast dye, stop metformin prior to/at the time of the procedure and resume it 48 hours after dye administration only if renal function is normal
• Avoid excessive alcohol use (increases risk of lactic acidosis)
• Do not use in diabetic ketoacidosis or as antihyperglycemic therapy for type 1 diabetes mellitus

• Nausea, vomiting, diarrhea, flatulence, indigestion; incidence can be decreased by drug initiation at a low dose, with slow upwards titration of dose, as described above
• Cobalamin (Vitamin B-12) deficiency
• Asthenia (physical weakness or loss of strength)

• Megaloblastic anemia due to Vitamin B-12 deficiency. Metformin appears to decrease the absorption of Vitamin B-12 from the gut.
• Lactic acidosis -- rare, but fatal in about 50% of cases. More common in patients with predisposing conditions including renal insufficiency, dehydration, excessive alcohol intake, liver disease, sepsis, congestive heart failure, cardiovascular collapse, acute myocardial infarction, the elderly (especially > 80 years old), and any other condition causing tissue hypoxemia and hypoperfusion (excess lactate production or decreased lactate clearance). Metformin increases blood lactate levels as a result of enhanced lactate production.

DRUG INTERACTIONS

• Iodinated contrast agents may enhance the adverse/toxic effect of metformin-associated lactic acidosis. Metformin should be temporarily stopped in patients receiving iodinated contrast agents prior to or at the time of the procedure and for at least 48 hours after administration of any iodinated contrast agent. Adequate renal function should be documented prior to restarting metformin.
• Dofetilide (an antiarrhythmic drug) is eliminated by both glomerular filtration and active tubular secretion via the cation transport system. Because metformin may compete with dofetilide for this pathway, the elimination of dofetilide may be decreased, resulting in increased dofetilide plasma concentrations which increases risk of cardiac toxicity. Metformin and dofetilide should be used in combination with caution.
• Caution when using metformin with other drugs that may increase serum creatinine; discontinue metformin if serum creatinine exceeds above recommendations.

PHARMACOKINETIC

COMMENTS

• After at least 3 months on maximal dose metformin monotherapy, overall HbA1c reduction is about 1-2%.
• Metformin is effective, has a long track record, has a desirable weight loss effect in most patients, does not cause hypoglycemia when used as monotherapy, and is cheap. Thus, it remains a drug of first choice for most newly diagnosed overweight type 2 diabetic patients if no contraindications exist.
• Overweight patients with type 2 diabetes mellitus on insulin therapy often require lower doses of insulin if metformin is also on board, due to metformin's insulin sensitizing effects. If discontinuing metformin, expect to increase insulin dose. 
• If patients are having radiologic studies requiring intravenous iodinated contrast dye, stop metformin prior to/at the time of the procedure and resume it 48 hours after dye administration only if renal function is normal. 
• In hospitalized patients, consider holding metformin and temporarily substituting insulin therapy; resume metformin upon hospital discharge only if creatinine meets criteria above.
• Caution in using metformin in the elderly, who may have normal serum creatinine levels despite impaired renal function, and who may also be subject to polypharmacy which might contribute to renal dysfunction and increased risk of lactic acidosis.
• Check hematologic indices and Vitamin B-12 levels in patients on chronic metformin therapy, especially those receiving higher doses for longer durations. Replace B-12 if necessary.

REFERENCES

RELATED MODULES

• Cardiovascular Disease Screening and Management
• Elderly and Diabetes
• Heart Failure
• Incretin Mimetics and Amylin Analogues
• Introduction to Diabetes
• Key Studies in Diabetes Care: Prevention and Glycemic Control
• Key Studies in Diabetes Care: Efficacy of Therapies
• Nutrition for Type 2 Diabetes
• Peripheral Neuropathy
• Stroke
• Type 2 Diabetes: Sequencing Therapies