metFORMIN

Class: Biguanides
ATC Class: A10BA02
VA Class: HS502
Chemical Name: 1,1-Dimethylbiguanide monohydrochloride
Molecular Formula: C₄H₁₁N₅ • HCl
CAS Number: 1115-70-4
Brands: Fortamet, Glucophage, Glucophage XR, Glumetza, Riomet

Medically reviewed by Drugs.com. Last updated on Nov 18, 2019.

Warning

Lactic acidosis rare but potentially fatal.⁶ ¹⁸ ²⁰ ²⁷ ²⁹ ³⁰ ⁶² ⁸⁹ ⁹⁶ ¹⁵⁸ Increased risk of lactic acidosis in patients with renal impairment and advanced age.¹ ² ⁶² ⁹⁶ ¹¹⁹
Generally has occurred in diabetic patients with severe renal insufficiency who frequently had concomitant medical and/or surgical problems and were receiving multiple drugs; metformin plasma concentrations >5 mcg/mL often found in patients with lactic acidosis.¹ ² ³ ²⁰ ⁵⁰ ⁶² ⁶⁴ ⁷⁶ ⁹⁶ ¹²³ ¹⁵⁸ ¹⁶⁴ ¹⁶⁵
Periodically monitor renal function and use the minimum effective dosage.¹ ³² ⁶² ⁶³ ⁶⁵ ⁷⁶ ⁸⁵ ⁹¹ ⁹³ ⁹⁶ ¹²³ ¹²⁴ ¹⁵⁸ ¹⁶⁴ ¹⁶⁵ ²⁴⁷ ²⁵⁸ ³¹³ ³¹⁴ Withhold metformin promptly in patients with any condition associated with hypoxemia, sepsis, or dehydration.¹ ² ⁶² ⁶³ ⁹³ ³¹³ Avoid use in patients with clinical or laboratory evidence of hepatic impairment.¹ ² ⁶³ ⁶⁵ ⁸⁵ ⁹¹ ⁹³ ¹⁵⁶ ¹⁵⁸ ³¹³ ³¹⁴ Manufacturers state to temporarily discontinue metformin therapy before or at the time of an iodinated contrast imaging procedure in patients with eGFR of 30–60 mL/minute per 1.73 m² and in patients with a history of liver disease, alcoholism, or heart failure.¹ ³³⁰ ³³⁶ Withhold metformin temporarily in patients undergoing surgery or receiving intra-arterial iodinated contrast agents. ¹ ² ³⁰ ⁶² ⁶³ ⁹³ ¹⁵⁸ ²³⁴ ²⁴⁷ ²⁵⁴ ²⁶¹ ³¹³ ³¹⁴ ³³⁰ ³³⁶ Drugs that may affect renal function or alter metformin elimination should be used with caution.¹

However, the American College of Radiology states that in patients with no evidence of acute kidney injury and eGFR ≥30 mL/minute per 1.73 m², there is no need to discontinue metformin either before or following the administration of iodinated contrast media, nor is there a need to reassess the patient's renal function after the test or procedure.³³⁵
Advise patients not to consume excessive amounts of alcohol.¹ ² ⁶³ ⁷⁶ ⁹¹ ⁹³ ¹⁵⁸
If lactic acidosis occurs, discontinue metformin.¹ ³⁰ ³¹³ ³¹⁴ Treat as medical emergency; immediate hospitalization and treatment required; hemodialysis recommended.¹ ²³ ³² ⁶² ¹¹⁷ ¹¹⁹ ³¹³ ³¹⁴

Introduction

Antidiabetic agent; a biguanide, chemically and pharmacologically unrelated to sulfonylurea antidiabetic agents.¹ ² ³ ⁴ ¹⁸ ²⁰ ²² ²³ ²⁷ ²⁸ ²⁹ ³⁰ ³³ ⁷² ¹⁴⁶ ²⁴³ ²⁴⁵ ²⁴⁶

Uses for metFORMIN

Type 2 Diabetes Mellitus

Used as an adjunct to diet and exercise for the management of type 2 diabetes mellitus.¹ ³ ⁴ ⁶ ⁸ ¹⁵ ¹⁶ ¹⁷ ¹⁸ ¹⁹ ²⁰ ²⁷ ²⁹ ⁹⁵ ¹⁶⁶ ²⁴³ ²⁴⁵ ²⁴⁶

May be used in combination with a sulfonylurea, repaglinide, a thiazolidinedione antidiabetic agent, a dipeptidyl peptidase-4 [DPP-4] inhibitor, a glucagon-like peptide-1 (GLP-1) agonist, or a sodium-glucose cotransporter-2 [SGLT2] inhibitor for the management of type 2 diabetes mellitus in patients who do not achieve adequate glycemic control on monotherapy with metformin or any of these drugs.¹ ³ ⁶ ¹⁵ ¹⁸ ²⁰ ²² ²⁷ ²⁹ ³⁰ ⁴⁸ ⁵⁹ ⁷⁸ ⁸⁸ ⁹⁵ ⁹⁷ ⁹⁹ ¹¹² ¹³⁴ ¹⁶⁶ ¹⁹¹ ²³⁴ ²³⁷ ²³⁸ ²³⁹ ²⁴¹ ²⁴² ²⁴³ ²⁴⁵ ²⁴⁶ ²⁴⁹ ²⁵⁰ ²⁶⁰ ³⁵² ³⁵⁵ ³⁶² ³⁶⁸ ³⁷⁰ ³⁷² ³⁷⁴ ³⁷⁶ ³⁷⁸ ⁵⁹⁸ ⁶⁰⁴ ⁶¹⁰ Also used concomitantly with nateglinide.²⁴⁸

May be used with insulin to improve glycemic control and/or decrease the required dosage of insulin.¹ ³ ⁶ ⁸⁸ ⁹⁰ ⁹⁴ ⁹⁵ ¹⁴⁶

Commercially available in fixed combination with glyburide or glipizide for use as an adjunct to diet and exercise in adults with type 2 diabetes mellitus.²³⁴ ²⁵⁴ May add a thiazolidinedione antidiabetic agent if patient has inadequate glycemic control with fixed-combination metformin/glyburide therapy.²³⁴

Commercially available in fixed combination with rosiglitazone for use when treatment with both rosiglitazone and metformin is appropriate.²⁴⁷

Commercially available in fixed combination with pioglitazone (as immediate- or extended-release tablets) for use as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who have inadequate glycemic control with pioglitazone or metformin monotherapy or in those who are already receiving pioglitazone and metformin concurrently as separate components.²⁶⁰

Commercially available in fixed combination with repaglinide for use as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who are already receiving repaglinide and metformin concurrently as separate components or in those who have inadequate glycemic control with repaglinide or metformin monotherapy.³¹³

Commercially available in fixed combination with the DPP-4 inhibitors alogliptin, linagliptin, saxagliptin, or sitagliptin for use as an adjunct to diet and exercise when treatment with both drug components is appropriate.³¹⁴ ³⁵² ³⁶⁸ ³⁷⁶ ³⁷⁸ ⁶¹⁰

Commercially available in fixed combinations with the SGLT2 inhibitors canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin for use when treatment with both drugs components is appropriate.³⁵⁵ ³⁶² ³⁷² ³⁷⁰

Metformin generally is the preferred initial oral antidiabetic agent for patients with type 2 diabetes mellitus.²⁶⁴ Potential advantages of metformin compared with sulfonylureas or insulin include minimal risk of hypoglycemia, more favorable effects on serum lipids, reduction of hyperinsulinemia, and weight loss or lack of weight gain.¹ ² ³ ⁶ ¹⁶ ¹⁷ ¹⁸ ¹⁹ ²⁰ ²⁷ ³⁰ ⁴² ⁶⁰ ⁶⁸ ¹⁰² ¹³⁴ ¹⁴⁶ ¹⁶⁶ ²⁶⁴

Not effective as sole therapy in patients with diabetes mellitus complicated by acidosis, ketosis, or coma.¹ ⁶ ³⁰ ¹⁴⁶ ¹⁹¹ ¹⁹²

Polycystic Ovary Syndrome

Has been used in the management of metabolic and reproductive abnormalities associated with polycystic ovary syndrome†.²⁸⁹ ²⁹⁰ ²⁹¹ ²⁹² ²⁹³ ²⁹⁴ ²⁹⁵ ²⁹⁶ ²⁹⁷ ²⁹⁸ ²⁹⁹ ³⁰⁰ ³⁰¹ ³⁰² ³⁰³ ³⁰⁴ ³⁰⁵ ³⁰⁶ ³⁰⁷ ³⁰⁸ ³⁰⁹ ³¹⁰ ³¹¹ ³¹²

metFORMIN Dosage and Administration

General

When therapy is transferred from most sulfonylurea antidiabetic agents to metformin, sulfonylurea agent may be abruptly discontinued (no transition period generally required).¹ ²
Patients whose therapy is transferred from chlorpropamide to metformin should be monitored closely for hypoglycemia during the initial 2 weeks following transfer.¹ ² ³⁰
Goal of therapy should be to reduce both fasting glucose and HbA_1c values to normal or near normal using the lowest effective dosage of metformin hydrochloride, either when used as monotherapy or combined with another antidiabetic agent.¹ ⁸ ¹³ ¹⁴ ⁷⁸ ⁸⁵ ⁸⁸ ¹⁰⁵ ¹³⁴ ¹⁴⁶ ¹⁶⁶ ²³⁴ ²³⁵ ²⁴³ ²⁴⁵ ²⁴⁶

Administration

Oral Administration

Administer orally with meals to reduce adverse GI effects.¹ ² ³ ¹⁸ ⁵³ ⁸⁵ ²⁴³ ²⁴⁵ ²⁴⁶

Administer immediate-release tablets 2 or 3 times daily.¹ ²⁴³ ²⁴⁵ ²⁴⁶ Administer in 2 divided doses if total dosage ≤2 g daily or in 3 divided doses if total dosage is >2 g daily.¹

Administer extended-release tablets once daily with the evening meal; swallow whole and do not chew, cut, or crush.¹ ²⁵⁸ ²⁵⁹ ²⁶⁰ ²⁶¹ In addition, administer Fortamet extended-release tablets with a full glass of water.²⁵⁸

Administer immediate-release metformin hydrochloride in fixed combination with canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, pioglitazone, rosiglitazone, repaglinide, alogliptin, linagliptin, or sitagliptin in divided doses daily with meals to reduce the GI effects of the metformin hydrochloride component.²⁴⁷ ²⁶⁰ ³¹³ ³¹⁴ ³⁵⁵ ³⁶² ³⁷⁰ ³⁷² ³⁷⁶ ⁶¹⁰

Administer metformin/repaglinide fixed-combination tablets within 15 minutes before meals.³¹³ If a meal is skipped, omit dose for that meal.³¹³

Administer extended-release metformin hydrochloride in fixed combination with canagliflozin, dapagliflozin, or empagliflozin once daily with the morning meal.³⁶² ³⁷⁰ ³⁷⁴

Administer the fixed combination of extended-release metformin hydrochloride and linagliptin once daily with a meal.³⁷⁸ Administer the fixed combination of extended-release metformin hydrochloride and sitagliptin once daily with a meal, preferably the evening meal.³⁵² Administer extended-release metformin hydrochloride in fixed combination with saxagliptin once daily with the evening meal.³⁶⁸

Dosage

Available as metformin hydrochloride; dosage expressed in terms of the salt.¹

Individualize dosage carefully based on patient’s glycemic response and tolerance.¹ ⁴ ²⁴³ ²⁴⁵ ²⁴⁶

Pediatric Patients

Type 2 Diabetes Mellitus

Oral

Immediate-release tablets or oral solution in children 10–16 years of age: Initially, 500 mg twice daily with meals.¹ ²⁵⁷ Increase daily dosage in increments of 500 mg at weekly intervals to a maximum of 2 g daily given in divided doses.¹ ²⁵⁷

Adults

Type 2 Diabetes Mellitus

Metformin Hydrochloride Monotherapy

Oral

Immediate-release tablets or oral solution: Initially, 500 mg twice daily or 850 mg once daily with meals.¹ ²⁵⁷ Increase daily dosage by 500 mg at weekly intervals or by 850 mg at biweekly (every 2 week) intervals up to a maximum of 2 g daily given in divided doses.¹ ²⁵⁷ May increase dosage from 500 mg twice daily to 850 mg twice daily after 2 weeks.¹ ²⁵⁷ Clinically important responses generally not observed at dosages <1.5 g daily.¹ ²⁵⁷

Initial dosage of 500 mg once daily suggested by some experts.²⁶⁴

For additional glycemic control, increase dosage (as immediate-release tablets or oral solution) up to a maximum daily dosage of 2.55 g given in divided doses.¹ ²⁵⁷

Extended-release tablets (Glucophage XR) in patients ≥17 years of age: Initially, 500 mg once daily with the evening meal.¹ ²⁵⁹ Increase daily dosage by 500 mg at weekly intervals to a maximum of 2 g daily.¹ ²⁵⁹ If glycemic control is not achieved with 2 g once daily, consider administering 1 g twice daily.¹ ²⁵⁹ If >2 g daily is required, switch to immediate-release tablet formulation and increase dosage up to 2.55 g daily in divided doses (preferably 3 doses per day for daily dosages >2 g).¹ ²⁵⁹

Extended-release tablets (Fortamet) in patients ≥17 years of age: Initially, 1 g once daily with the evening meal; 500 mg once daily may be used when clinically appropriate.²⁵⁸ Increase daily dosage by 500 mg at weekly intervals to a maximum of 2.5 g daily with the evening meal.²⁵⁸

Immediate-release Metformin Hydrochloride in Fixed Combination with Glipizide (e.g., Metaglip)

Oral

Patients with inadequate glycemic control on diet and exercise alone: Initially, 250 mg of metformin hydrochloride and 2.5 mg of glipizide once daily with a meal.²⁵⁴ For more severe hyperglycemia (fasting plasma glucose concentrations of 280–320 mg/dL), 500 mg of metformin hydrochloride and 2.5 mg of glipizide twice daily.²⁵⁴ Increase daily dosage in increments of one tablet (using the tablet strength at which therapy was initiated) at 2-week intervals until adequate glycemic control is achieved or maximum daily dosage of 2 g of metformin hydrochloride and 10 mg of glipizide is reached.²⁵⁴ ²⁵⁶

Efficacy of metformin hydrochloride and glipizide in fixed combination not established in patients with fasting plasma glucose concentrations >320 mg/dL.²⁵⁴ No experience with total initial daily dosages exceeding 2 g of metformin hydrochloride and 10 mg of glipizide.²⁵⁴

Patients with inadequate glycemic control on either a sulfonylurea or metformin alone: Initially, 500 mg of metformin hydrochloride and 2.5 or 5 mg of glipizide twice daily with the morning and evening meals.²⁵⁴ Initial dosage of the fixed combination should not exceed the patient's current daily dosage of metformin hydrochloride or glipizide (or equivalent dosage of another sulfonylurea).²⁵⁴ Titrate daily dosage in increments not exceeding 500 mg of metformin hydrochloride and 5 mg of glipizide until adequate glycemic control achieved or maximum daily dosage of 2 g of metformin hydrochloride and 20 mg of glipizide is reached.²⁵⁴

Patients currently receiving combined therapy with separate metformin and glipizide (or another sulfonylurea) preparations: May switch to 500 mg of metformin hydrochloride and 2.5 or 5 mg of glipizide; initial dosage of the fixed-combination preparation should not exceed the patient's current daily dosage of metformin hydrochloride and glipizide (or equivalent dosage of another sulfonylurea).²⁵⁴ Use clinical judgment regarding whether to switch to the nearest equivalent dosage or to titrate dosage.²⁵⁴ Titrate daily dosage in increments not exceeding until adequate glycemic control is achieved or maximum daily dosage of 2 g of metformin hydrochloride and 20 mg of glipizide is reached.²⁵⁴

Immediate-release Metformin Hydrochloride in Fixed Combination with Glyburide (e.g., Glucovance)

Oral

Patients with inadequate glycemic control on diet and exercise alone: Initially, 250 mg of metformin hydrochloride and 1.25 mg of glyburide once daily with a meal.²³⁴ For more severe hyperglycemia (i.e., fasting plasma glucose concentrations >200 mg/dL or HbA_1c >9%), may consider initial dosage of 250 mg of metformin hydrochloride and 1.25 mg of glyburide twice daily with the morning and evening meals.²³⁴ Titrate daily dosage in increments of 250 mg of metformin hydrochloride and 1.25 mg of glyburide at 2-week intervals until adequate glycemic control is achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 10 mg of glyburide is reached.²³⁴

Do not use the fixed combination of metformin hydrochloride 500 mg and glyburide 5 mg as initial therapy due to an increased risk of hypoglycemia.²³⁴

Patients with inadequate glycemic control on a sulfonylurea and/or metformin: Initially, 500 mg of metformin hydrochloride and 2.5 or 5 mg of glyburide twice daily.²³⁴ Initial dosage of the fixed combination should not exceed the patient's current daily dosage of glyburide (or equivalent dosage of another sulfonylurea antidiabetic agent) and metformin hydrochloride.²³⁴ Increase daily dosage in increments not exceeding 500 mg of metformin hydrochloride and 5 mg of glyburide until adequate glycemic control is achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 20 mg of glyburide is reached.²³⁴

Patients currently receiving combined therapy with separate metformin and glyburide (or another sulfonylurea agent) preparations: Initial dosage of the fixed combination should not exceed the previous dosage of metformin hydrochloride and glyburide (or the equivalent dosage of the other sulfonylurea).²³⁴ Titrate daily dosage in increments not exceeding 500 mg of metformin hydrochloride and 5 mg of glyburide until adequate glycemic control is achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 20 of mg glyburide is reached.²³⁴

For patients whose hyperglycemia is not adequately controlled on the fixed combination, may add a thiazolidinedione (e.g., pioglitazone, rosiglitazone) at its recommended initial dosage and continue same dosage of the fixed combination.²³⁴ In patients requiring further glycemic control, increase thiazolidinedione dosage as recommended.²³⁴

Immediate-release Metformin Hydrochloride in Fixed Combination with Rosiglitazone (Avandamet)

Oral

Dosage of the fixed combination is based on the patient’s current dosages of metformin hydrochloride and/or rosiglitazone.²⁴⁷ (See Table 1.) In rosiglitazone-naive patients, initiate rosiglitazone component at the lowest recommended dosage.²⁴⁷

In patients currently receiving metformin monotherapy, the usual initial dosage of rosiglitazone is 4 mg daily given in divided doses with patient's existing dosage of metformin hydrochloride.²⁴⁷

In patients currently receiving rosiglitazone monotherapy, the usual initial dosage of metformin hydrochloride is 1 g daily given in divided doses with patient's existing dosage of rosiglitazone.²⁴⁷

Individualize therapy in patients already receiving metformin hydrochloride at doses not available in the fixed combination (i.e., doses other than 1 or 2 g).²⁴⁷

Table 1. Initial Dosage of the Fixed Combination of Metformin Hydrochloride and Rosiglitazone (Avandamet)247
Prior Therapy	Usual Initial Dosage of Avandamet
Total Daily Dosage	Tablet Strength	Number of Tablets
Metformin Hydrochloride
1 g	2 mg/500 mg	1 tablet twice daily
2 g	2 mg/1 g	1 tablet twice daily
Rosiglitazone
4 mg	2 mg/500 mg	1 tablet twice daily
8 mg	4 mg/500 mg	1 tablet twice daily

For patients switching from combined therapy with separate metformin and rosiglitazone preparations, the usual initial dosage of the fixed combination is the same as the patient's existing dosage of the individual drugs.²⁴⁷

If additional glycemic control is needed following transfer, increase daily dosage in increments of 500 mg of metformin hydrochloride and/or 4 mg of rosiglitazone until adequate glycemic control is achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 8 mg of rosiglitazone is reached.²⁴⁷ Following increase in dosage of metformin hydrochloride, further dosage adjustment recommended if adequate glycemic control not achieved in 1–2 weeks. ²⁴⁷ Following increase in dosage of rosiglitazone, further dosage adjustment recommended if adequate glycemic control not achieved in 8–12 weeks.²⁴⁷

Immediate-release Metformin Hydrochloride in Fixed Combination with Pioglitazone (Actoplus Met)

Oral

Individualize dosage based on the patient’s current dosage regimen, effectiveness, and tolerability.²⁶⁰

Usual initial dosage is 500 or 850 mg of metformin hydrochloride and 15 mg of pioglitazone given once or twice daily.²⁶⁰

Gradually titrate dosage as needed based on therapeutic response.²⁶⁰ Allow sufficient time (e.g., 8–12 weeks) to assess response.²⁶⁰

Safety and efficacy of transferring from therapy with other oral antidiabetic agents to Actoplus Met not established; undertake any such change with caution and appropriate monitoring.²⁶⁰

Extended-release Metformin Hydrochloride in Fixed Combination with Pioglitazone (Actoplus Met XR)

Oral

Individualize dosage based on the patient’s current dosage regimen, effectiveness, and tolerability.²⁶⁰

Usual initial dosage is 1 g of metformin hydrochloride and 15 or 30 mg of pioglitazone given once daily.²⁶⁰

Gradually titrate dosage as needed based on therapeutic response.²⁶⁰ Allow sufficient time (e.g., 8–12 weeks) to assess response.²⁶⁰

Safety and efficacy of transferring from therapy with other oral antidiabetic agents to Actoplus Met XR not established; undertake any such change with caution and appropriate monitoring.²⁶⁰

Immediate-release Metformin Hydrochloride in Fixed Combination with Repaglinide (PrandiMet)

Oral

Individualize dosage based on the patient’s current dosage regimen, effectiveness, and tolerability.³¹³

Patients with inadequate glycemic control on metformin monotherapy: Initially, 500 mg of metformin hydrochloride and 1 mg of repaglinide twice daily with meals; gradually increase dosage as needed.³¹³

Patients with inadequate glycemic control on repaglinide monotherapy: Initially, 500 mg of the metformin hydrochloride component (given in fixed combination with repaglinide) twice daily; gradually increase dosage as needed.³¹³

Patients switching from combined therapy with separate metformin and repaglinide preparations: Initiate with dosages that are similar to (but do not exceed) patient's existing dosages of the individual drugs.³¹³

Safety and efficacy of transferring to PrandiMet from therapy with other oral antidiabetic agents not established; undertake any such change with caution and appropriate monitoring.³¹³

Immediate-release Metformin Hydrochloride in Fixed Combination with Alogliptin (Kazano)

Oral

Individualize dosage based on current antidiabetic regimen, effectiveness, and patient tolerability.⁶¹⁰ Increase dosage gradually to minimize adverse GI effects, up to a maximum daily dosage of 2 g of metformin hydrochloride and 25 mg of alogliptin.⁶¹⁰

Immediate-release Metformin Hydrochloride in Fixed Combination with Linagliptin (Jentadueto)

Oral

Individualize dosage based on effectiveness and patient tolerability.³⁷⁶ May increase dosage up to a maximum daily dosage of 2 g of metformin hydrochloride and 5 mg of linagliptin.³⁷⁶

Patients not currently receiving metformin hydrochloride: Initially, 1 g of metformin hydrochloride and 5 mg of linagliptin administered in 2 divided doses.³⁷⁶

Patients currently receiving metformin hydrochloride: Initially, a total daily metformin hydrochloride dosage similar to patient's existing dosage and 5 mg of linagliptin, administered in 2 divided doses.³⁷⁶

Patients currently receiving linagliptin and metformin hydrochloride: Initially, same total daily dosage of each component administered in 2 divided doses daily.³⁷⁶

Extended-release Metformin Hydrochloride in Fixed Combination with Linagliptin (Jentadueto XR)

Oral

Individualize dosage based on effectiveness and patient tolerability.³⁷⁸ May increase dosage up to a maximum daily dosage of 2 g of metformin hydrochloride and 5 mg of linagliptin.³⁷⁸

Patients not currently receiving metformin hydrochloride: Initially, 1 g of metformin hydrochloride and 5 mg of linagliptin once daily.³⁷⁸

Patients currently receiving linagliptin and metformin hydrochloride: Initially, a total daily metformin hydrochloride dosage similar to the patient’s existing dosage and 5 mg of linagliptin, administered once daily.³⁷⁸

Extended-release Metformin Hydrochloride in Fixed Combination with Saxagliptin (Kombiglyze XR)

Oral

Patients inadequately controlled on monotherapy with saxagliptin 5 mg daily: Initially, 500 mg of metformin hydrochloride and 5 mg of saxagliptin once daily; increase dosage gradually to minimize adverse GI effects of metformin.³⁶⁸

Patients inadequately controlled on monotherapy with extended-release metformin hydrochloride: Dosage of the fixed combination should provide metformin hydrochloride at the current dosage or the nearest therapeutically appropriate dosage.³⁶⁸

Following a switch from immediate-release to extended-release metformin hydrochloride, closely monitor glycemic control and adjust dosage accordingly.³⁶⁸

Patients inadequately controlled on monotherapy with saxagliptin 2.5 mg daily: Initially, 1 g of metformin hydrochloride and 2.5 mg of saxagliptin daily.³⁶⁸ Use the individual components in patients who require 2.5 mg of saxagliptin and are either metformin naive or require a metformin hydrochloride dose >1 g.³⁶⁸

If used with a potent CYP3A4/5 inhibitor, limit dosage of saxagliptin to 2.5 mg once daily.³⁶⁸

Immediate-release Metformin Hydrochloride in Fixed Combination with Sitagliptin (Janumet)

Oral

Patients not currently receiving metformin hydrochloride: Initially, 500 mg of metformin hydrochloride and 50 mg of sitagliptin twice daily.³¹⁴

Patients currently receiving metformin hydrochloride: Initially, 500 mg of metformin hydrochloride and 50 mg of sitagliptin twice daily or 1 g of metformin hydrochloride and 50 mg of sitagliptin twice daily, depending on the patient's existing dosage of metformin hydrochloride.³¹⁴

Patients currently receiving immediate-release metformin hydrochloride 850 or 1000 mg twice daily: 1 g of metformin hydrochloride and 50 mg of sitagliptin twice daily.³¹⁴

Maintain the same total daily dosage of sitagliptin and metformin hydrochloride when transitioning between the fixed combination of sitagliptin and immediate-release metformin hydrochloride (Janumet) and the fixed combination of sitagliptin and extended-release metformin hydrochloride (Janumet XR).³⁵²

Efficacy and safety of switching therapy from oral antidiabetic agents other than sitagliptin or metformin hydrochloride to the fixed combination of sitagliptin and metformin hydrochloride not established.³¹⁴

Extended-release Metformin Hydrochloride in Fixed Combination with Sitagliptin (Janumet XR)

Oral

Patients not currently receiving metformin hydrochloride: Initially, 1 g of metformin hydrochloride and 100 mg of sitagliptin once daily.³⁵²

Patients currently receiving metformin hydrochloride: Initially, 1 g of metformin hydrochloride and 100 mg of sitagliptin once daily or 2 g of metformin hydrochloride and 100 mg of sitagliptin once daily, depending on the patient's existing dosage of metformin hydrochloride.³⁵²

Patients currently receiving immediate-release metformin hydrochloride 850 or 1000 mg twice daily: 2 g of metformin hydrochloride and 100 mg of sitagliptin once daily.³¹⁴ ³⁵²

Immediate-release Metformin Hydrochloride in Fixed Combination with Canagliflozin (Invokamet)

Oral

Individualize dosage based on patient's current antidiabetic regimen.³⁷⁰ May increase dosage gradually based on effectiveness and tolerability.³⁷⁰

Patients not currently receiving either canagliflozin or metformin hydrochloride: Initially, 500 mg of metformin hydrochloride and 50 mg of canagliflozin twice daily.³⁷⁰

Patients currently receiving metformin hydrochloride: Initially, a total daily metformin hydrochloride dosage similar to the patient's existing dosage and 100 mg of canagliflozin, administered in 2 divided doses.³⁷⁰ In patients currently receiving an evening dose of extended-release metformin hydrochloride, skip last dose of extended-release metformin hydrochloride prior to initiating therapy with the fixed combination of metformin hydrochloride and canagliflozin the following morning.³⁷⁰

Patients currently receiving canagliflozin: Initially, 1 g of metformin hydrochloride and same daily dosage of canagliflozin administered in 2 divided doses.³⁷⁰

Patients currently receiving metformin hydrochloride and canagliflozin: Initially, a total daily metformin hydrochloride dosage similar to patient's existing dosage and same daily dosage of canagliflozin, administered in 2 divided doses.³⁷⁰

Extended-release Metformin Hydrochloride in Fixed Combination with Canagliflozin (Invokamet XR)

Oral

Individualize dosage of based on patient's current antidiabetic regimen.³⁷⁰ May increase dosage gradually based on effectiveness and tolerability.³⁷⁰

Patients not currently receiving either canagliflozin or metformin hydrochloride: Initially, 1 g of metformin hydrochloride and 100 mg of canagliflozin once daily.³⁷⁰

Patients currently receiving metformin hydrochloride: Initially, a total daily metformin hydrochloride dosage similar to the patient's existing dosage and 100 mg of canagliflozin, administered once daily.³⁷⁰ In patients currently receiving an evening dose of extended-release metformin hydrochloride, skip last dose of extended-release metformin hydrochloride prior to initiating therapy with the fixed combination of metformin hydrochloride and canagliflozin the following morning.³⁷⁰

Patients currently receiving canagliflozin: Initially, 1 g of metformin hydrochloride and same daily dosage of canagliflozin administered once daily.³⁷⁰

Extended-release Metformin Hydrochloride in Fixed Combination with Dapagliflozin (Xigduo XR)

Oral

Initial dosage based on patient's current regimen with metformin hydrochloride and/or dapagliflozin.³⁶² May increase dosage gradually based on effectiveness and tolerability.³⁶²

Patients not currently receiving dapagliflozin: Initially, 5 mg of the dapagliflozin component once daily.³⁶² Titrate gradually based on effectiveness and tolerability, up to a maximum daily dosage of 2 g of extended-release metformin and 10 mg of dapagliflozin.³⁶²

Patients already receiving extended-release metformin hydrochloride in the evening who are switching to the fixed combination of metformin hydrochloride and dapagliflozin: Skip last dose of metformin hydrochloride before initiating therapy with the fixed combination the following morning.³⁶²

Immediate-release Metformin Hydrochloride in Fixed Combination with Empagliflozin (Synjardy)

Oral

Individualize dosage based on the patient's current antidiabetic regimen.³⁷² May increase dosage gradually based on effectiveness and tolerability.³⁷²

Patients currently receiving metformin hydrochloride: Initially, a total daily metformin hydrochloride dosage similar to patient's existing dosage and 10 mg of empagliflozin, administered in 2 divided doses.³⁷²

Patients currently receiving empagliflozin: Initially, 1 g of metformin hydrochloride and same daily dosage of empagliflozin administered in 2 divided doses.³⁷²

Patients currently receiving empagliflozin and metformin hydrochloride: Initially, a total daily metformin hydrochloride dosage similar to patient's existing dosage and same daily dosage of empagliflozin, administered in 2 divided doses.³⁷²

Extended-release Metformin Hydrochloride in Fixed Combination with Empagliflozin (Synjardy XR)

Oral

Individualize dosage based on the patient's current antidiabetic regimen.³⁷⁴ May increase dosage gradually based on effectiveness and tolerability.³⁷⁴

Patients currently receiving empagliflozin: Initially, 1 g of metformin hydrochloride and same daily dosage of empagliflozin administered once daily.³⁷⁴

Immediate-release Metformin Hydrochloride in Fixed Combination with Ertugliflozin (Segluromet)

Oral

Initial dosage based on patient's current regimen with metformin hydrochloride and/or ertugliflozin.³⁵⁵ May increase dosage gradually based on effectiveness and tolerability.³⁵⁵

Patients currently receiving metformin hydrochloride: Initially, total daily metformin hydrochloride dosage similar to patient's existing dosage and total daily dosage of 5 mg of ertugliflozin (administered as fixed combination with 2.5 mg of ertugliflozin), given in 2 divided doses daily.³⁵⁵

Patients currently receiving ertugliflozin: Initially, total daily dosage of 1 g of metformin hydrochloride (administered as fixed combination with 500 mg of metformin hydrochloride) and a total daily ertugliflozin dosage similar to the patient's existing dosage, given in 2 divided doses daily.³⁵⁵

Patients currently receiving metformin hydrochloride and ertugliflozin (administered as separate tablets): Initially, give fixed combination containing a total daily metformin hydrochloride dosage similar to patient's existing dosage and same total daily dose of ertugliflozin, in 2 divided doses daily.³⁵⁵

Metformin Hydrochloride Dosage in Patients Transferred from Insulin

Oral

Initially, 500 mg once daily; increase dosage by 500 mg daily at weekly intervals until adequate glycemic control is achieved or a maximum daily dosage of 2.5 g (immediate-release tablets) or 2 g (extended-release tablets) is reached.¹ Concurrent insulin dosage initially remains unchanged.¹ When fasting plasma glucose concentration decreases to <120 mg/dL, decrease insulin dosage by 10–25%.¹

Polycystic Ovary Syndrome†

Oral

In general, 1.5–2.25 g daily in divided doses.²⁹¹ ²⁹² ²⁹⁴ ²⁹⁶ ²⁹⁹ ³⁰⁰ ³⁰¹ ³⁰² ³⁰³ ³⁰⁵ ³⁰⁶ ³⁰⁷

Prescribing Limits

Pediatric Patients

Type 2 Diabetes Mellitus

Oral

Children 10–16 years of age: Maximum 2 g daily as immediate-release tablets or oral solution.¹ ²⁵⁷

Adults

Type 2 Diabetes Mellitus

Metformin Hydrochloride Monotherapy

Oral

Maximum 2.55 g daily as immediate-release tablets or oral solution, 2.5 g daily as Fortamet extended-release tablets, or 2 g daily as certain other extended-release tablets (e.g., Glucophage XR).¹ ² ³ ⁴ ¹⁴ ¹⁸ ²² ⁸⁵ ²⁵⁷ ²⁵⁸ ²⁵⁹ Switch to immediate-release tablets for further dosage titration if required dosage exceeds 2 g daily.¹ ²⁵⁹

Metformin Hydrochloride in Fixed Combination with Glyburide (e.g., Glucovance)

Oral

Maximum daily dosage as second-line therapy is 2 g of metformin hydrochloride and 20 mg of glyburide.²³⁴

No experience with total daily dosages exceeding 2 g of metformin hydrochloride and 10 mg of glipizide in clinical trials in patients receiving the fixed combination as initial therapy.²³⁴

Metformin Hydrochloride in Fixed Combination with Glipizide (e.g., Metaglip)

Oral

Maximum daily dosage is 2 g of metformin hydrochloride and 20 mg of glipizide.²⁵⁴ ²⁵⁶

Metformin Hydrochloride in Fixed Combination with Linagliptin (Jentadueto, Jentadueto XR)

Oral

Maximum daily dosage is 2 g of metformin hydrochloride and 5 mg of linagliptin.³⁷⁶ ³⁷⁸

Metformin Hydrochloride in Fixed Combination with Saxagliptin (Kombiglyze XR)

Oral

Maximum daily dosage is 2 g of metformin hydrochloride and 5 mg of saxagliptin.³⁶⁸

Metformin Hydrochloride in Fixed Combination with Sitagliptin (Janumet, Janumet XR)

Oral

Maximum daily dosage is 2 g of metformin hydrochloride and 100 mg of sitagliptin.³¹⁴ ³⁵²

Metformin Hydrochloride in Fixed Combination with Canagliflozin (Invokamet, Invokamet XR)

Oral

Patients with eGFR ≥60 mL/minute per 1.73 m²: Maximum daily dosage is 2 g of metformin hydrochloride and 300 mg of canagliflozin.³⁷⁰

Patients with eGFR 45 to <60 mL/minute per 1.73 m²: Maximum daily dosage is 2 g of metformin hydrochloride and 100 mg of canagliflozin.³⁷⁰

Metformin Hydrochloride in Fixed Combination with Dapagliflozin (Xigduo XR)

Oral

Maximum daily dosage is 2 g of metformin hydrochloride and 10 mg of dapagliflozin.³⁶²

Metformin Hydrochloride in Fixed Combination with Empagliflozin (Synjardy, Synjardy XR)

Oral

Maximum daily dosage is 2 g of metformin hydrochloride and 25 mg of empagliflozin.³⁷² ³⁷⁴

Metformin Hydrochloride in Fixed Combination with Ertugliflozin (Segluromet)

Oral

Maximum daily dosage is 2 g of metformin hydrochloride and 15 mg of ertugliflozin.³⁵⁵

Special Populations

Renal Impairment

eGFR 30–45 mL/minute per 1.73 m²: Do not initiate metformin; assess benefits and risks of continued treatment in patients already receiving metformin.³³⁰ ³³⁶ ³⁵⁰

eGFR <30 mL/minute per 1.73 m²: Use contraindicated; discontinue in patients already receiving metformin.³³⁰ ³³⁶ ³⁵⁰

National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) states that the exact GFR cutoff for metformin use is controversial.³⁴¹ NKF-KDOQI suggests reviewing use of metformin in GFR <45 mL/minute per 1.73 m².³⁴¹ NKF-KDOQI and other clinicians suggest avoiding metformin therapy if GFR <30 mL/minute but suggest considering risk-benefit of such therapy if GFR stable.³⁴⁰ ³⁴¹

Hepatic Impairment

Avoid use in those with hepatic disease.¹

Geriatric Patients

In general, do not titrate to the maximum dosage recommended for younger adults;¹ ² ³ ⁴ ¹⁶⁵ ²⁴³ ²⁴⁵ ²⁴⁶ ³¹⁴ limited data suggest reducing initial dosage by approximately 33% in geriatric patients.³⁰ ¹⁷⁴

Monitor renal function regularly to determine appropriate dosage.¹ ² ³ ⁴ ¹⁶⁴ ¹⁶⁵ ²⁴³ ²⁴⁵ ²⁴⁶ ³¹⁴

Cautions for metFORMIN

Contraindications

Acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma.¹ ² ²³⁴ ²⁴⁷
Severe renal impairment (eGFR <30 mL/minute per 1.73 m²),¹ ²³⁴ ²⁴⁷ ³³⁰ which may result from conditions such as cardiovascular collapse (shock), acute MI, or septicemia.¹ ²³⁴
Known hypersensitivity to metformin hydrochloride or any ingredient in the formulations.¹ ² ²³⁴ ²⁴⁷ ²⁵⁴

Warnings/Precautions

Warnings

Lactic Acidosis

See Boxed Warning.

General Precautions

Hypoglycemia

Uncommon in patients receiving metformin as monotherapy.¹ ¹⁵ ³⁰ ⁷⁸ ⁹⁴ ⁹⁹ Debilitated, malnourished, or geriatric patients and patients with renal or hepatic impairment or adrenal or pituitary insufficiency may be particularly susceptible.¹ ² Strenuous exercise, alcohol ingestion, insufficient caloric intake, or use in combination with other antidiabetic agents may increase risk.¹ ² Hypoglycemia may be difficult to recognize in geriatric patients or in those receiving β-adrenergic blocking agents.¹ ⁸³ ⁹¹ ¹²⁸ ¹⁴³ ¹⁵³ ¹⁵⁹ (See Specific Drugs under Interactions.)

Hematologic Effects

Decreased serum vitamin B₁₂ concentrations, ¹ ¹⁸ with or without clinical manifestations (e.g., anemia).¹

Symptoms rapidly reversible following discontinuation of metformin or supplementation with vitamin B₁₂.¹ ³ ⁶ ²⁰ ³⁰ ⁷⁰ ⁷⁷ ⁸² ¹³⁴ Monitor hematologic parameters (e.g., hemoglobin, serum vitamin B₁₂ concentrations)¹ ⁸² ¹¹⁴ ¹²² ¹³⁴ ¹⁴⁸ prior to initiation of therapy and at least annually during treatment and any abnormality properly investigated.¹ ³⁵⁰

Consider periodic supplementation with parenteral vitamin B₁₂ in patients at high risk for developing subnormal serum vitamin B₁₂ concentrations (e.g., alcoholics, patients with low calcium or vitamin B₁₂ intake or absorption).¹ ⁸² ¹¹⁴ ¹²² ¹³⁴ ¹⁴⁸ ⁵⁹⁸

Cardiovascular Effects

Possible increased cardiovascular mortality associated with other biguanide antidiabetic agents (i.e., phenformin).¹ ¹⁹¹ ¹⁹² ²⁰⁰ The American Diabetes Association (ADA) and other clinicians do not recommend changing current guidelines regarding the use of metformin as monotherapy or in combination with sulfonylureas pending the results of further studies of metformin alone or in combination with sulfonylureas.²²⁰ ²²¹ ²²⁴

Use of metformin in combination with rosiglitazone and insulin is not recommended; adverse cardiovascular events (e.g., edema, CHF) have occurred with combined rosiglitazone and insulin therapy.²⁴⁷

Concurrent Illness

Evaluate serum electrolytes and ketones, blood glucose, and if indicated, blood pH, lactate, pyruvate, and metformin concentrations for evidence of ketoacidosis or lactic acidosis.¹ ⁸⁸ ¹³⁴ ¹⁵⁶ ¹⁶⁹

Temporary withdrawal of metformin therapy and administration of insulin may be required to maintain glycemic control during periods of stress.¹

Use of Fixed Combinations

When used in fixed combination with other drugs, consider the cautions, precautions, contraindications, and interactions associated with the concomitant agent(s).²³⁴ ²³⁷ ²⁴⁷ ²⁵⁴ ²⁶⁰ ³¹³ ³¹⁴ ³⁵² ³⁵⁵ ³⁶² ³⁶⁸ ³⁷⁰ ³⁷² ³⁷⁴ ³⁷⁶ ³⁷⁸ ⁶¹⁰

Specific Populations

Pregnancy

Category B.¹

Most clinicians recommend use of insulin during pregnancy in diabetic patients to maintain optimum control of blood glucose concentrations.¹ ³ ⁴ ¹⁸ ⁷² ⁸⁸ ⁹²

Lactation

Distributed into milk in rats; small amounts distributed into human milk.¹ ²⁸⁴ ²⁸⁵ ²⁸⁶ Discontinue nursing or the drug.¹ ³ ⁴

Pediatric Use

Safety and efficacy of metformin as immediate-release tablets or oral solution in children <10 years of age have not been established.¹ ²⁵⁷

Safety and efficacy of metformin as extended-release tablets in children <17 years of age have not been established.¹ ²⁵⁸ ²⁵⁹

Safety and efficacy of metformin in fixed combination with glipizide, pioglitazone, repaglinide, rosiglitazone, or sitagliptin in children have not been established.¹ ³ ⁴ ³⁰ ¹³⁴ ²⁴⁷ ²⁵⁴ ²⁶⁰ ³¹³ ³¹⁴ Data from a clinical trial in children 9–16 years of age comparing combined therapy with metformin and glyburide (Glucovance) with each drug as monotherapy did not reveal unexpected safety findings.²³⁴

Geriatric Use

Insufficient number of geriatric patients in controlled clinical trials of metformin hydrochloride immediate-release (Glucophage) and extended-release tablets (Glucophage XR, Glumetza) to determine if such patients respond differently than younger adults.¹ ²⁶¹ ³¹⁴ With another extended-release preparation of metformin hydrochloride (Fortamet), no overall differences in safety or efficacy in geriatric patients were observed compared with younger adults.²⁵⁸

Use with caution, since renal function declines with age.¹ ³ ⁴ ³⁰ ⁸⁵ ¹⁷⁴ ²³⁴ ²⁴⁷ ²⁵⁴ ³¹⁴

Monitor renal function periodically.¹ ² ³ ⁴ ¹⁶⁴ ¹⁶⁵ ³¹⁴

Do not initiate in patients ≥80 years of age without confirmation of adequate renal function as measured by Cl_cr.¹ ²⁰⁹ ²¹⁴ ³¹³ ³¹⁴

Geriatric patients particularly susceptible to hypoglycemia,¹ ² which may be difficult to recognize.¹ ⁸³ ⁹¹ ¹²⁸ ¹⁴³ ¹⁵³ ¹⁵⁹

Renal Impairment

Do not use in patients with severe renal disease or dysfunction.¹ ³³⁰ (See Contraindications.)

Evaluate renal function prior to initiation of therapy and at least annually thereafter.¹ ² ⁷⁷ ⁸⁵ ²³⁴

Monitor more frequently if development of impaired renal function is anticipated (e.g., those with blood glucose concentrations >300 mg/dL, those who may develop renal dysfunction as a result of polyuria and volume depletion).¹⁵⁶

Discontinue metformin if patient's eGFR <30 mL/minute per 1.73 m²; contraindicated in such patients.³³⁰

Hepatic Impairment

Generally avoid use in patients with clinical or laboratory evidence of hepatic disease.¹ ¹⁶⁵ Elimination of lactate may be substantially reduced.¹ (See Boxed Warning.)

Common Adverse Effects

Diarrhea,¹ ³¹ ⁴⁸ ⁴⁹ ⁵³ ⁷⁸ ¹⁰⁹ ¹¹⁸ ¹²² ¹³⁵ nausea,¹ ³¹ ⁵³ ⁷⁸ ¹⁰⁹ ¹¹⁸ ¹²² vomiting,¹ ¹¹⁸ ¹²² abdominal bloating, abdominal cramping or pain,¹ ³¹ ³⁵ ⁴² ⁵³ ¹¹⁸ ¹²² flatulence,¹ anorexia.¹ ³ ⁶ ¹⁸

Interactions for metFORMIN

Cationic Agents Secreted by Proximal Renal Tubules

Pharmacokinetic interaction with cimetidine (decreased excretion of metformin).¹ ⁷⁵

Potential pharmacokinetic interaction with other cationic drugs that undergo substantial tubular secretion (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, vancomycin).¹ ³⁰

Monitor carefully; consider dosage adjustment of either agent.¹

Protein-bound Drugs

Pharmacokinetic interaction unlikely.¹

Drugs That May Antagonize Hypoglycemic Effects

Calcium-channel blocking agents, corticosteroids, thiazide diuretics, estrogens and progestins (e.g., oral contraceptives), isoniazid, niacin, phenothiazines, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline); observe patient closely for evidence of altered glycemic control when such drugs are added to or withdrawn from therapy.¹ ³⁰ ⁸⁰ ⁸⁵ ⁹¹ ¹²⁰ ¹²¹ ¹³⁴ ¹³⁹ ¹⁴³ ¹⁵¹ ¹⁵² ¹⁵³ ¹⁵⁴ ¹⁵⁹ ¹⁶⁰

Specific Drugs or Foods

Drug	Interaction	Comments
Acarbose	Acute decrease in metformin bioavailability in single-dose study¹³⁸ ²⁰¹
ACE inhibitors	Potential risk of hypoglycemia/hyperglycemia when ACE inhibitor therapy is initiated/withdrawn¹³¹ ¹³² ¹³⁴ ¹⁵² ¹⁵⁵ ¹⁶⁰	Monitor blood glucose concentrations during dosage adjustments with either agent¹³⁰ ¹³¹ ¹³² ¹³⁴ ¹⁵² ¹⁵⁵ ¹⁶⁰
Alcohol	Increased risk of hypoglycemia and lactic acidosis¹ ² ¹⁸ ³³ ⁶³ ⁷² ⁷⁶ ⁹¹ ⁹³ ¹⁰⁷ ¹⁴³	Avoid excessive alcohol intake¹
Antidiabetic agents (e.g., sulfonylureas, meglitinides, insulin)	Possible hypoglycemia¹ ¹⁵ ⁷⁸ ⁹⁴ ⁹⁹ ²⁶⁰ ³¹³	May need to reduce dosage of concomitant antidiabetic agent¹
β-Adrenergic blocking agents	May impair glucose tolerance; ⁷³ ¹⁴³ ¹⁵² ¹⁵³ ¹⁵⁹ may increase frequency or severity of hypoglycemia and hypoglycemia-induced complications⁹¹ ¹²⁷ ¹⁵³ ¹⁵⁹	If concomitant therapy necessary, a β₁-selective adrenergic blocking agent or β-adrenergic blocking agents with intrinsic sympathomimetic activity preferred³⁶ ¹⁴³ ¹⁵² ¹⁶⁰ ¹⁷³
Cimetidine	Possible decreased excretion of metformin¹ Increased peak concentrations and AUC of metformin; negligible effects on cimetidine pharmacokinetics¹	Carefully monitor patient; consider need for dosage adjustment¹
Clomiphene	Possible resumption of ovulation in premenopausal patients with polycystic ovary syndrome²¹⁰
Furosemide	Increased peak concentrations of metformin and decreased peak concentrations and terminal half-life of furosemide in single-dose study¹
Glyburide	Pharmacokinetics and pharmacodynamics of metformin not altered in single-dose study¹ ²⁶⁰ ²⁶¹ ³¹⁴ Variable decreases in AUC and peak blood concentration of glyburide¹ ²⁶⁰ ³¹⁴	Clinical importance uncertain¹
Guar gum	Reduced and delayed GI absorption of metformin ¹⁸ ⁸⁵ ⁹⁹ ¹⁰⁶
Nifedipine	Enhanced absorption and increased urinary excretion of metformin; minimal effects on nifedipine pharmacokinetics¹
Thiazide diuretics	May exacerbate diabetes mellitus¹ ⁹¹ ¹³⁹ ¹⁴³ ¹⁵¹ ¹⁵² ¹⁵³ ¹⁵⁴ ¹⁵⁹ ¹⁶⁰	Consider using less diabetogenic diuretic (e.g., potassium-sparing diuretic), reducing dosage of or discontinuing diuretic, or increasing dosage of oral antidiabetic agent⁷³ ¹³⁴ ¹⁵² ¹⁵³ ¹⁵⁴ ¹⁵⁹ ¹⁶⁰

metFORMIN Pharmacokinetics

Absorption

Bioavailability

Approximately 50–60% (absolute) with dosages of 0.5–1.5 g.¹ ² ³ ⁴ ¹⁸ ³³ ⁴³ ⁵⁰ ⁶⁵ ⁷² ⁸⁵ ⁸⁹

Fixed-combination preparation containing 500 mg of metformin hydrochloride and 4 mg of rosiglitazone is bioequivalent to mg-equivalent dosages of individual components administered separately under fasted conditions.²⁴⁷

Onset

Therapeutic response usually apparent within a few days to 1 week.¹⁸ ⁵³ ⁷² ⁹⁸ ¹³⁴ Maximal glycemic response within 2 weeks.¹⁸ ⁵³ ⁷² ⁹⁸ ¹³⁴

Duration

Blood glucose concentrations increase within 2 weeks following discontinuance of metformin therapy.⁵³ ¹³⁴

Food

Food decreases and slightly delays absorption of immediate-release tablets.¹ ² ³ ⁴ ¹⁸ ²⁰⁸ ³¹⁴

Food increases the extent of absorption of extended-release tablets (Glucophage XR, Fortamet).¹ ²⁵⁸ Peak plasma concentrations and time to achieve peak plasma concentrations not altered by administration of one extended-release preparation (Glucophage XR) with food; ¹ food increases peak plasma concentrations and prolongs time to peak plasma concentrations of another extended-release tablet preparation (Fortamet).²⁵⁸

Peak concentrations and AUC of the extended-release metformin hydrochloride component increased by approximately 98 and 85%, respectively, when Actoplus Met XR was given with food.²⁶⁰ Time to peak concentration prolonged by approximately 3 hours for pioglitazone and 2 hours for extended-release metformin hydrochloride under fed conditions.²⁶⁰

Food increases the extent of absorption and delays the time to peak plasma concentrations of the oral solution.²⁵⁷ Fat content of meals does not appreciably affect the pharmacokinetics of metformin hydrochloride oral solution.²⁵⁷

Distribution

Extent

Rapidly distributed into peripheral body tissues and fluids, particularly GI tract.³⁰ ⁵⁰ ⁶⁵ ⁷² ⁸⁹ ¹³⁴ ¹⁶² ¹⁶⁷

Slowly distributed into erythrocytes and a deep tissue compartment (probably GI tissue).³⁰ ⁵⁰ ⁶⁵ ⁷² ⁸⁹ ¹³⁴ ¹⁶² ¹⁶⁷

Plasma Protein Binding

Negligible.¹ ¹⁸ ⁵⁰ ⁵¹ ⁶⁵ ⁸⁵ ⁸⁹

Elimination

Metabolism

Not metabolized in the liver or GI tract and not excreted into bile.¹ ⁵⁰ ⁵¹ ⁸⁹ No metabolites identified in humans.¹ ⁵⁰ ⁵¹ ⁸⁹ ³¹⁴

Elimination Route

Excreted in urine (approximately 35–52%)⁵⁰ ⁵¹ ⁸⁹ and feces (20–33%).⁶ ³³ ⁴³ ⁵⁰ ⁷² ⁸⁹ Eliminated as unchanged drug.¹ ² ⁶ ³³ ⁵⁰ ⁶³ ⁶⁵ ⁷⁵ ⁸⁵ ⁸⁹ ³¹⁴

Half-life

Approximately 6.2 hours.¹ ² ⁶ ¹⁸ ³³ ³⁸ ⁵⁰ ⁵¹ ⁶⁵ ⁸⁵ ⁸⁹ ¹²⁵ ¹³⁴ ³¹⁴

Special Populations

Renal impairment may reduce clearance, including in geriatric patients with age-related decline in renal function.¹ ³³ ⁵¹ ¹⁷⁴ Renal impairment results in increased peak plasma concentrations, prolonged time to peak plasma concentration and half-life, and decreased volume of distribution.¹ ³ ⁵¹ ¹⁷⁴

Stability

Storage

Oral

Tablets

Immediate-release tablets: Tight, light-resistant containers at 20–25°C (may be exposed to 15–30°C).¹

Extended-release tablets: Tight, light resistant containers at 20–25° C (may be exposed to 15–30°C).¹ ²⁵⁸

Metformin/glyburide fixed combination: Light-resistant containers at 25°C.²³⁴

Metformin/glipizide fixed combination: 20–25° C (may be exposed to 15–30°C).²⁵⁴

Metformin/rosiglitazone fixed combination: Tight, light-resistant containers at 25°C (may be exposed to 15–30°C).²⁴⁷

Metformin/pioglitazone fixed combination: Tight (Actoplus Met) or tight, light-resistant (Actoplus Met XR) containers at 25°C (may be exposed to 15–30°C).²⁶⁰

Metformin/repaglinide fixed combination: Tight containers at temperatures not exceeding 25°C.³¹³

Metformin/linagliptin fixed combination: 25°C (may be exposed to 15–30°C); protect from exposure to high humidity.³⁷⁶ ³⁷⁸

Metformin/saxagliptin fixed combination: 20–25°C (may be exposed to 15–30°C).³⁶⁸

Metformin/sitagliptin fixed combination: 20–25°C (may be exposed to 15–30°C).³¹⁴

Metformin/canagliflozin fixed combination: 20–25°C (may be exposed to 15–30°C).³⁷⁰ Store and dispense in original container.³⁷⁰ May store in pillbox for ≤30 days.³⁷⁰

Metformin/dapagliflozin: 20–25°C (may be exposed to 15–30°C).³⁶²

Metformin/empagliflozin: 25°C (may be exposed to 15–30°C).³⁷² ³⁷⁴

Metformin/ertugliflozin: 20–25°C (may be exposed to 15–30°C); protect from moisture and store in a dry place.³⁵⁵

Solution

15–30°C.²⁵⁷

Actions

Lowers blood glucose concentrations in patients with type 2 (non-insulin-dependent) diabetes mellitus (NIDDM) without increasing insulin secretion from pancreatic β cells.¹ ² ³ ⁴ ¹⁸ ²⁰ ²⁷ ³¹ ⁴⁰ ⁶⁰ ¹³⁴ Ineffective in the absence of some endogenous or exogenous insulin.¹⁸ ²⁷ ⁴⁰ ⁷¹ ¹²²
Usually does not lower glucose concentrations below euglycemia, but hypoglycemia occasionally may occur with overdosage.¹ ² ¹⁸ ²⁰ ²⁷ ²⁸ ²⁹ ⁷² ¹⁰² ¹⁰³ ¹¹¹
Lowers both basal (fasting) and postprandial glucose concentrations in patients with type 2 diabetes mellitus.¹ ² ¹⁸ ²² Improves insulin sensitivity by decreasing hepatic glucose production and enhancing insulin-stimulated uptake and utilization of glucose by peripheral tissues (e.g., skeletal muscle, adipocytes).¹⁸ ³¹ ⁴⁰ ⁴¹ ⁴² ⁴⁴ ⁶⁰ ⁸¹ ¹⁴⁶ ¹⁴⁹ Insulin secretion usually remains unchanged.¹ ² ³ ¹⁸ ²⁰ ⁴² ⁶⁰ ⁶⁸ ¹⁰² ¹⁶⁶

Advice to Patients

Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs, dietary or herbal supplements, and alcohol consumption, as well as any concomitant illnesses (e.g., renal disease).¹ Importance of avoiding excessive alcohol consumption.¹
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹
Importance of adherence to diet and exercise regimens.¹
Possibility of primary and secondary failure with metformin therapy.¹
Risks of hypoglycemia, symptoms and treatment of hypoglycemic reactions, and conditions that predispose to the development of such reactions.¹
Importance of regular laboratory evaluations, including fasting blood (or plasma) glucose determinations.¹ ² ⁸⁵
Risks of lactic acidosis and conditions that predispose to its development.¹
Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

metFORMIN Hydrochloride
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Solution	500 mg/5 mL*	metFORMIN Hydrochloride Solution
			Riomet	Ranbaxy
	Tablets, extended-release	500 mg*	Fortamet	Shionogi Pharma
			Glucophage XR	Bristol-Myers Squibb
			Glumetza	Depomed
			metFORMIN Hydrochloride Extended-Release Tablets
		750 mg*	Glucophage XR	Bristol-Myers Squibb
			metFORMIN Hydrochloride Extended-Release Tablets
		1 g*	Fortamet	Shionogi Pharma
			Glumetza	Depomed
	Tablets, film-coated	500 mg*	Glucophage	Bristol-Myers Squibb
			metFORMIN Hydrochloride Tablets
		625 mg*	metFORMIN Hydrochloride Tablets
		750 mg*	metFORMIN Hydrochloride Tablets
		850 mg*	Glucophage	Bristol-Myers Squibb
			metFORMIN Hydrochloride Tablets
		1 g*	Glucophage	Bristol-Myers Squibb
			metFORMIN Hydrochloride Tablets

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

metFORMIN Hydrochloride Combinations
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, extended-release	500 mg with Immediate-release Canagliflozin (anhydrous) 50 mg	Invokamet XR	Janssen
		500 mg with Immediate-release Canagliflozin (anhydrous) 150 mg	Invokamet XR	Janssen
		500 mg with Immediate-release Dapagliflozin Propanediol 5 mg (of dapagliflozin)	Xigduo XR	AstraZeneca
		500 mg with Immediate-release Dapagliflozin Propanediol 10 mg (of dapagliflozin)	Xigduo XR	AstraZeneca
		500 mg with Immediate-release Saxagliptin 5 mg	Kombiglyze XR	AstraZeneca
		500 mg with Immediate-release Sitagliptin 50 mg	Janumet XR	Merck
		1 g with Immediate-release Canagliflozin 50 mg (anhydrous)	Invokamet XR	Janssen
		1 g with Immediate-release Canagliflozin (anhydrous) 150 mg	Invokamet XR	Janssen
		1 g with Immediate-release Dapagliflozin Propanediol 2.5 mg (of dapagliflozin)	Xigduo XR	AstraZeneca
		1 g with Immediate-release Dapagliflozin Propanediol 5 mg (of dapagliflozin)	Xigduo XR	AstraZeneca
		1 g with Immediate-release Dapagliflozin Propanediol 10 mg (of dapagliflozin)	Xigduo XR	AstraZeneca
		1 g with Immediate-release Empagliflozin 5 mg	Synjardy XR	Boehniger Ingelheim
		1 g with Immediate-release Empagliflozin 10 mg	Synjardy XR	Boehniger Ingelheim
		1 g with Immediate-release Empagliflozin 12.5 mg	Synjardy XR	Boehniger Ingelheim
		1 g with Immediate-release Empagliflozin 25 mg	Synjardy XR	Boehniger Ingelheim
		1 g with Immediate-release Linagliptin 2.5 mg	Jentadueto XR	Boehringer Ingelheim
		1 g with Immediate-release Linagliptin 5 mg	Jentadueto XR	Boehringer Ingelheim
		1 g with Immediate-release Pioglitazone Hydrochloride 15 mg (of pioglitazone)	Actoplus Met XR	Takeda
		1 g with Immediate-release Pioglitazone Hydrochloride 30 mg (of pioglitazone)	Actoplus Met XR	Takeda
		1 g with Immediate-release Saxagliptin 2.5 mg	Kombiglyze XR	AstraZeneca
		1 g with Immediate-release Saxagliptin 5 mg	Kombiglyze XR	AstraZeneca
		1 g with Immediate-release Sitagliptin 50 mg	Janumet XR	Merck
		1 g with Immediate-release Sitagliptin 100 mg	Janumet XR	Merck
	Tablets, film-coated	250 mg with Glipizide 2.5 mg*	Metaglip	Bristol-Myers Squibb
			metFORMIN Hydrochloride and Glipizide Tablets
		250 mg with Glyburide 1.25 mg*	Glucovance	Bristol-Myers Squibb
			metFORMIN Hydrochloride and Glyburide Tablets
		500 mg with Alogliptin Benzoate 12.5 mg (of alogliptin)	Kazano	Takeda
		500 mg with Canagliflozin (anhydrous) 50 mg	Invokamet	Janssen
		500 mg with Canagliflozin (anhydrous) 150 mg	Invokamet	Janssen
		500 mg with Empagliflozin 5 mg	Synjardy	Boehringer Ingelheim
		500 mg with Empagliflozin 12.5 mg	Synjardy	Boehringer Ingelheim
		500 mg with Ertugliflozin L-pyroglutamic Acid 2.5 mg (of ertugliflozin)	Segluromet	Merck
		500 mg with Ertugliflozin L-pyroglutamic Acid 7.5 mg (of ertugliflozin)	Segluromet	Merck
		500 mg with Glipizide 2.5 mg*	Metaglip	Bristol-Myers Squibb
			metFORMIN Hydrochloride and Glipizide Tablets
		500 mg with Glipizide 5 mg*	Metaglip	Bristol-Myers Squibb
			metFORMIN Hydrochloride and Glipizide Tablets
		500 mg with Glyburide 2.5 mg*	Glucovance	Bristol-Myers Squibb
			metFORMIN Hydrochloride and Glyburide Tablets
		500 mg with Glyburide 5 mg*	Glucovance	Bristol-Myers Squibb
			MetFORMIN Hydrochloride and Glyburide Tablets
		500 mg with Linagliptin 2.5 mg	Jentadueto	Boehringer Ingelheim
		500 mg with Pioglitazone Hydrochloride 15 mg (of pioglitazone)	Actoplus Met	Takeda
		500 mg with Repaglinide 1 mg	Prandimet	Novo Nordisk
		500 mg with Repaglinide 2 mg	Prandimet	Novo Nordisk
		500 mg with Rosiglitazone Maleate 2 mg (of rosiglitazone)	Avandamet	GlaxoSmithKline
		500 mg with Rosiglitazone Maleate 4 mg (of rosiglitazone)	Avandamet	GlaxoSmithKline
		500 mg with Sitagliptin Phosphate 50 mg (of sitagliptin)	Janumet	Merck
		850 mg with Linagliptin 2.5 mg	Jentadueto	Boehringer Ingelheim
		850 mg with Pioglitazone Hydrochloride 15 mg (of pioglitazone)	Actoplus Met	Takeda
		1 g with Alogliptin Benzoate 12.5 mg (of alogliptin)	Kazano	Takeda
		1 g with Canagliflozin (anhydrous) 50 mg	Invokamet	Janssen
		1 g with Canagliflozin (anhydrous) 150 mg	Invokamet	Janssen
		1 g with Empagliflozin 5 mg	Synjardy	Boehringer Ingelheim
		1 g with Empagliflozin 12.5 mg	Synjardy	Boehringer Ingelheim
		1 g with Ertugliflozin L-pyroglutamic Acid 2.5 mg (of ertugliflozin)	Segluromet	Merck
		1 g with Ertugliflozin L-pyroglutamic Acid 7.5 mg (of ertugliflozin)	Segluromet	Merck
		1 g with Linagliptin 2.5 mg	Jentadueto	Boehringer Ingelheim
		1 g with Rosiglitazone Maleate 2 mg (of rosiglitazone)	Avandamet	GlaxoSmithKline
		1 g with Rosiglitazone Maleate 4 mg (of rosiglitazone)	Avandamet	GlaxoSmithKline
		1 g with Sitagliptin Phosphate 50 mg (of sitagliptin)	Janumet	Merck

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Bristol-Myers Squibb Company. Glucophage (metformin hydrochloride) tablets and Glucophage XR (metformin hydrochloride) extended-release tablets prescribing information. Princeton, NJ; 2009 Jan.

2. Bristol-Myers Squibb Company. Product information form for American Hospital Formulary Service: Glucophage (metformin hydrochloride). Princeton, NJ; 1995 Mar.

3. Bristol-Myers Squibb Company. Executive summary (product information) on Glucophage (metformin hydrochloride). Princeton, NJ; 1995 Mar.

4. Bristol-Myers Squibb Company. Glucophage (metformin hydrochloride) tablets product monograph. Princeton, NJ; 1995 Apr.

5. Marchetti P, Benzi L, Cecchetti P et al. Plasma biguanide levels are correlated with metabolic effects in diabetic patients. Clin Pharmacol Ther. 1987; 41:450-4. http://www.ncbi.nlm.nih.gov/pubmed/3829580?dopt=AbstractPlus

6. Bailey CJ. Biguanides and NIDDM. Diabetes Care. 1992; 15:755-72. http://www.ncbi.nlm.nih.gov/pubmed/1600835?dopt=AbstractPlus

7. National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes. 1979; 28:1039-57. http://www.ncbi.nlm.nih.gov/pubmed/510803?dopt=AbstractPlus

8. Henry R R. Glucose control and insulin resistance in non-insulin-dependent diabetes mellitus. Ann Intern Med. 1996; 124:97-103. http://www.ncbi.nlm.nih.gov/pubmed/8554221?dopt=AbstractPlus

9. DeFronzo RA. The triumvirate: β-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988; 37:667-87. http://www.ncbi.nlm.nih.gov/pubmed/3289989?dopt=AbstractPlus

10. Scientific Advisory Panel of the Executive Committee, American Diabetes Association. Policy statement: the UGDP controversy. Diabetes. 1979; 28:168-70.

11. Polonsky KS, Sturis J, Bell GI. Non-insulin-dependent diabetes mellitus—a genetically programmed failure of the beta cell to compensate for insulin resistance. N Engl J Med. 1996; 334:777-83. http://www.ncbi.nlm.nih.gov/pubmed/8592553?dopt=AbstractPlus

12. American Diabetes Association. Office guide to diagnosis and classification of diabetes mellitus and other categories of glucose intolerance. Diabetes Care. 1995; 18(Suppl 1):4.

13. Lebovitz HE. Stepwise and combination drug therapy for the treatment of NIDDM. Diabetes Care. 1994; 17:1542-4. http://www.ncbi.nlm.nih.gov/pubmed/7882832?dopt=AbstractPlus

14. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care. 2003; 26(Suppl 1):S33-50.

15. Hermann LS, Scherstén B, Bitzén PO et al. Therapeutic comparison of metformin and sulfonylurea, alone and in various combinations. Diabetes Care. 1994; 17:1100-9. http://www.ncbi.nlm.nih.gov/pubmed/7821128?dopt=AbstractPlus

16. Clarke BF, Campbell IW. Comparison of metformin and chlropropamide in non-obese, maturity-onset diabetics uncontrolled by diet. Br Med J. 1977; 2:1576-8. http://www.ncbi.nlm.nih.gov/pubmed/589351?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1632725&blobtype=pdf

17. Clarke BF, Duncan LJP. Comparison of chlorpropamide and metformin treatment on weight and blood-glucose response of uncontrolled obese diabetics. Lancet. 1968; 1:123-6. http://www.ncbi.nlm.nih.gov/pubmed/4169605?dopt=AbstractPlus

18. Dunn CJ, Peters DH. Metformin: a review of its pharmacological properties and therapeutic use in non-insulin-dependent diabetes mellitus. Drugs. 1995; 49:721-49. http://www.ncbi.nlm.nih.gov/pubmed/7601013?dopt=AbstractPlus

19. United Kingdom Prospective Diabetes Study Group. United Kingdom prospective diabetes study (UKPDS) 13: relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years. BMJ. 1995; 310:83-8. http://www.ncbi.nlm.nih.gov/pubmed/7833731?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2548496&blobtype=pdf

20. Bailey CJ, Nattrass M. Treatment—metformin. Baillieres Clin Endocrinol Metab. 1988; 2:455-76. http://www.ncbi.nlm.nih.gov/pubmed/3075902?dopt=AbstractPlus

21. Haupt E, Knick B, Koschinsky T et al. Oral antidiabetic combination therapy with sulphonylureas and metformin. Diabetes Metab. 1991; 17:224-31.

22. Reaven GM, Johnston P, Hollenbeck CB et al. Combined metformin-sulfonylurea treatment of patients with noninsulin-dependent diabetes in fair to poor glycemic control. J Clin Endocrinol Metab. 1992; 74:1020-6. http://www.ncbi.nlm.nih.gov/pubmed/1569149?dopt=AbstractPlus

23. Krentz AJ, Ferner RE, Bailey CJ. Comparative tolerability profiles of oral antidiabetic agents. Drug Saf. 1994; 11:223-41. http://www.ncbi.nlm.nih.gov/pubmed/7848543?dopt=AbstractPlus

24. Anon. Diabetes mellitus. NIH Cons Dev Conf Statement. 1986; 6:1-7.

25. Blake GH. Control of type II diabetes: reaping the rewards of exercise and weight loss. Postgrad Med. 1992; 92:129-32. http://www.ncbi.nlm.nih.gov/pubmed/1437899?dopt=AbstractPlus

26. Kerr CP. Improving outcomes in diabetes: a review of the outpatient care of NIDDM patients. J Fam Pract. 1995; 40:63-75. http://www.ncbi.nlm.nih.gov/pubmed/7807040?dopt=AbstractPlus

27. Gerich JE. Oral hypoglycemic agents. N Engl J Med. 1989; 321:1231-45. http://www.ncbi.nlm.nih.gov/pubmed/2677730?dopt=AbstractPlus

28. Kahn CR, Shechter Y. Insulin, oral hypoglycemic agents, and the pharmacology of the endocrine pancreas. In: Gilman AG, Rawl TW, Nies AS et al, eds. Goodman and Gilman’s pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press; 1990:1463-95.

29. Anon. Metformin for noninsulin-dependent diabetes mellitus. Med Lett Drugs Ther. 1995; 37:41-2. http://www.ncbi.nlm.nih.gov/pubmed/7739421?dopt=AbstractPlus

30. Bristol-Myers Squibb, Princeton, NJ: personal communication.

31. DeFronzo RA, Barzilai N, Simonson DC. Mechanism of metformin action in Obese and Lean Noninsulin-Dependent Diabetic Subjects. J Clin Endocrinol Metab. 1991; 73:1294-1300. http://www.ncbi.nlm.nih.gov/pubmed/1955512?dopt=AbstractPlus

32. Gan SC, Barr J, Arieff AI et al. Biguanide-associated lactic acidosis. Arch Intern Med. 1992; 152:2333-36. http://www.ncbi.nlm.nih.gov/pubmed/1444694?dopt=AbstractPlus

33. Anon. Metformin. Phase III Drug Profiles. 1994; 4:1-15.

34. Nagi DK, Yudkin JS. Effects of metformin on insulin resistance, risk factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects. Diabetes Care. 1993; 16:621-629. http://www.ncbi.nlm.nih.gov/pubmed/8462390?dopt=AbstractPlus

35. Jeppesen J, Chen YDI, Zhou M et al. Effect of metformin on postprandial lipemia in patients with fairly to poorly controlled NIDDM. Diabetes Care. 1994; 17:1093-99. http://www.ncbi.nlm.nih.gov/pubmed/7821127?dopt=AbstractPlus

36. Hoffman BB, Lefkowitz RJ. Catecholamines, sympoathomimetic drugs, and adrenergic receptor antagonists. In: Hardman JG, Limbird LE, Molinoff PB et al, eds. Goodman and Gilman’s the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill; 1995:207-48.

37. Klip A, Leiter LA. Cellular mechanism of action of metformin.. Diabetes Care. 1990; 13:696-704. http://www.ncbi.nlm.nih.gov/pubmed/2162756?dopt=AbstractPlus

38. Caille G, Lacassw Y, Raymond M et al. Bioavailability of metformin in tablet form using a new high pressure liquid chromatography assay method. Biopharmaceutics & Drug Disposition. 1993; 14:257-63.

39. Widen EI, Eriksson JG, Groop LC. Metformin normalizes nonoxidative glucose metabolism in insulin-resistant. Diabetes. 1992; 41:354-58. http://www.ncbi.nlm.nih.gov/pubmed/1551495?dopt=AbstractPlus

40. Matthaei S, Reibold JP, Hamann A et al. In vivo metformin treatment ameliorates insulin resistance: evidence for potentiation of insulin-induced translocation and increased functional activity of glucose transporters in obese (fa/fa) zucker rat adipocytes. Ednocrinology. 1993; 133:304-11.

41. Nosadini R, Avogaro A, Trevisan R et al. Effect of metformin on insulin-stimulated glucose turnover and insulin binding to receptors in type II diabetes. Diabetes Care. 1987; 10:62-67. http://www.ncbi.nlm.nih.gov/pubmed/3552515?dopt=AbstractPlus

42. Wu MS, Johnston P, Hollenbeck CB et al. Effect of metformin on carbohydrate and lipoprotein metabolism in NIDDM patients. Diabetes Care. 1990; 13:1-8. http://www.ncbi.nlm.nih.gov/pubmed/2404714?dopt=AbstractPlus

43. Vidon N, Chaussade S, Noel M et al. Metformin in the digestive tract. Diabetes Res and Clin Practice. 1988; 4:223-29.

44. Jackson RA, Hawa MI, Jaspan JB et al. Mechanism of metformin action in non-insulin-dependent diabetes. Diabetes. 1987; 36:632-40. http://www.ncbi.nlm.nih.gov/pubmed/3552795?dopt=AbstractPlus

45. Hermann LS, Karlsson JE, Sjostrand A. Prospective comparative study in NIDDM patients of metformin and glibenclamide with special reference to lipid profiles. Eur J Clin Pharmacol. 1991; 41:263-265. http://www.ncbi.nlm.nih.gov/pubmed/1748145?dopt=AbstractPlus

46. Rains SGH, Wilson GA, Richmond W et al. The effect of glibenclamide and metformin on serum lipoproteins in type II diabetes. Diabetic Medicine. 1988; 5:653-59. http://www.ncbi.nlm.nih.gov/pubmed/2975549?dopt=AbstractPlus

47. Sarabia V, Lam L, Leiter LA et al. Glucose transport in human skeletal muscle cells in culture. J Clin Invest. 1992; 90:1386-95. http://www.ncbi.nlm.nih.gov/pubmed/1401073?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=443184&blobtype=pdf

48. Lim P, Khoo OT. Metformin compared to tolbutamide in the treatment of maturity-onset diabetes mellitus. Med J Aust. 1970; 1:271-273. http://www.ncbi.nlm.nih.gov/pubmed/5440868?dopt=AbstractPlus

49. Sirtori CR, Tremoli E, Sirtori M et al. Treatment of hypertriglyceridemia with metformin. Atherosclerosis. 1977; 26:583-592. http://www.ncbi.nlm.nih.gov/pubmed/193525?dopt=AbstractPlus

50. Pentikainen PJ, Neuvonen PJ, Penttila A. Pharmacokinetics of metformin after intravenous and oral administration to man. Eur J Clin Pharmacol. 1979; 16:195-202. http://www.ncbi.nlm.nih.gov/pubmed/499320?dopt=AbstractPlus

51. Sirtori CR, Franceschini G, Galli-Kienle M et al. Disposition of metformin (N,N-dimethylbiguanide) in man. Clin Pharmacol and Ther. 1978; 24:683-93.

52. Hundal H, Ramlal T, Reyes R et al. Cellular mechanism of metformin actioninvolves glucose transporter translocation from an intracellular pool to the plasma membrane in L6 muscle cells. Endocrinology. 1992; 131:1165-73. http://www.ncbi.nlm.nih.gov/pubmed/1505458?dopt=AbstractPlus

53. Campbell IW, Duncan C, Patton NW et al. The effect of metformin on glycaemic control, intermediary metabolism and blood pressure in non-insulin-dependent diabetes mellitus. Diabetic Medicine. 1987; 4:337-41. http://www.ncbi.nlm.nih.gov/pubmed/2956047?dopt=AbstractPlus

54. Fantus IG, Brosseau R. Mechanism of action of metformin: insulin receptor and postreceptor effects in vitro and in vivo. J Clin Endocrinol Metab. 1986; 63:898-905. http://www.ncbi.nlm.nih.gov/pubmed/3745404?dopt=AbstractPlus

55. Grant PJ. The effects of metformin on the fibrinolytic system in diabetic and non-diabetic subjects. Diabete et Metabolisme. 1991; 17:168-73. http://www.ncbi.nlm.nih.gov/pubmed/1936471?dopt=AbstractPlus

56. Chakrabarti R, Hocking ED, Fearnley GR. Fibrinolytic effect of metformin in cornorary-artery disease. Lancet. 1965; 2:256-259. http://www.ncbi.nlm.nih.gov/pubmed/14330058?dopt=AbstractPlus

57. Chan JCN, Cockram CS, Tomlinson B et al. Metabolic and hemodynamic effects of metformin and glibenclamide in normotensive NIDDM patients. Diabetes Care. 1993; 16:1035-38. http://www.ncbi.nlm.nih.gov/pubmed/8359098?dopt=AbstractPlus

58. Landin K, Tengborn L, Smith U. Treating insulin resistance in hypertension with metformin reduces both blood pressure and metabolic risk factors. J Int Med. 1991; 229:181-87.

59. Giugliano D, Quatraro A, Consoli G et al. Metformin for obese, insulin-treated diabetic patients: improvement in glycaemic control and reduction of metabolic risk factors. Eur J Clin Pharmacol. 1993; 44:107-12. http://www.ncbi.nlm.nih.gov/pubmed/8453955?dopt=AbstractPlus

60. Hother-Nielsen O, Schmitz O, Andersen PH et al. Metformin improves peripheral but not hepatic insulin action in obese patients with type II diabetes. Acta Endocrinol. 1989; 120:257-65. http://www.ncbi.nlm.nih.gov/pubmed/2648723?dopt=AbstractPlus

61. Nattrass M, Todd PG, Hinks L et al. Comparative effects of phenformin, metformin and glibenclamide on metabolic rhythms in maturity-onset diabetics. Diabetologia. 1977; 13:145-52. http://www.ncbi.nlm.nih.gov/pubmed/404205?dopt=AbstractPlus

62. Assan R, Heuclin C, Ganeval D et al. Metformin-induced lactic acidosis in the presence of acute renal failure. Diabetologia. 1977; 13:211-17. http://www.ncbi.nlm.nih.gov/pubmed/406158?dopt=AbstractPlus

63. Alberti KGMM, Nattrass M. Lactic acidosis. Lancet. 1977; 2:25-9. http://www.ncbi.nlm.nih.gov/pubmed/69109?dopt=AbstractPlus

64. Waters AK, Morgan DB, Wales JK. Blood lactate and pyruvate levels in diabetic patients treated with biguanides with and without sulphonylureas. Diabetologia. 1978; 14:95-100. http://www.ncbi.nlm.nih.gov/pubmed/631461?dopt=AbstractPlus

65. Lucis OJ. The status of metformin in Canada. Can Med Assoc J. 1983; 128:24-6. http://www.ncbi.nlm.nih.gov/pubmed/6847752?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1874707&blobtype=pdf

66. Lefkowitz RJ, Hoffman BB, Taylor P. Neuotransmission: the autonomic and somatic motor nervous systems. In: Goodman & Gilman’s The pharmacological basis of therapeutics. 9th ed. 1995:105-139.

67. Vigneri R, Pezzino V, Wong K et al. Comparison of the in vitro effect of biguanides and sulfonylureas on insulin binding to its receptors in target cells. J Clin Endocrinol Metab. 1982; 54:95-100. http://www.ncbi.nlm.nih.gov/pubmed/7033271?dopt=AbstractPlus

68. Riccio A, Del Prato S, Vigili De Kreutzenberg S et al. Glucose and lipid metabolism in non-insulin-dependent diabetes: effect of metformin. Diab Metab. 1991; 17:180-84.

69. McIntyre HD, Ma A, Bird DM et al. Metformin increases insulin sensitivity and basal glucose clearance in type 2 (non-insulin dependent) diabetes mellitus. Aust N Z J Med. 1991; 21:714-19. http://www.ncbi.nlm.nih.gov/pubmed/1759920?dopt=AbstractPlus

70. Tomkin GH, Hadden DR, Weaver JA et al. Vitamin-B12 status of patients on long-term metformin therapy. Br Med J. 1971; 2:685-87. http://www.ncbi.nlm.nih.gov/pubmed/5556053?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1796258&blobtype=pdf

71. Schernthaner G. Improvement of insulin action is an important part of the antidiabetic effect of metformin. Hormone Metab Res. 1985; 15:116-120.

72. Hermann LS, Melander A. Biguanides: basic aspects and clinical use. In: Alberti KGMM, DeFronzo RA, Keen H et al, eds. International textbook of diabetes mellitus. New York: John Wiley & Sons; 1992; 773-95.

73. Swislocki A. Insulin resistance and hypertension. Am J Med Sci. 1990; 300:104-15. http://www.ncbi.nlm.nih.gov/pubmed/2206054?dopt=AbstractPlus

74. Klapholz L, Leitersdorf E, Weinrauch L. Leucocytoclastic vasculitis and pneumonitis induced by metformin. BMJ. 1986; 293:483. http://www.ncbi.nlm.nih.gov/pubmed/3091170?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1341115&blobtype=pdf

75. Somogyi A, Stockley C, Keal J et al. Reduction of metformin renal tubular secretion by cimetidine in man. Br J Clin Pharmacol. 1987;23: 545-51.

76. Wiholm BE, Myrhed M. Metformin-associated lactic acidosis in Sweden 1977-1991. Eur J Clin Pharmacol. 1993; 44:589-91. http://www.ncbi.nlm.nih.gov/pubmed/8405019?dopt=AbstractPlus

77. Berger W. Incidence of severe side effects during therapy with sulfonylureas and giguanides. Hormone Metab Res. 1985;15: 11-15.

78. DeFronzo RA, Goodman AM, and the Multicenter Metformin Study Group. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. N Engl J Med. 1995; 333:541-49. http://www.ncbi.nlm.nih.gov/pubmed/7623902?dopt=AbstractPlus

79. Cigolini M, Bosello O, Zancanaro C et al. Influence of metformin on metabolic effect of insulin in human adipose tissue in vitro. Diab Metab. 1984; 10:311-15.

80. Cordingley FT, Crawford GPM. Diabetogenic effects of nifedipine. BMJ. 1984; 289:19.

81. Stumvoll M, Nurjahan N, Perriello G et al. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med. 1995; 333:550-54. http://www.ncbi.nlm.nih.gov/pubmed/7623903?dopt=AbstractPlus

82. Tomkin GH. Malabsorption of vitamin B12 in diabetic patients treated with phenformin: a comparison with metformin. Br Med J. 1973; 3:673-75. http://www.ncbi.nlm.nih.gov/pubmed/4742454?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1587044&blobtype=pdf

83. Bailey CJ, Flatt PR, Marks V. Drugs inducing hypoglycemia. Pharmacol Ther. 1989; 42:361-84. http://www.ncbi.nlm.nih.gov/pubmed/2672051?dopt=AbstractPlus

84. Pedersen O, Hother Nielsen, Bak J et al. The effects of metformin on adipocyte insulin action and metabolic control in obese subjects with type 2 diabetes. Diabet Med. 1989; 6:249-56. http://www.ncbi.nlm.nih.gov/pubmed/2523787?dopt=AbstractPlus

85. Johnston P, Rough T. Metformin: a newly approved oral hypoglycemic. Diabetologia. 1983; 24:351-54. http://www.ncbi.nlm.nih.gov/pubmed/6347782?dopt=AbstractPlus

86. Pagano G, Tagliaferro V, Caselle MT et al. Metformin reduces insulin requirement in type 1 (insulin-dependent) diabetes. Diabetologia. 1983; 24:351-54. http://www.ncbi.nlm.nih.gov/pubmed/6347782?dopt=AbstractPlus

87. Gin H, Messerchmitt C, Brottier E et al. Metformin improved insulin resistance in type 1, insulin-dependent, diabetic patients. Metab Clin Exp. 1985; 34:923-25. http://www.ncbi.nlm.nih.gov/pubmed/4046836?dopt=AbstractPlus

88. Expert Committee of the Canadian Diabetes Advisory Board. Clinical practice guidelines for treatment of diabetes mellitus. CMAJ. 1992; 147:697-712. http://www.ncbi.nlm.nih.gov/pubmed/1521215?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1336391&blobtype=pdf

89. Tucker GT, Casey C, Phillips PJ et al. Metformin kinetics in healthy subjects and in patients with diabetes mellitus. Br J Clin Pharmacol. 1981; 12:235-46. http://www.ncbi.nlm.nih.gov/pubmed/7306436?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1401849&blobtype=pdf

90. Yki-Jarvinen H, Esko N, Eero H et al. Clinical benefits and mechanisms of a sustained response to intermittent insulin therapy in type 2 diabetic patients with secondary drug failure. Am J Med. 1988; 84:185-192. http://www.ncbi.nlm.nih.gov/pubmed/3044067?dopt=AbstractPlus

91. Chan JCN, Cockram CS. Drug-induced disturbances of carbohydrate metabolism. Adv Drug React Toxicol Rev. 1991; 10:1-29.

92. Piacquadio K, Hollingsworth D, Murphy H. Effects of in-utero oral hypoglycaemic drugs. Lancet. 1991; 338:866-69. http://www.ncbi.nlm.nih.gov/pubmed/1681225?dopt=AbstractPlus

93. Campbell IW. Metformin and the sulphonylureas: the comparative risk. Horm Metab Res. 1985; 15(Suppl):105-11.

94. Chow CC, Tsang L, Sorensen J et al. Comparison of insulin with or without continuation of oral hypoglycemic agents in the treatment of secondary failure in NIDDM patients. Diabetes Care. 1995; 18:307-14. http://www.ncbi.nlm.nih.gov/pubmed/7555472?dopt=AbstractPlus

95. Zimmerman B, Espenshade J, Fujimoto W et al. The pharmacological treatment of hyperglycemia in NIDDM. Diabetes Care. 1995; 18:1510-18. http://www.ncbi.nlm.nih.gov/pubmed/8722084?dopt=AbstractPlus

96. Lalau J, Lacroix C, Compagnon P et al. Role of metformin accumulation in metformin-associated lactic acidosis. Diabetes Care. 1995; 18:779-84. http://www.ncbi.nlm.nih.gov/pubmed/7555503?dopt=AbstractPlus

97. Gregorio F, Ambrosi F, Marchetti P et al. Low dose metformin in the treatment of type II non-insulin-dependent diabetes: clinical and metabolic evaluations. Acta Diabetol Lat. 1990; 27:139-55. http://www.ncbi.nlm.nih.gov/pubmed/2198745?dopt=AbstractPlus

98. Lord JM, White SI, Bailey CJ et al. Effect of metformin on insulin receptor binding and glycaemic control in type II diabetes. BMJ. 1983; 286:830-31. http://www.ncbi.nlm.nih.gov/pubmed/6403102?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1547150&blobtype=pdf

99. Hermann L. Biguanides and sulfonylureas as combination therapy in NIDDM. Diabetes Care. 1990; 13:37-41. http://www.ncbi.nlm.nih.gov/pubmed/2209342?dopt=AbstractPlus

100. Klein W. Sulfonylurea-metformin-combination versus sulfonylurea-inslin-combination in secondary failures of sulfonylurea monotherapy. Diab Metab. 1991; 17(Suppl 1):235-40.

101. Groop L, Widen E. Treatment strategies for secondary sulfonylurea failure. Should we start insulin or add metformin? Is there a place for intermittent insulin therapy? Diab Metab. 1991; 17(Suppl 1):218-23.

102. Hollenbeck CB, Johnston P, Varasteh BB et al. Effects of metformin on glucose insulin and lipid metabolism in patients with mild hypertriglyceridaemia and non-insulin dependent diabetes by glucose tolerance test criteria. Diab Metab. 1991; 17:483-90.

103. Holman RR, Steemson J, Turner RC. Sulphonylurea failure in type 2 diabetes: treatment with a basal insulin supplement. Diabet Med. 1987; 4:457-62. http://www.ncbi.nlm.nih.gov/pubmed/2959438?dopt=AbstractPlus

104. Trischitta V, Italia S, Mazzarino S et al. Comparison of combined therapies in treatment of secondary failure to glyburide. Diabetes Care. 1992; 15:539-42. http://www.ncbi.nlm.nih.gov/pubmed/1499473?dopt=AbstractPlus

105. Dornan T, Heller S, Peck G et al. Double-blind evaluation of efficacy and tolerability of metformin in NIDDM. Diabetes Care. 1991; 14:342-44. http://www.ncbi.nlm.nih.gov/pubmed/2060439?dopt=AbstractPlus

106. Gin H, Orgerie MB, Aubertin J. The influence of guar gum on absorption of metformin from the gut in healthy volunteers. Horm Metab Res. 1989; 21:81-83. http://www.ncbi.nlm.nih.gov/pubmed/2722133?dopt=AbstractPlus

107. Schaffalitzky de Muckadell OB, Mortensen H, Lyngsoe J. Metabolic effects of glucocorticoid and ethanol administration in phenformin- and metformin-treated obese diabetics. ACTA Medica Scandinavica. 1979; 206:269-73. http://www.ncbi.nlm.nih.gov/pubmed/506799?dopt=AbstractPlus

108. Juhan-Vague I, Alessi MC, Badier C et al. Metformin decreases the high plasminogen activator inhibition capacity, plasma insulin and triglyceride levels in non-diabetic obese subjects. Thromb Haemost. 1987; 57:326-28. http://www.ncbi.nlm.nih.gov/pubmed/3310318?dopt=AbstractPlus

109. Collier A, Watson HHK, Patrick AW et al. Effect of glycaemic control, metformin and gliclazide on platelet density and aggregability in recently diagnosed type 2 (non-insulin-dependent) diabetic patients. Diab Metab. 1989; 15:420-25.

110. Gustafson A, Bjorntorp P, Fahlen M. Metformin administration in hyperlipidemic states. ACTA Medica Scandinavica. 1971; 190:491-494. http://www.ncbi.nlm.nih.gov/pubmed/5149092?dopt=AbstractPlus

111. Sambol NC, O’Connor MD, Lin ET et al. Pharmacokinetics (PK) and pharmacodynamics (PD) of metformin HCL (MET) in healthy individuals and individuals with noninsulin-dependent diabetes mellitus (NIDDM). Clin Pharmacol Ther. 1993; 53:211.

112. Chiasson J, Josse R, Hunt J et al. The efficacy of acarbose in the treatment of patients with non-insulin-dependent diabetes mellitus. Ann Intern Med. 1994; 121:929-935.

113. Bayer Corp. Precose™ (acarbose) tablets product information. West Haven, CT; 1995 Oct.

114. Wall R, Linford S, Akhter M. Megaloblastic anaemia due to vitamin B12 malabsorption associated with long-term metformin treatment. JAMA. 1963; 183:482-85.

115. Coretzee EJ, Jackson WPU. Pregnancy in established non-insulin-dependent diabetics. S Afr Med J. 1980; 58:795-802. http://www.ncbi.nlm.nih.gov/pubmed/6777880?dopt=AbstractPlus

116. Coscelli C, Palmari V, Saccardi F et al. Evidence that metformin addition to insulin induces an amelioration of glycaemic profile in type I (insulin-dependent) diabetes mellitus. Curr Ther Res. 1984; 35:1058-64.

117. Scapa E, Haagensen DE, Thomas P et al. Treatment of metformin-associated lactic acidosis with closed recirculation bicarbonate-buffered hemodialysis. Arch Intern Med. 1984; 144:203-5.

118. Josephkutty S, Potter JM. Comparison of tolbutamide and metformin in elderly diabetic patients. Diabet Med. 1990; 7:510-14. http://www.ncbi.nlm.nih.gov/pubmed/2142054?dopt=AbstractPlus

119. McLelland J. Recovery from metformin overdose. Diabet Med. 1985; 2:410-11. http://www.ncbi.nlm.nih.gov/pubmed/2951106?dopt=AbstractPlus

120. Giugliano D, Torella R, Cacciapuoti F et al. Impairment of insulin secretion in man by nifedipine. Eur J Clin Pharmacol. 1980; 18:395-8. http://www.ncbi.nlm.nih.gov/pubmed/7002569?dopt=AbstractPlus

121. Schauben J. Calcium channel blockers and insulin secretion. it/Drug Intell Clin Pharm. 1982; 16:881-2. Letter.

122. Melchior W, Jaber L. Metformin: an antihyperglycemic agent for treatment of type II diabetes. Ann Pharmacother. 1996; 30:158-63. http://www.ncbi.nlm.nih.gov/pubmed/8835050?dopt=AbstractPlus

123. DeFronzo RA, Goodman AM. Efficacy of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med. 1996; 334:269-70.

124. Bosisio E, Galli-Kienle M, Ciconali M et al. Defective hydroxylation of phenformin as a determinant of drug toxicity. Diabetes. 1981; 30:644-9. http://www.ncbi.nlm.nih.gov/pubmed/7250534?dopt=AbstractPlus

125. Arafat T, Kaddoumi A, Shami M et al. Pharmacokinetics and pharamcodynamics of two oral formulations of metformin hydrochloride. Adv Ther. 1994; 11:21-33.

126. Brookes LG, Sambol NC, Lin ET et al. Effect of dosage form, dose and food on the pharmacokinetics of metformin. Pharm Res. 1991; 8:S320. http://www.ncbi.nlm.nih.gov/pubmed/1905809?dopt=AbstractPlus

127. Holland B, Kaplan N. Propranolol in the treatment of hypertension. N Engl J Med. 1976; 294:930-6. http://www.ncbi.nlm.nih.gov/pubmed/1256484?dopt=AbstractPlus

128. Merck Sharp and Dohme. Blocardren (timolol maleate) tabelts prescribing information (dated 1993 Aug). In: Physicians’ desk reference. 50th ed. Montvale, NJ: Medical Economics Company Inc; 1996:1614-7.

129. Nicklin P, Keates AC, Page T et al. Transfer of metformin across monolayers of human intestinal Caco-2 cells and across rat intestine. Intl J Pharm. 1996; 128:155-62.

130. Rett K, Wickimayr M, Dietze G et al. Hypoglycemia in hypertensive diabetic patients treated with sulfonylureas, biguanides, and captopril. N Engl J Med. 1988; 319:1609. http://www.ncbi.nlm.nih.gov/pubmed/3059189?dopt=AbstractPlus

131. Ferriere M, Lachkar H, Richard J et al. Captopril and insulin sensitivity. Ann Intern Med. 1985; 102:134-5. http://www.ncbi.nlm.nih.gov/pubmed/3881067?dopt=AbstractPlus

132. McMurray J, Fraser DM. Captopril, enalapril, and blood glucose. Lancet. 1986; 1:1035. http://www.ncbi.nlm.nih.gov/pubmed/2871313?dopt=AbstractPlus

133. Passa Ph, Marre M, Leblanc H. Enalapril, captopril, and blood glucose. Lancet. 1986; 1:1447. http://www.ncbi.nlm.nih.gov/pubmed/2872551?dopt=AbstractPlus

134. Reviewers’ comments (personal observations).

135. Cusi K, Consoli A, DeFronzo RA. Metabolic effects of metformin on glucose and lactate metabolism in NIDDM. (unpublished observations).

136. GrantPJ. The effects of high- and medium-dose metformin therapy on cardiovascular risk factors in patients with type II diabetes. Diabetes Care. 1996; 19:64-6. http://www.ncbi.nlm.nih.gov/pubmed/8720537?dopt=AbstractPlus

137. Dachman AH. New contraindication to intravascular iodinated contrast material. Radiology. 1995; 197:545. http://www.ncbi.nlm.nih.gov/pubmed/7480710?dopt=AbstractPlus

138. Anon. Acarbose for diabetes mellitus. Med Lett Drugs Ther. 1996; 38:9-10. http://www.ncbi.nlm.nih.gov/pubmed/8559114?dopt=AbstractPlus

139. Jackson EK. Diuretics. In: Hardman JG, Limbird LE,Molinoff PB et al, eds. Goodman and Gilman’s the pharmacological basis of therapeutics. 9th ed. New York: McGraw Hill; 1996:685-713.

140. Molloy AM, Ardill J, Tomkin GH. The effect of metformin treatment on gastric acid secretion and gastrointestinal hormone levels in normal subjects. Diabetologia. 1980; 19:93-6. http://www.ncbi.nlm.nih.gov/pubmed/7418969?dopt=AbstractPlus

141. Adams JF, Clar JS, Ireland JT et al. Malabsorption of vitamin B12 and intrinsic factor secretion during giguanide therapy. Diabetologia. 1983; 24:16-8. http://www.ncbi.nlm.nih.gov/pubmed/6825978?dopt=AbstractPlus

142. Tomkin G. Metformin and B12 malabsorption. Ann Intern Med. 1972; 76:668. http://www.ncbi.nlm.nih.gov/pubmed/4640327?dopt=AbstractPlus

143. White Jr J, Harman J, Campbell K. Drug interactions in diabetic patients. Postgrad Med. 1993; 93:131-9.

144. Rotter A. New contraindication to intravascular iodinated contrast material. Radiology. 1995; 197:545-6. http://www.ncbi.nlm.nih.gov/pubmed/7480711?dopt=AbstractPlus

145. DeFronzo RA, Bonadonna RC, Ferannini E. Pathogenesis of NIDDM: a balanced overview. Diabetes Care. 1992; 15:318-68. http://www.ncbi.nlm.nih.gov/pubmed/1532777?dopt=AbstractPlus

146. Bailey C, Turner R. Metformin. N Engl J Med. 1996; 334:574-9. http://www.ncbi.nlm.nih.gov/pubmed/8569826?dopt=AbstractPlus

147. Oates NS, Shah RR, Idle JR et al. Influence of oxidation polymorphism on phenformin kinetics and dynamics. Clin Pharmacol Ther. 1983;34:827-34.

148. Shaw S, Jayatilleke E, Bauman W et al. The mechanism of B12 malabsorption and depletion due to metformin and its Reversal with Dietary Calcium. Diabetes. 1994; 43:167A.

149. Bailey CJ, Puah JA. Effect of metformin on glucose metabolism in mouse soleus muscle. Diabete Metabol (Paris). 1986; 12:212-8.

150. Frayn Kn, Adnitt PI. Effects of metformin on glucose uptake by isolated diaphragm from normal and diabetic rats. Biochem Pharmacol. 1972; 21:3153-62. http://www.ncbi.nlm.nih.gov/pubmed/4650637?dopt=AbstractPlus

151. Lant A. Diuretics clinical pharmacology and therapeutic use (Part II). Drugs. 1985; 29:162-88. http://www.ncbi.nlm.nih.gov/pubmed/3884320?dopt=AbstractPlus

152. Houston M. The effects of antihypertensive drugs on glucose intolerance in hypertensive nondiabetics and diabetics. Am Heart J. 1988; 115:640-56. http://www.ncbi.nlm.nih.gov/pubmed/3278578?dopt=AbstractPlus

153. Joseph J, Schuna A. Management of hypertension in the diabetic patient. Clin Pharm. 1990; 9:864-73. http://www.ncbi.nlm.nih.gov/pubmed/2272152?dopt=AbstractPlus

154. Antidiabetic drug interactions: thiazide diuretics. In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc; 1993:387.

155. Angiotensin-converting enzyme inhibitor drug interactions: antidiabetics. In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc; 1993:127.

156. Gueriguian J, Green L, Misbin RI et al. Efficacy of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med. 1996; 334:269. http://www.ncbi.nlm.nih.gov/pubmed/8532012?dopt=AbstractPlus

157. Bailey CJ. Hypoglycaemic, antihyperglycaemic and antidiabetic drugs. Diabetic Med. 1992; 9:482-3. http://www.ncbi.nlm.nih.gov/pubmed/1611838?dopt=AbstractPlus

158. Sirtori CR, Pasik C. Re-evaluation of a biguanide, metformin: mechanism of action and tolerability. Pharmacol Res. 1994; 30:187-228. http://www.ncbi.nlm.nih.gov/pubmed/7862618?dopt=AbstractPlus

159. Hurel S, Taylor R. Drugs and glucose tolerance. Adverse Drug Reaction Bulletin. 1995; 174:659-62.

160. Pandit M, Burke J, Gustafson A et al. Drug-induced disorders of glucose tolerance. Ann Intern Med. 1993; 118:529-39. http://www.ncbi.nlm.nih.gov/pubmed/8442624?dopt=AbstractPlus

161. Bailey CJ. Metformin-an update. Gen Pharmacol. 1993; 24:1299-309. http://www.ncbi.nlm.nih.gov/pubmed/8112499?dopt=AbstractPlus

162. Wilcock C, Bailey CJ. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica. 1994; 24:49-57. http://www.ncbi.nlm.nih.gov/pubmed/8165821?dopt=AbstractPlus

163. Anon. ASHP therapeutic position statement on strict glycemic control in selected patients with insulin-dependent diabetes mellitus. Am J Health-Syst Pharm. 1995; 52:2709-11. http://www.ncbi.nlm.nih.gov/pubmed/8601269?dopt=AbstractPlus

164. KhanIH, Catto GRD, MacLeod AM. Severe lactic acidosis in patient receiving continuous ambulatory peritoneal dialysis. BMJ. 1993; 307:1056-7. http://www.ncbi.nlm.nih.gov/pubmed/8251784?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1679237&blobtype=pdf

165. Anon. Fatal lactic acidosis with metformin. Aust Adv Drug React Bull. 1995; 14:6-7.

166. United Kingdom prospective diabetes study group. United Kingdom prospective diabetes study (UKPDS) 16: overview of 6 years’ therapy of type II diabetes: a progressive disease. Diabetes. 1995; 44:1240-58.

167. Scheen AJ. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 1996; 30:359-71. http://www.ncbi.nlm.nih.gov/pubmed/8743335?dopt=AbstractPlus

168. Stabler SP. Screening the older population for cobalamin (vitamin B₁₂ deficiency. J Am Geriatrics Soc. 1995; 43:1295-6.

169. Anon. Urine glucose and ketone determinations. Diabetes Care. 1995; 18:.

170. Ferguson JE, Dyson DC, Holborok RH et al. Cardiovascular and metabolic effects associated with nifedipine and ritodrine tocolysis. Am J Obstet Gynecol. 1989; 161:788-95. http://www.ncbi.nlm.nih.gov/pubmed/2782362?dopt=AbstractPlus

171. Astra. Yutopar (ritodrine hydrochloride) injection prescribing information (dated 1995 Apr). In: Physicians’ desk reference. 50th ed. Montvale, NJ: Medical Economics Company Inc; 1996:570-2.

172. MacDonald IA, Bennett T, Fellows IW. Catecholamines and the control of metabolism in man. Clinical Science. 1985; 68:613-9. http://www.ncbi.nlm.nih.gov/pubmed/2485261?dopt=AbstractPlus

173. Kendall MJ. Impact of beta1 selectivity and intrinsic sympathomimetic activity on potential unwanted noncardiovascular effects of beta blockers. Am J Cardiol. 1987; 59:44-7.

174. Sambol NC, Chiang J, Kin ET et al. Kidney function and age are both predictors of pharmacokinetics of metformin. J Clin Pharmacol. 1995; 35:1094-102. http://www.ncbi.nlm.nih.gov/pubmed/8626883?dopt=AbstractPlus

175. Wollen N, Bailey CJ. Inhibition of hepatic gluconeogenesis by metformin. Clin Pharmacol. 1988; 37:4353-8.

176. Argaud D, Roth H, Wiernsperger N et al. Metformin decreases gluconeogenesis by enhancing the pyruvate kinase flux in isolated rat hepatocytes. Eur J Biochem. 1993; 213:1341-8. http://www.ncbi.nlm.nih.gov/pubmed/8504825?dopt=AbstractPlus

177. Alengrin F, Grossi G, Canivet B et al. Inhibitory effects of metformin on insulin and glucagon action in rat hepatocytes involve post-receptor alterations. Diabete Metabol (Paris). 1987; 13:591-7.

178. Scheen AJ, Letiexhe MR, Lefèbvre PJ. Effects of metformin in obese patients with impaired glucose tolerance. Diabetes/Metabolism Reviews. 1995; 11:S69-80.

179. Williams G. Management of non-insulin-dependent diabetes mellitus. Lancet. 1994; 95-100.

180. Genuth S. Exogenous insulin administration and cardiovascular risk in non-insulin-dependent and insulin-dependent diabetes mellitus. Ann Intern Med. 1996;124(1 Pt 2):104-9.

181. Ilarde A, Tuck M. Treatment of non-insulin-dependent diabetes mellitus and its complications. Drugs Aging. 1994; 4:470-91. http://www.ncbi.nlm.nih.gov/pubmed/8075474?dopt=AbstractPlus

182. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993; 329:977-86. http://www.ncbi.nlm.nih.gov/pubmed/8366922?dopt=AbstractPlus

183. Klein R, Klein BE, Moss SE. Relation of glycemic control to diabetic microvascular complications in diabetes mellitus. Ann Intern Med. 1996; 124(1 Pt 2):90-6. http://www.ncbi.nlm.nih.gov/pubmed/8554220?dopt=AbstractPlus

184. Turner R, Cull C, Holman R et al. United Kingdom Prospective Diabetes Study 17: a 9-year update of a randomized, controlled trial on the effect of improved metabolic control on complications in non-insulin-dependent diabetes mellitus. Ann Intern Med. 1996; 124(1 Pt 2):136-45. http://www.ncbi.nlm.nih.gov/pubmed/8554206?dopt=AbstractPlus

185. Clark CM Jr. Where do we go from here? Ann Intern Med. 1996; 124(1 Part 2):184-6. Editorial.

186. Ohkubo Y, Kishikawa H, Araki E et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus; a randomized prospective 6-year study. Diabetes Res Clin Pract. 1995; 28:103-17. http://www.ncbi.nlm.nih.gov/pubmed/7587918?dopt=AbstractPlus

187. Henry RR, Genuth S. Forum One: Current recommendations about intensification of metabolic control in non-insulin-dependent diabetes mellitus. Ann Intern Med. 1996; 124(1 Pt 2):175-7. http://www.ncbi.nlm.nih.gov/pubmed/8554214?dopt=AbstractPlus

188. Laakso M. Glycemic control and the risk for coronary heart disease in patients with non-insulin-dependent diabetes mellitus. The Finnish studies. Ann Intern Med. 1996;124(1 Pt 2):127-30.

189. Crofford OB. Metformin. N Engl J Med. 1995; 333:588-9. http://www.ncbi.nlm.nih.gov/pubmed/7623910?dopt=AbstractPlus

190. Reichard P, Nilsson B-Y, Rosenqvist U. The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med. 1993; 329:304-9. http://www.ncbi.nlm.nih.gov/pubmed/8147960?dopt=AbstractPlus

191. The Upjohn Company. Micronase (glyburide) prescribing information. Kalamazoo, MI; 2002 Mar.

192. Hoechst-Roussel Pharmaceuticals Inc. DiaBeta (glyburide) prescribing information. Somerville, NJ; 1987 Dec.

193. Calle-Pascual AL, Garcia-Honduvilla J, Martin-Alvarez PJ et al. Comparison between acarbose, metformin, and insulin treatment in type 2 diabetic patients with secondary failure to sulfonylurea treatment. Diabete & Metabolisme (Paris). 1995; 21:256-60.

194. Coniff RF, Shapiro JA, Seaton TB. Long-term efficacy and safety of acarbose in the treatment of obese subjects with non-insulin-dependent diabetes mellitus. Arch Intern Med. 1994; 154:2442-8. http://www.ncbi.nlm.nih.gov/pubmed/7979840?dopt=AbstractPlus

195. Balfour JA, McTavish D. Acarbose: an update of its pharmacology and therapeutic use in diabetes mellitus. Drugs. 1993; 46:1025-54. http://www.ncbi.nlm.nih.gov/pubmed/7510610?dopt=AbstractPlus

196. Zimmerman BR. Preventing long term complications: implicationsfor combination therapy with acarbose. Drugs. 1992; 44:54-9. http://www.ncbi.nlm.nih.gov/pubmed/1280578?dopt=AbstractPlus

197. Asmal AC, Marble A. Oral hypoglycaemic agents: an update. Drugs. 1984; 28:62-78. http://www.ncbi.nlm.nih.gov/pubmed/6378583?dopt=AbstractPlus

198. Jackson JE, Bressler R. Clinical pharmacology of sulphonylurea hypoglycaemic agents: part 1. Drugs. 1981; 22:211-45. http://www.ncbi.nlm.nih.gov/pubmed/7021124?dopt=AbstractPlus

199. Lebovitz HE. Clinical utility of oral hypoglycemic agents in the management of patients with noninsulin-dependent diabetes mellitus. Am J Med. 1983; 75(Suppl 5B):94-9. http://www.ncbi.nlm.nih.gov/pubmed/6369972?dopt=AbstractPlus

200. Food and Drug Administration. Labeling for oral hypoglycemic drugs of the sulfonylurea class. [Docet No. 75N-0062] Fed Regist. 1984; 49:14303-31.

201. Scheen AJ, Alves de Magalhaes F, Lefebvre ST et al. Reduction of metformin acute bioavailability by the alpha-glucosidase inhibitor acarbose in normal man. Eur J Clin Invest. 1993; 23(Suppl 1):A43.

202. Klein R, Klein BEK, Moss SE et al. Glycosylated hemoglobin predicts the incidence and progression of diabetic retinopathy. JAMA. 1988; 260:2864-71. http://www.ncbi.nlm.nih.gov/pubmed/3184351?dopt=AbstractPlus

203. Howanitz PJ, Howantiz JH. Carbohydrates. In: Henry JB, ed. Todd-Sanford-Davidsohn clinical diagnosis and management by laboratory methods. 17th ed. Philadelphia: WB Saunders Company; 1984:165-179.

204. USP DI: drug information for the health care provider. 20th ed. Englewood, CO: Micromedex, Inc; 2000;1:306.

205. Bayraktar M, Adalar N, Van Thiel DH. A comparison of acarbose versus metformin as an adjuvant therapy in sulfonylurea-treated NIDDM patients. Diabetes Care. 1996; 19:252-4. http://www.ncbi.nlm.nih.gov/pubmed/8742572?dopt=AbstractPlus

206. American Diabetes Association. Implications of the diabetes control and complications trial. Diabetes Care. 1996; 19:50-2S.

207. Sacher RA, McPherson RA, Campos JM. Glucose measurement. In: Sacher RA, McPherson RA, Campos JM, eds. Widman’s clinical interpretation of laboratory tests. 10th ed. Philadelphia: FA Davis Company; 1991:323-.

208. Saffar F, Aiache JM, Andre P. Influence of food on the disposition of the antidiabetic drug metformin in diabetic patients at steady-state. Meth Find Exp Clin Pharmacol. 1995; 17:483-7.

209. Misbin RI, Green L, Stadel BV et al. Lactic acidosis in patients with diabetes treated with metformin. New Engl J Med. 1998; 338:265-6. http://www.ncbi.nlm.nih.gov/pubmed/9441244?dopt=AbstractPlus

210. Nestler JE, Jakubowicz DA, Evans WS et al. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. New Engl J Med. 1998; 338:1876-80. http://www.ncbi.nlm.nih.gov/pubmed/9637806?dopt=AbstractPlus

211. Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17α activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. New Wngl J Med. 1996; 335:617-23.

212. Dunaif A, Scott D, Finegood D et al. The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metabol. 1996; 81:3299-306.

213. Babich MM, Pike I, Shiffman ML et al. Metformin-induced acute hepatitis. Am J Med. 1998; 104:490-2. http://www.ncbi.nlm.nih.gov/pubmed/9626034?dopt=AbstractPlus

214. Bristol-Myers Squibb Company. Glucophage (metformin hydrochloride) tablets and Glucophage XR (metformin hydrochloride) extended-release tablets patient information. Princeton, NJ; 2001 Jun.

215. Har SP, Walker JD. Is metformin contra-indicated in diabetic patients with chronic heart failure? Pract Diabetes Intern. 1996; 13:18-20.

216. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998; 352:854-65. http://www.ncbi.nlm.nih.gov/pubmed/9742977?dopt=AbstractPlus

217. Davis TM. United Kingdom Prospective Diabetes Study: the end of the beginning? Med J Aust. 1998; 169:511-2.

218. Nathan DM. Some answers, more controversy, from UKDS. Lancet. 1998; 352:832-3. http://www.ncbi.nlm.nih.gov/pubmed/9742972?dopt=AbstractPlus

219. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998; 352:837-53. http://www.ncbi.nlm.nih.gov/pubmed/9742976?dopt=AbstractPlus

220. American Diabetes Association. Position Statement: implications of the United Kingdom Prospective Diabetes Study. Diabetes Care. 1999; 22(Suppl. 1):S27-S31.

221. American Diabetes Association. The United Kingdom Prospective Diabetes Study (UKPDS) for type 2 diabetes: what you need to know about the results of a long-term study. Washington, DC; September 15, 1998. From American Diabetes Association web site (http://www.diabetes.org).

222. Genuth P. United Kingdom prospective diabetes study results are in J Fam Pract. 1998; 47:(Suppl.5):S27.

223. Matthews DR, Cull CA, Stratton RR et al. UKPDS 26: sulphonylurea failure in non-insulin-dependent diabetic patients over 6 years. Diabet Med. 1998; 15:297-303. http://www.ncbi.nlm.nih.gov/pubmed/9585394?dopt=AbstractPlus

224. Watkins PJ. UKPDS: a message of hope and a need for change. Diabet Med. 1998; 15:895-6. http://www.ncbi.nlm.nih.gov/pubmed/9827842?dopt=AbstractPlus

225. Bretzel RG, Voit K, Schatz H et al. The United Kingdom Prospective Diabetes Study (UKPDS): implications for the pharmacotherapy of type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes. 1998; 106:369-72. http://www.ncbi.nlm.nih.gov/pubmed/9831300?dopt=AbstractPlus

226. Morgensen CE. Combined high blood pressure and glucose in type 2 diabetes: double jeopardy. BMJ. 1998; 317:693-4. http://www.ncbi.nlm.nih.gov/pubmed/9732334?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1113869&blobtype=pdf

227. American Diabetes Association. Consensus statement: treatment of hypertension in diabetes. Diabetes Care. 1993; 16:1394-1401. http://www.ncbi.nlm.nih.gov/pubmed/8269800?dopt=AbstractPlus

228. UK Prospective Diabetes Study (UKPDS) Group. Efficacy of atenolol and captopril in reducing risk of macrovascular complications in type 2 diabetes mellitus: UKPDS 39. BMJ. 1998; 317:713-20. http://www.ncbi.nlm.nih.gov/pubmed/9732338?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=28660&blobtype=pdf

229. United Kingdom Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998; 317:703-13. http://www.ncbi.nlm.nih.gov/pubmed/9732337?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=28659&blobtype=pdf

230. Genuth S, Brownless MA, Kuller LH et al. Consensus development conference on insulin resistance: November 5-6 1997. Diabetes Care. 1998; 21:310-4. http://www.ncbi.nlm.nih.gov/pubmed/9540000?dopt=AbstractPlus

231. Turner RC, Cull CA, Frighi V et al. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirements for multiple therapies (UKPDS 49). JAMA. 1999; 281:2005-12. http://www.ncbi.nlm.nih.gov/pubmed/10359389?dopt=AbstractPlus

232. University Group Diabetes Program. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. Diabetes. 1970; 19(Suppl 2):747-830.

233. August K, Brooks L (California Department of Health and Human Services). State health director warns consumers about prescription drugs in herbal products. Rockville, MD; 2000 Feb 15. News release No. 09-00. News release from FDA web site (http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm171209.htm).

234. Bristol-Myers-Squibb Company. Glucovance(glyburide and metformin hydrochloride) tablets prescribing information. Princeton, NJ; 2010 May.

235. American Diabetes Association. Type 2 diabetes in children and adolescents. Pediatrics. 2000; 105:671-80. http://www.ncbi.nlm.nih.gov/pubmed/10699131?dopt=AbstractPlus

236. American Diabetes Association. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2000; 23(Suppl 1):S4-19.

237. Takeda Pharmaceuticals America. Actos (pioglitazone hydrochloride) tablets prescribing information. Deerfield, IL; 2011 Jul.

238. Moses R, Carter J, Slobodniuk R et al. Effect of repaglinide addition to metformin monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 1999; 22:119-24. http://www.ncbi.nlm.nih.gov/pubmed/10333912?dopt=AbstractPlus

239. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999; 131:281-303. http://www.ncbi.nlm.nih.gov/pubmed/10454950?dopt=AbstractPlus

240. Fonseca V,, Rosenstock J, Patwardhan R et al. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. JAMA. 2000; 283:1695-702. http://www.ncbi.nlm.nih.gov/pubmed/10755495?dopt=AbstractPlus

241. Aventis Pharmaceuticals Amaryl (glimepiride) tablets 1, 2, and 4 mg prescribing information. Kansas City, MO; 2000 Apr.

242. Pfizer. Glucotrol XL (glipizide) extended release tablets prescribing information. New York, NY; 1999 Aug.

243. Mylan Pharmaceuticals. Metformin hydrochloride tablets prescribing information. Morgantown, WV; 2002 Jan.

244. Bayer Corporation. Precose (acarbose) tablets prescribing information. West Haven, CT; 2003 Mar.

245. IVAX Pharmaceuticals. Metformin hydrochloride tablets prescribing information. Miami, FL; 2002 Jan.

246. PurePac Pharmaceutical Company. Metformin hydrochloride tablets prescribing information. Elizabeth, NJ; 2002 Feb.

247. GlaxoSmithKline. Avandamet(rosiglitazone maleate and metformin hydrochloride) tablets prescribing information. Research Triangle Park, NC; 2011 May.

248. Novartis. Starlix (nateglinide) tablets prescribing information. East Hanover, NJ; 2011 Aug.

249. Novo Nordisk. Prandin(repaglinide) tablets prescribing information. Princeton, NJ; 2009 Jun.

250. GlaxoSmithKline. Avandia (rosiglitazone maleate) tablets prescribing information. Research Triangle Park, NC; 2011 May.

251. Einhorn D, Rendell M, Rosenzweig J et al. Pioglitazone in combination with metformin in the treatment of type 2 diabetes mellitus: a randomized, placebo-controlled study. Clin Ther. 2000; 22:1395-409. http://www.ncbi.nlm.nih.gov/pubmed/11192132?dopt=AbstractPlus

252. Horton ES, Foley J, Clinkingbeard C et al. Nateglinide alone and in combination with metformin improves glycemic control by reducing mealtime glucose levels in type 2 diabetes. Diabetes Care. 2000; 23:1660-65. http://www.ncbi.nlm.nih.gov/pubmed/11092289?dopt=AbstractPlus

253. National Institute for Clinical Excellence, National Health Service. The clinical effectiveness and cost effectiveness of rosiglitazone for type 2 diabetes mellitus: health technology report. London, United Kingdom; 2000 Aug. From the NICE web site: http://www.nice.org.uk

254. Bristol-Myers Squibb Company. Metaglip (glipizide and metformin hydrochloride) prescribing information. Princeton, NJ; 2009 Feb.

255. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA. 2002; 287:2563-9. http://www.ncbi.nlm.nih.gov/pubmed/12020338?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2622728&blobtype=pdf

256. Bristol Myers Squibb, Princton, NJ: Personal communications.

257. Ranbaxy Laboratories Inc. Riomet (metformin hydrochloride) oral solution prescribing information. Jacksonville, FL; 2011 Jun.

258. Andrx Laboratories. Fortamet (metformin hydrochloride) extended-release tablets prescribing information. Weston, FL; 2005 May.

259. Teva Pharmaceutical USA. Metformin hydrochloride tablets 500 mg, 850 mg, and 1000 mg and metformin hydrochloride extended-release tablets 500 mg prescribing information. Sellersville, PA; 2004 Apr.

260. Takeda Pharmaceuticals America. Actoplus Met (pioglitazone hydrochloride and metformin hydrochloride) tablets prescribing information. Lincolnshire, IL; 2011 Jul.

261. Depomed. Glumetza (metformin hydrochloride) extended release tablets prescribing information. Menlo Park, CA; 2006 Apr.

262. Depomed. Technology: diffusional. Available at http://www.depomedinc.com. Accessed 2006 Aug 7.

263. American Diabetes Association. Preconception care of women with diabetes. Diabetes Care. 2004; 27(Suppl 1):S76-78.

264. Nathan DM, Buse JB, Davidson MB et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2006; 29:1963-72. http://www.ncbi.nlm.nih.gov/pubmed/16873813?dopt=AbstractPlus

265. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2003 clinical paractuce guidelines for the prevention and management of diabetes in Canada. Can J Diabetes. 2003; 27(Suppl 2):S1-152.

267. GlaxoSmithKline. Avandamet (rosiglitazone maleate and metformin hydrochloride) tablets prescribing information. Research Triangle Park, NC; 2007 Aug.

268. American Diabetes Association. Summary of revisions for the 2009 clinical practice recommendations. Diabetes Care. 2009; 32:S3-S5. http://www.ncbi.nlm.nih.gov/pubmed/19118287?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2613585&blobtype=pdf

269. Klein S, Allison DB, Heymsfield SB et al. Waist circumference and cardiometabolic risk: a consensus statement from shaping America's health: Association for Weight Management and Obesity Prevention; NAASO, the Obesity Society; the American Society for Nutrition; and the American Diabetes Association. Diabetes Care. 2007; 30:1647-52. http://www.ncbi.nlm.nih.gov/pubmed/17360974?dopt=AbstractPlus

270. Dluhy RG, McMahon GT. Intensive glycemic control in the ACCORD and ADVANCE trials. N Engl J Med. 2008; 358:2630-33. Editorial. http://www.ncbi.nlm.nih.gov/pubmed/18539918?dopt=AbstractPlus

271. Stratton IM, Adler AI, Neil HA et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000; 321:405-12. http://www.ncbi.nlm.nih.gov/pubmed/10938048?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=27454&blobtype=pdf

272. Henry RR. Glucose control and insulin resistance in non-insulin-dependent diabetes mellitus. Ann Intern Med. 1996; 124:97-103. http://www.ncbi.nlm.nih.gov/pubmed/8554221?dopt=AbstractPlus

273. Skyler JS, Bergenstal R, Bonow RO et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Diabetes Care. 2009; 32:187-92. http://www.ncbi.nlm.nih.gov/pubmed/19092168?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2606812&blobtype=pdf

274. , Patel A, MacMahon S et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008; 358:2560-72. http://www.ncbi.nlm.nih.gov/pubmed/18539916?dopt=AbstractPlus

275. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008; 358:2545-59. http://www.ncbi.nlm.nih.gov/pubmed/18539917?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4551392&blobtype=pdf

276. Duckworth W, Abraira C, Moritz T et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009; 360:129-39. http://www.ncbi.nlm.nih.gov/pubmed/19092145?dopt=AbstractPlus

277. American Diabetes Association. Aspirin therapy in diabetes: position statement. Diabetes Care. 2001; 24(Suppl.1):S62-3. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2663516&blobtype=pdf

278. Ismail-Beigi F, Moghissi ES. Glycemia management and cardiovascular risk in type 2 diabetes: an evolving perspective. Endocr Pract. 2008 Jul-Aug; 14:639-43.

279. Weiss IA, Valiquette G, Schwarcz MD. Impact of glycemic treatment choices on cardiovascular complications in type 2 diabetes. Cardiol Rev. 2009; 17(4):165-75. http://www.ncbi.nlm.nih.gov/pubmed/19525678?dopt=AbstractPlus

280. Holman RR, Paul SK, Bethel MA et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008; 359:1577-89. http://www.ncbi.nlm.nih.gov/pubmed/18784090?dopt=AbstractPlus

281. Nathan DM, Cleary PA, Backlund JY et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005; 353:2643-53. http://www.ncbi.nlm.nih.gov/pubmed/16371630?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2637991&blobtype=pdf

282. Skyler JS. Non-insulin-dependent diabetes mellitus: a clinical strategy. Diabetes Care. 1984; 7(Suppl 1):118-29. http://www.ncbi.nlm.nih.gov/pubmed/6376024?dopt=AbstractPlus

283. Defronzo RA, Ferrannini E, Koivisto V. New concepts in the pathogenesis and treatment of noninsulin-dependent diabetes mellitus. Am J Med. 1983; 74(Suppl 1A):52-81. http://www.ncbi.nlm.nih.gov/pubmed/6337486?dopt=AbstractPlus

284. Metformin. In: Briggs GG, Freeman RK, Yaffe SJ. Drug in pregnancy and lactation: a reference guide to fetal and neonatal risk. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2008:1155-9.

285. Hale TW, Kristensen JH, Hackett LP et al. Transfer of metformin into human milk. Diabetologia. 2002; 45(11):1509-14. http://www.ncbi.nlm.nih.gov/pubmed/12436333?dopt=AbstractPlus

286. Briggs GG, Ambrose PJ, Nageotte MP et al. Excretion of metformin into breast milk and the effect on nursing infants. Obstet Gynecol. 2005; 105(6):1437-41. http://www.ncbi.nlm.nih.gov/pubmed/15932841?dopt=AbstractPlus

287. Salpeter SR, Greyber E, Pasternak GA et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database of Systematic Reviews. 2010; Issue 1. Art. No.: CD002967.

288. Brown JB, Herson MK, Pedula K et al. Lactic acidosis rates in type 2 diabetes. Diabetes Care. 1998; 21:1659-63. http://www.ncbi.nlm.nih.gov/pubmed/9773726?dopt=AbstractPlus

289. Tso LO, Costello MF, Albuquerque LE et al. Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. Cochrane Database of Systematic Reviews. 2009, Issue 2. Art. No.: CD006105.

290. Costello MF, Shrestha B, Eden J et al. Insulin-sensitizing drugs versus the combined oral contraceptive pill for hirsutism, acne and risk of diabetes, cardiovascular disease, and endometrial cancer in polycystic ovary syndrome. Cochrane Database of Systematic Reviews. 2007, Issue 1. Art. No.: CD005552.

291. Fedorcsák P, Dale PO, Storeng R et al. The effect of metformin on ovarian stimulation and in vitro fertilization in insulin-resistant women with polycystic ovary syndrome: an open-label randomized cross-over trial. Gynecol Endocrinol. 2003; 17(3):207-14.

292. Practice Committee of the American Society for Reproductive Medicine. Use of insulin sensitizing agents in the treatment of polycystic ovary syndrome. Fertil Steril. 2004; 82 Suppl 1):S181-3. http://www.ncbi.nlm.nih.gov/pubmed/15363722?dopt=AbstractPlus

293. Ehrmann DA. Polycystic ovary syndrome. New Engl J Med. 2005; 352:1223-36. http://www.ncbi.nlm.nih.gov/pubmed/15788499?dopt=AbstractPlus

294. Tang T, Lord JM, Norman RJ et al. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro- inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database of Systematic Reviews. 2010, Issue 1. Art. No.: CD003053.

295. Meyer C, McGrath BP, Teede HJ. Effects of medical therapy on insulin resistance and the cardiovascular System in polycystic ovary syndrome. Diabetes Care. 2007; 30:471-8. http://www.ncbi.nlm.nih.gov/pubmed/17327307?dopt=AbstractPlus

296. Doldi N, Persico P, Di Sebastiano F et al. Gonadotropin-releasing hormone antagonist and metformin for treatment of polycystic ovary syndrome patients undergoing in vitro fertilization-embryo transfer. Gynecol Endocrinol. 2006; 22(5):235-8. http://www.ncbi.nlm.nih.gov/pubmed/16785142?dopt=AbstractPlus

297. Lobo RA. Choice of treatment for women with polycystic ovary syndrome. Fertil Steril. 2006; 86(suppl 1):S22-3. http://www.ncbi.nlm.nih.gov/pubmed/16798280?dopt=AbstractPlus

298. Teede HJ, Meyer C, Hutchison SK et al. Endothelial function and insulin resistance in polycystic ovary syndrome: the effects of medical therapy. Fertil Steril. 2010; 93:184-91. http://www.ncbi.nlm.nih.gov/pubmed/19019358?dopt=AbstractPlus

299. Practice Committee, American Society for Reproductive Medicine. Use of insulin sensitizing agents in the treatment of polycystic ovary syndrome. Fertil Steril. 2006; 86(Suppl 4):S221-3. http://www.ncbi.nlm.nih.gov/pubmed/17055827?dopt=AbstractPlus

300. Radosh L. Drug treatments for polycystic ovary syndrome. Am Fam Physician. 2009;79:671-6.

301. Creanga AA, Bradley HM, McCormick C et al. Use of metformin in polycystic ovary syndrome. Obstet Gynecol. 2008; 111:959-68. http://www.ncbi.nlm.nih.gov/pubmed/18378757?dopt=AbstractPlus

302. Nestler JE. Metformin for the treatment of the polycystic ovary syndrome. N Engl J Med. 2008; 358:47-54. http://www.ncbi.nlm.nih.gov/pubmed/18172174?dopt=AbstractPlus

303. Liu JH, Bill AH. Expanding applications for metformin in polycystic ovarian syndrome. J Pediatr. 2006; 148:573-4. Editorial. http://www.ncbi.nlm.nih.gov/pubmed/16737862?dopt=AbstractPlus

304. Urman B, Yahin K. Ovulatory disorders and infertility. J Reprod Med. 2006; 51:267-82. http://www.ncbi.nlm.nih.gov/pubmed/16737024?dopt=AbstractPlus

305. Siebert TI, Kruger, TF, Steyn DW et al. Is the addition of metformin efficacious in the treatment of clomiphene citrate-resistant patients with polycystic ovary syndrome? Fertil Steril. 2006; 86:1432-7.

306. Pillai AS, Bang H, Green C. Metformin & glitazones: Do they really help PCOS patients? J Fam Pract. 2007; 56:444-53.

307. Practice Committee of the American Society for Reproductive Medicine. Use of insulin-sensitizing agents in the treatment of polycystic ovary syndrome. Fertil Steril. 2008; 90(Suppl 3):S69-73. http://www.ncbi.nlm.nih.gov/pubmed/19007650?dopt=AbstractPlus

308. Nestler JE. Metformin in the treatment of infertility in polycystic ovarian syndrome: an alternative perspective. Fertil Steril. 2008; 90:14-6. Editorial. http://www.ncbi.nlm.nih.gov/pubmed/18550055?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2495076&blobtype=pdf

309. Legro RS, Barnhart HX, Schlaff WD et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007; 356:551-66. http://www.ncbi.nlm.nih.gov/pubmed/17287476?dopt=AbstractPlus

310. Guzick DS. Treating the polycystic ovary syndrome the old-fashioned way. N Engl J Med. 2007; 356:622-4. Editorial. http://www.ncbi.nlm.nih.gov/pubmed/17287483?dopt=AbstractPlus

311. Palomba S, Orio F Jr, Falbo A et al. Clomiphene citrate versus metformin as first-line approach for the treatment of anovulation in infertile patients with polycystic ovary syndrome. J Clin Endocrinol Metab. 2007; 92:3498-3503. http://www.ncbi.nlm.nih.gov/pubmed/17595241?dopt=AbstractPlus

312. Barbieri RL. Clomiphene versus metformin for ovulation induction in polycystic ovary syndrome: the winner is....J Clin Endocrinol Metab. 2007; 92:3399-3401. Editorial. http://www.ncbi.nlm.nih.gov/pubmed/17823274?dopt=AbstractPlus

313. Novo Nordisk A/S. Prandimet (repaglinide/metformin hydrochloride) tablets prescribing information. Princeton, NJ; 2011 Sept.

314. Merck. Janumet (sitagliptin/metformin hydrochloride) tablets prescribing information. Whitehouse Station, NJ; 2011 Apr.

315. Moses R, Carter J, Slobodniuk R et al. Effect of repaglinide addition to metformin monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 1999; 22:119-24. http://www.ncbi.nlm.nih.gov/pubmed/10333912?dopt=AbstractPlus

316. Stang M, Wysowski DK, Butler-Jones D. Incidence of lactic acidosis in metformin users. Diabetes Care. 1999; 22:925-7. http://www.ncbi.nlm.nih.gov/pubmed/10372243?dopt=AbstractPlus

317. Lalau JD, Race JM. Lactic acidosis in metformin therapy: searching for a link with metformin in reports of “metformin-associated lactic acidosis”. Diabetes Obes Metab. 2001; 3:195-201. http://www.ncbi.nlm.nih.gov/pubmed/11412284?dopt=AbstractPlus

318. Salpeter SR, Greyber E, Pasternak GA et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Arch Intern Med. 2003; 163:2594-2602. http://www.ncbi.nlm.nih.gov/pubmed/14638559?dopt=AbstractPlus

319. Bolen S, Feldman L, Vassy J et al. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med. 2007; 147:386-99. http://www.ncbi.nlm.nih.gov/pubmed/17638715?dopt=AbstractPlus

320. Tahrani AA, Varughese GI, Scarpello JH et al. Metformin, heart failure, and lactic acidosis: is metformin absolutely contraindicated? Br Med J. 2007; 335:508-12.

321. Misbin RI. The phantom of lactic acidosis due to metformin in patients with diabetes. Diabetes Care. 2004; 27:1791-3. Commentary. http://www.ncbi.nlm.nih.gov/pubmed/15220268?dopt=AbstractPlus

322. Bodmer M, Jick SS, Meier C et al. Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia. Diabetes Care. 2008; 31:2086-91. http://www.ncbi.nlm.nih.gov/pubmed/18782901?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2571051&blobtype=pdf

323. US Food and Drug Administration. FDA significantly restricts access to the diabetes drug Avandia. Rockville, MD; 2010 Sep 23. News release from FDA web site. Accessed 2010 Nov 15. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm226975

324. Woodcock J (US Food and Drug Administration). Decision on continued marketing of rosiglitazone (Avandia, Avandamet, Avandaryl). Rockville, MD; Available at FDA website. Accessed 2010 Nov 15. http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM226959.pdf

325. Food and Drug Administration. FDA drug safety communication: Updated risk evaluation and mitigation strategy (REMS) to restrict access to rosiglitazone-containing medicines including Avandia, Avandamet, and Avandaryl. Rockville, MD; 2011 May 18. Available from FDA website. Accessed 2011 Jun 20. http://www.fda.gov/Drugs/DrugSafety/ucm255005.htm

326. Avandia (rosiglitazone maleate), Avandamet (rosiglitazone maleate and metformin hydrochloride), and Avandaryl (rosiglitazone maleate and glimepiride) tablets risk evaluation and mitigation strategy (REMS). Available from FDA web site. Accessed 2011 Aug 25. http://www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm255624.pdf

327. Food and Drug Administration. FDA advisory committee meeting briefing document for NDA 21071 Avandia (rosiglitazone maleate). Rockville, MD; July 13 and 14, 2010. From FDA website. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM218493.pdf

328. Lipska KJ, Ross JS. Switching from rosiglitazone: thinking outside the class. JAMA. 2011; 305:820-1. http://www.ncbi.nlm.nih.gov/pubmed/21304068?dopt=AbstractPlus

330. Food and Drug Administration. FDA drug safety communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function. Silver Spring, MD; 2016 Apr 8. Available from FDA website. http://www.fda.gov/downloads/Drugs/DrugSafety/UCM494140.pdf

331. Rachmani R, Slavachevski I, Levi Z et al. Metformin in patients with type 2 diabetes mellitus: reconsideration of traditional contraindications. Eur J Intern Med. 2002; 13:428. http://www.ncbi.nlm.nih.gov/pubmed/12384131?dopt=AbstractPlus

332. Kamber N, Davis WA, Bruce DG et al. Metformin and lactic acidosis in an Australian community setting: the Fremantle Diabetes Study. Med J Aust. 2008; 188:446-9. http://www.ncbi.nlm.nih.gov/pubmed/18429709?dopt=AbstractPlus

333. Roussel R, Travert F, Pasquet B et al. Metformin use and mortality among patients with diabetes and atherothrombosis. Arch Intern Med. 2010; 170:1892-9. http://www.ncbi.nlm.nih.gov/pubmed/21098347?dopt=AbstractPlus

334. Ekström N, Schiöler L, Svensson AM et al. Effectiveness and safety of metformin in 51 675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register. BMJ Open. 2012; 2:. http://www.ncbi.nlm.nih.gov/pubmed/22798258?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3400073&blobtype=pdf

335. American College of Radiology (ACR) Committee on Drugs and Contrast Media. ACR manual on contrast media: metformin. 2016. Available at ACR website. Accessed 2016 Aug 4. http://www.acr.org/~/media/ACR/Documents/PDF/QualitySafety/Resources/Contrast%20Manual/2016_Contrast_Media.pdf

336. . In brief: New recommendations for use of metformin in renal impairment. Med Lett Drugs Ther. 2016; 58:51.

340. Inker LA, Astor BC, Fox CH et al. KDOQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for the Evaluation and Management of CKD. AM J Kidney Dis. 2014; 63(5):713-35. http://www.ncbi.nlm.nih.gov/pubmed/24647050?dopt=AbstractPlus

341. National Kidney Foundation. KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 update. AM J Kidney Dis. 2012; 60(5):850-86. http://www.ncbi.nlm.nih.gov/pubmed/23067652?dopt=AbstractPlus

350. Bristol-Myers Squibb Company. Glucophage (metformin hydrochloride) tablets and Glucophage XR (metformin hydrochloride) prescribing information. Princeton, NJ; 2018 May.

351. Bristol-Myers Squibb Company. Glucophage (metformin hydrochloride) tablets and Glucophage XR (metformin hydrochloride) patient information. Princeton, NJ; 2018 May.

352. Merck. Janumet XR (sitagliptin/extended-release metformin hydrochloride) tablets prescribing information. Whitehouse Station, NJ; 2018 Feb.

355. Merck. Segluromet (ertugliflozin and metformin hydrochloride) tablets prescribing information. Whitehouse Station, NJ; 2018 Oct.

360. Richy FF, Sabidó-Espin M, Guedes S et al. Incidence of lactic acidosis in patients with type 2 diabetes with and without renal impairment treated with metformin: a retrospective cohort study. Diabetes Care. 2014; 37:2291-5. http://www.ncbi.nlm.nih.gov/pubmed/24879835?dopt=AbstractPlus

361. Kraut JA, Madias NE. Lactic acidosis. N Engl J Med. 2014; 371:2309-19. http://www.ncbi.nlm.nih.gov/pubmed/25494270?dopt=AbstractPlus

362. AstraZeneca Pharmaceuticals. Xigduo XR (dapagliflozin and extended-release metformin hydrochloride) tablets prescribing information. Wilmington, DE; 2018 Oct.

363. AstraZeneca Pharmaceuticals. Xigduo XR (dapagliflozin and extended-release metformin hydrochloride) medication guide. Wilmington, DE; 2018 Oct.

368. AstraZeneca. Kombiglyze XR (saxagliptin and metformin HCl extended-release) tablets prescribing information. Wilmington, DE; 2014 Jun.

369. AstraZeneca. Kombiglyze XR (saxagliptin and metformin HCl extended-release) tablets medication guide. Wilmington, DE; 2014 Jun.

370. Janssen Pharmaceuticals, Inc. Invokamet/Invokamet XR (canagliflozin and immediate- or extended-release metformin hydrochloride) tablets prescribing information. Titusville, NJ; 2018 Oct.

371. Janssen Pharmaceuticals, Inc. Invokamet/Invokamet XR (canagliflozin and immediate- or extended-release metformin hydrochloride) medication guide. Titusville, NJ; 2018 Oct.

372. Boehringer Ingelheim Pharmaceuticals, Inc. Synjardy (empagliflozin and metformin hydrochloride) tablets prescribing information. Ridgefield, CT; 2018 Oct.

373. Boehringer Ingelheim Pharmaceuticals, Inc. Synjardy (empagliflozin and metformin hydrochloride) medication guide. Ridgefield, CT; 2018 Oct.

374. Boehringer Ingelheim Pharmaceuticals, Inc. Synjardy XR (empagliflozin and metformin hydrochloride extended-release) tablets prescribing information. Ridgefield, CT; 2018 Oct.

375. Boehringer Ingelheim Pharmaceuticals, Inc. Synjardy XR (empagliflozin and metformin hydrochloride extended-release) medication guide. Ridgefield, CT; 2018 Oct.

376. Boehringer Ingelheim Pharmaceuticals, Inc. Jentadueto (linagliptin and immediate-release metformin hydrochloride) tablets prescribing information. Ridgefield, CT; 2017 Aug.

377. Boehringer Ingelheim Pharmaceuticals, Inc. Jentadueto (linagliptin and immediate-release metformin hydrochloride) tablets medication guide. Ridgefield, CT; 2017 Aug.

378. Boehringer Ingelheim Pharmaceuticals, Inc. Jentadueto XR (linagliptin and extended-release metformin hydrochloride) tablets prescribing information. Ridgefield, CT; 2019 Jul.

379. Boehringer Ingelheim Pharmaceuticals, Inc. Jentadueto XR (linagliptin and extended-release metformin hydrochloride) tablets medication guide. Ridgefield, CT; 2019 Jul.

598. Garber AJ, Abrahamson MJ, Barzilay JI et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endorinology on the comprehensive type 2 diabetes management algorithm - 2019 executive summary. Endocr Pract. 2019; 25:69-100. http://www.ncbi.nlm.nih.gov/pubmed/30742570?dopt=AbstractPlus

602. American Diabetes Association. 6. Glycemic targets: standards of medical care in diabetes-2019. Diabetes Care. 2019; 42:S61-S70. http://www.ncbi.nlm.nih.gov/pubmed/30559232?dopt=AbstractPlus

604. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2019. Diabetes Care. 2019; 42:S90-S102. http://www.ncbi.nlm.nih.gov/pubmed/30559235?dopt=AbstractPlus

605. American Diabetes Association. 10. Cardiovascular disease and risk management: standards of medical care in diabetes-2019. Diabetes Care. 2019; 42:S103-S123. http://www.ncbi.nlm.nih.gov/pubmed/30559236?dopt=AbstractPlus

609. American Diabetes Association. 14. Management of diabetes in pregnancy: standards of medical care in diabetes-2019. Diabetes Care. 2019; 42:S165-S172. http://www.ncbi.nlm.nih.gov/pubmed/30559240?dopt=AbstractPlus

610. Takeda. Kazano (alogliptin and metformin hydrochloride) tablets, for oral use, prescribing information. Deerfield, IL; 2019 Jun.

611. Nauck MA, Ellis GC, Fleck PR et al. Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo-controlled study. Int J Clin Pract. 2009; 63:46-55. http://www.ncbi.nlm.nih.gov/pubmed/19125992?dopt=AbstractPlus