Skip to main content

metFORMIN (Monograph)

Brand names: Fortamet, Glumetza, Riomet
Drug class: Biguanides
ATC class: A10BA02
VA class: HS502
Chemical name: 1,1-Dimethylbiguanide monohydrochloride
Molecular formula: C4H11N5 • HCl
CAS number: 1115-70-4

Medically reviewed by Drugs.com on Jun 11, 2024. Written by ASHP.

Warning

    Lactic Acidosis

  • Lactic acidosis rare but potentially fatal.1 6 18 20 27 29 30 62 89 96 158 234 254 Increased risk of lactic acidosis in patients with renal impairment and advanced age.1 2 62 96 119 234 254 260 314 352 355 361

  • Generally has occurred in diabetic patients with severe renal insufficiency and concomitant medical and/or surgical problems who 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 96 123 158 164 165 234 254 314

  • Periodically monitor renal function and use the minimum effective dosage.1 32 62 63 65 76 85 91 93 96 119 123 124 158 164 165 234 254 258 287 314 Withhold metformin promptly in patients with any condition associated with hypoxemia, sepsis, or dehydration.1 2 62 63 93 234 260 314 340 Avoid use in patients with clinical or laboratory evidence of hepatic impairment.1 2 63 65 85 91 93 156 158 234 254 314 352 355 Manufacturers state to temporarily discontinue metformin therapy before or at the time of an intravascular (e.g., IV, intra-arterial) 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.1 234 254 330 336 352 355 610 Withhold metformin temporarily in patients undergoing surgery. 1 2 30 62 63 93 158 234 254 261 314 330 336 352 355 610 Concomitant drugs that may affect renal function, produce substantial hemodynamic changes, or alter metformin elimination should be used with caution.1 134 234 254

    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, 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, acutely or chronically.1 2 63 76 91 93 158 234 314 352 355

  • If lactic acidosis occurs, discontinue metformin and institute general supportive therapy immediately.1 30 260 314 Treat as medical emergency, with immediate hospitalization and treatment required; prompt hemodialysis recommended.1 23 32 62 117 119 234 254 260 314 352 355

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 72 146 234 254

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 95 166 234 254 698 704

May be used in combination with a glucagon-like peptide-1 (GLP-1) agonist, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, a dipeptidyl peptidase-4 (DPP-4) inhibitor, a thiazolidinedione antidiabetic agent, a sulfonylurea, or a meglitinide (repaglinide, nateglinide) 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 99 112 134 166 191 234 237 238 239 241 242 248 249 250 254 260 352 355 362 368 370 372 374 376 378 610 698 704

May be used with insulin to improve glycemic control and/or decrease the required dosage of insulin.1 3 6 88 90 94 95 146 698 704

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 pioglitazone 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 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 drug components is appropriate.355 362 370 372 374

Current guidelines for the treatment of type 2 diabetes mellitus generally recommend metformin as first-line therapy in addition to lifestyle modifications in patients with recent-onset type 2 diabetes mellitus or mild hyperglycemia because of its well-established safety and efficacy (i.e., beneficial effects on glycosylated hemoglobin [hemoglobin A1c; HbA1c], weight, and cardiovascular mortality).264 698 704 705 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 68 102 134 146 166 264 698 704

In patients with metformin contraindications or intolerance (e.g., risk of lactic acidosis, GI intolerance) or in selected other patients, some experts suggest that initial therapy with a drug from another class of antidiabetic agents (e.g., a GLP-1 receptor agonist, SGLT2 inhibitor, DPP-4 inhibitor, sulfonylurea, thiazolidinedione, basal insulin) may be acceptable based on patient factors.698 704

May need to initiate therapy with 2 agents (e.g., metformin plus another drug) in patients with high initial HbA1c (>7.5% or ≥1.5% above target).698 704 In such patients with metformin intolerance, some experts suggest initiation of therapy with 2 drugs from other antidiabetic drug classes with complementary mechanisms of action.698 704

Consider early initiation of combination therapy for the treatment of type 2 diabetes mellitus to extend the time to treatment failure and more rapidly attain glycemic goals.704

For patients with inadequate glycemic control on metformin monotherapy, consider patient comorbidities (e.g., atherosclerotic cardiovascular disease [ASCVD], established kidney disease, heart failure), hypoglycemia risk, impact on weight, cost, risk of adverse effects, and patient preferences when selecting additional antidiabetic agents for combination therapy.698 699 704 705 706

Consider early introduction of insulin for severe hyperglycemia (e.g., blood glucose ≥300 mg/dL or HbA1c >9–10%), especially if accompanied by catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis) or symptoms of hyperglycemia.698 704

Experts recommend that patients with type 2 diabetes mellitus who have established (or are at a high risk for) ASCVD, established kidney disease, or heart failure receive a GLP-1 receptor agonist or SGLT2 inhibitor with demonstrated cardiovascular disease benefit.704 705 In patients with these comorbidities, consider GLP-1 receptor agonist or SGLT2 inhibitor therapy independently of patient's HbA1c.704

In patients with type 2 diabetes mellitus and CKD, consider a GLP-1 receptor agonist or SGLT2 inhibitor shown to reduce the risk of CKD progression, cardiovascular events, or both, in addition to metformin therapy or in those in whom metformin cannot be used.704 705 706

In patients on metformin monotherapy without established ASCVD or indicators of high ASCVD risk, heart failure, or CKD, base decision regarding addition of other antidiabetic agents on avoidance of adverse effects, cost, and individual patient factors.704

Not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.1

Polycystic Ovary Syndrome

Has been used in the management of metabolic and reproductive abnormalities associated with polycystic ovary syndrome† [off-label].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

Administration

Oral Administration

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

Administer immediate-release tablets in 2 divided doses daily if total dosage ≤2 g daily or in 3 divided doses daily 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.1 258 260 261 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, glipizide, glyburide, pioglitazone, alogliptin, linagliptin, or sitagliptin in divided doses daily with meals to reduce the GI effects of the metformin hydrochloride component.234 254 260 314 355 362 370 372 376 610

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

Pediatric Patients

Type 2 Diabetes Mellitus
Oral

Immediate-release tablets or immediate-release oral solution in children or adolescents 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 2 divided doses.1 257

Adults

Type 2 Diabetes Mellitus
Metformin Hydrochloride Monotherapy
Oral

Immediate-release tablets or immediate-release oral solution: Initially, 500 mg twice daily or 850 mg once daily with meals.1 257 Initial dosage of 500 mg once daily has been suggested by some experts.264

Increase daily dosage by 500 mg at weekly intervals or by 850 mg at biweekly (every 2 week) intervals up to a maximum of 2.55 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

Certain extended-release tablets: Initially, 500 mg once daily with the evening meal.1 Increase daily dosage by 500 mg at weekly intervals based on glycemic control and tolerability up to a maximum of 2 g daily.1 If glycemic control is not achieved with 2 g once daily, consider administering 1 g twice daily.1 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 May switch from immediate-release to extended-release metformin hydrochloride tablets at the same total daily dosage, up to 2 g once daily.1 261

Extended-release tablets (Glumetza) in patients ≥18 years of age: Initially, 1 g once daily with the evening meal.261 Increase daily dosage by 500 mg at weekly intervals to a maximum of 2 g once daily with the evening meal.261 If glycemic control not achieved with 2 g once daily, consider administering 1 g twice daily.261

Manufacturer states that based on a clinical trial, therapy with immediate-release metformin may be switched to extended-release metformin (Glumetza) once daily at the same total daily dosage, up to 2 g once daily.261 Following a switch from immediate-release metformin to extended-release metformin hydrochloride (Glumetza), closely monitor glycemic control and adjust dosage accordingly.261

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 once daily with the evening meal.258

Manufacturer states that based on a clinical trial, therapy with immediate-release metformin may be switched to extended-release metformin (Fortamet) once daily at the same total daily dosage, up to 2.5 g once daily.258 Following a switch from immediate-release metformin to extended-release metformin hydrochloride (Fortamet), closely monitor glycemic control and adjust dosage accordingly.258

Combined Metformin Hydrochloride and Oral Sulfonylurea Therapy
Oral

Certain extended-release metformin hydrochloride tablets (Fortamet, Glumetza): Manufacturers suggest gradual addition of an oral sulfonylurea antidiabetic agent in patients not responding to 4 weeks of monotherapy with maximum dosages of metformin hydrochloride; continue metformin hydrochloride at the maximum dosage even if prior primary or secondary failure to a sulfonylurea has occurred.258 261 Adjust dosage of metformin hydrochloride (e.g., Fortamet, Glumetza) and the sulfonylurea to obtain the desired level of glycemic control with the minimum effective dosage.258 261 Concomitant metformin and sulfonylurea therapy may increase risk of hypoglycemia; take appropriate precautions.258 261 If patient has not responded satisfactorily to 1–3 months of concomitant therapy with maximum dosages of metformin hydrochloride (e.g., Fortamet, Glumetza) and an oral sulfonylurea, consider therapeutic alternatives, including switching to insulin with or without metformin.258 261

Immediate-release Metformin Hydrochloride in Fixed Combination with Glipizide
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), consider 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 1 or 2 g of metformin hydrochloride and 10 mg of glipizide in divided doses 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 daily dosages exceeding 2 g of metformin hydrochloride and 10 mg of glipizide as initial therapy.254 256

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 500 mg of metformin hydrochloride and 5 mg of glipizide 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
Oral

Patients not already receiving either glyburide (or another sulfonylurea) or metformin hydrochloride: Initially, 250 mg of metformin hydrochloride and 1.25 mg of glyburide once or twice daily with meals.234 Titrate daily dosage gradually based on glycemic control and tolerability up to a maximum daily dosage of 2 g of metformin hydrochloride and 20 mg of glyburide.234

Patients with inadequate glycemic control on either glyburide (or another sulfonylurea) or metformin hydrochloride monotherapy: Initially, 500 mg of metformin hydrochloride and 2.5 mg of glyburide or 500 mg of metformin hydrochloride and 5 mg of glyburide twice daily with meals.234 Increase daily dosage gradually based on glycemic control and tolerability up to a maximum daily dosage of 2 g of metformin hydrochloride and 20 mg of glyburide.234

Patients with inadequate glycemic control on the combination of a sulfonylurea and metformin: 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 gradually based on glycemic control and tolerability up to a maximum daily dosage of 2 g of metformin hydrochloride and 20 mg of glyburide.234

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

Patients in whom combination therapy with metformin and pioglitazone considered appropriate: Initially, 500 mg of metformin hydrochloride and 15 mg of pioglitazone twice daily or 850 mg of metformin hydrochloride and 15 mg of pioglitazone once daily.260

Patients inadequately controlled on metformin monotherapy: Initially, 500 mg of metformin hydrochloride and 15 mg of pioglitazone twice daily or 850 mg of metformin hydrochloride and 15 mg of pioglitazone once or twice daily (depending on metformin hydrochloride dosage already being taken).260

Patients inadequately controlled on pioglitazone monotherapy: Initially, 500 mg of metformin hydrochloride and 15 mg of pioglitazone twice daily or 850 mg of metformin hydrochloride and 15 mg of pioglitazone once daily.260

Patients switching from combination therapy with metformin hydrochloride and pioglitazone given as separate tablets: Use dosage of the fixed combination as close as possible to dosages of metformin hydrochloride and pioglitazone already being taken.260

Patients with NYHA class I or II congestive heart failure: Initially, 500 mg of metformin hydrochloride and 15 mg of pioglitazone or 850 mg of metformin hydrochloride and 15 mg of pioglitazone once daily.260 Initiation of the fixed combination in patients with NYHA class III or IV congestive heart failure contraindicated.260

Gradually titrate dosage as needed based on therapeutic response and tolerability to maximum daily dosage of 2.55 g of metformin hydrochloride and 45 mg of pioglitazone.260 Metformin hydrochloride dosages >2 g daily may be better tolerated if given in 3 divided doses daily.260

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 metformin hydrochloride: Initially, a total daily metformin hydrochloride dosage similar to patient's existing dosage and 5 mg of linagliptin, administered 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

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.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 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

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 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 metformin hydrochloride: Initially, a total daily metformin hydrochloride dosage similar to patient's existing dosage and 10 mg of empagliflozin, administered once daily.374

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

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 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 Receiving Insulin
Oral

Certain extended-release tablets (Fortamet, Glumetza): Initially, 500 mg once daily; concurrent insulin dosage initially remains unchanged.258 261 Increase metformin hydrochloride dosage by 500 mg daily at weekly intervals until adequate glycemic control is achieved or a maximum daily dosage of 2.5 g (Fortamet)258 or 2 g (Glumetza)261 is reached. When fasting plasma glucose concentration decreases to <120 mg/dL, decrease insulin dosage by 10–25%.258 261 Individualize further dosage adjustments according to glycemic response.258 261

Polycystic Ovary Syndrome† [off-label]
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 immediate-release oral solution.1 257

Adults

Type 2 Diabetes Mellitus
Metformin Hydrochloride Monotherapy
Oral

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

Metformin Hydrochloride in Fixed Combination with Glyburide
Oral

Maximum daily dosage is 2 g of metformin hydrochloride and 20 mg of glyburide.234

Metformin Hydrochloride in Fixed Combination with Glipizide
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: Initiation of metformin therapy not recommended; assess benefits and risks of continued treatment if eGFR falls below 45 mL/minute per 1.73 m2 in patients already receiving metformin.1 330 336

eGFR <30 mL/minute per 1.73 m2: Contraindicated; discontinue in patients already receiving metformin.1 165 260 287 314 330 336

Hepatic Impairment

Avoid use in those with clinical or laboratory evidence of hepatic disease.1 165 260 287 314 330 336

Geriatric Patients

In general, do not titrate to the maximum dosage recommended for younger adults;2 3 4 165 254 258 261 314 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 4 164 165 260 314

Detailed Metformin dosage information

Cautions for metFORMIN

Contraindications

Warnings/Precautions

Warnings

Lactic Acidosis

See Boxed Warning.

Other Warnings and 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 or Foods 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 82 114 122 134 148 698 prior to initiation of therapy and at least annually during treatment and any abnormality properly investigated.1

In patients who develop neuropathy while on metformin, monitor vitamin B12 levels698 704 and administer supplementation if needed;698 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

Macrovascular Outcomes

The manufacturer states that there have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin.1

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).234 237 254 260 314 352 355 362 368 370 372 374 376 378 610

Specific Populations

Pregnancy

Category B.1

Available studies suggest no clear association between metformin use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes.1 Use metformin during pregnancy only when clearly needed.3 4

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.1 260 284 285 286 Consider developmental and health benefits of breastfeeding along with mother's clinical need for the drug and potential adverse effects on breastfed child (e.g., hypoglycemia).234 254 Monitor breastfed infants for signs of hypoglycemia (e.g., jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, seizures).234 254

Pediatric Use

Safety and efficacy of metformin as immediate-release tablets or immediate-release 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

Safety and efficacy of metformin in fixed combination with glipizide, pioglitazone, or sitagliptin in children have not been established.1 3 4 30 134 254 260 314 Data from a clinical trial in children 9–16 years of age comparing combined therapy with metformin and glyburide 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 85 174 234 254 314

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 Clcr.1 209 314

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.1 165 260 287 314 330 336 (See Contraindications.)

Evaluate renal function prior to initiation of therapy and at least annually thereafter.1 2 77 85 234 254 260 330

Monitor more frequently if development of impaired renal function is anticipated (e.g., geriatric patients, those with blood glucose concentrations >300 mg/dL, those who may develop renal dysfunction as a result of polyuria and volume depletion).1 156 234 254 260 330

Discontinue metformin if patient's eGFR <30 mL/minute per 1.73 m2 or drops below 30 mL/minute per 1.73 m2 while on metformin therapy; contraindicated in such patients.1 234 254 257 260 330 336

Hepatic Impairment

Generally avoid use in patients with clinical or laboratory evidence of hepatic disease.1 165 260 287 314 330 336 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

Drug Interactions

Cationic Agents Secreted by Proximal Renal Tubules

Pharmacokinetic interaction with cimetidine (decreased excretion of metformin).1 75 234 254 260 314

Potential pharmacokinetic interaction with other cationic drugs that undergo substantial tubular secretion (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, vancomycin).1 30 254 260 314

Monitor carefully; consider dosage adjustment of either agent.1 314

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 314

Antidiabetic agents (e.g., sulfonylureas, meglitinides, insulin)

Possible hypoglycemia1 15 78 94 99 260

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

Carbonic anhydrase inhibitors

May reduce serum bicarbonate concentrations and induce non-anion gap, hyperchloremic metabolic acidosis; may increase risk for lactic acidosis1 234 254 260

Consider more frequent monitoring of patients receiving such concomitant therapy1 234 254 260

Cimetidine

Possible decreased excretion of metformin1 75 234 254 260 314

Increased peak concentrations and AUC of metformin; negligible effects on cimetidine pharmacokinetics1 75 314

Carefully monitor patient; consider need for dosage adjustment1 314

Clomiphene

Possible resumption of ovulation in premenopausal patients with polycystic ovary syndrome210 211 212 234

Furosemide

Increased peak concentrations of metformin and decreased peak concentrations and terminal half-life of furosemide in single-dose study1 314

Glyburide

Pharmacokinetics and pharmacodynamics of metformin not altered in single-dose study1 260 261 314

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 314

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 drug interactions (more detail)

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

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

Food increases the extent of absorption and delays the time to peak plasma concentrations of the immediate-release oral solution.257 Fat content of meals does not appreciably affect the pharmacokinetics of metformin hydrochloride immediate-release 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/pioglitazone fixed combination: Tight containers at 25°C.260

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

Advice to Patients

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

Glumetza

Depomed

metFORMIN Hydrochloride Extended-Release Tablets

750 mg*

metFORMIN Hydrochloride Extended-Release Tablets

1 g*

Fortamet

Shionogi Pharma

Glumetza

Depomed

metFORMIN Hydrochloride Extended-Release Tablets

Tablets, film-coated

500 mg*

metFORMIN Hydrochloride Tablets

625 mg*

metFORMIN Hydrochloride Tablets

750 mg*

metFORMIN Hydrochloride Tablets

850 mg*

metFORMIN Hydrochloride Tablets

1 g*

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 (anhydrous) 50 mg

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

Boehringer Ingelheim

1 g with Immediate-release Empagliflozin 10 mg

Synjardy XR

Boehringer Ingelheim

1 g with Immediate-release Empagliflozin 12.5 mg

Synjardy XR

Boehringer Ingelheim

1 g with Immediate-release Empagliflozin 25 mg

Synjardy XR

Boehringer 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 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*

metFORMIN Hydrochloride and Glipizide Tablets

250 mg with Glyburide 1.25 mg*

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*

metFORMIN Hydrochloride and Glipizide Tablets

500 mg with Glipizide 5 mg*

metFORMIN Hydrochloride and Glipizide Tablets

500 mg with Glyburide 2.5 mg*

metFORMIN Hydrochloride and Glyburide Tablets

500 mg with Glyburide 5 mg*

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 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 Sitagliptin Phosphate 50 mg (of sitagliptin)

Janumet

Merck

AHFS DI Essentials™. © Copyright 2024, Selected Revisions June 21, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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

References

1. Ascend Laboratories. Metformin hydrochloride tablets, film coated and metformin hydrochloride extended-release tablets prescribing information. Parsipanny, NJ; 2018 Oct.

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.

8. 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

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. Classification and diagnosis of diabetes: Standards of medical care in diabetes—2020. Diabetes Care. 2020; 43 Suppl 1:S14-31.

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

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.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1632725&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/589351?dopt=AbstractPlus

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.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2548496&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/7833731?dopt=AbstractPlus

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.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=443184&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/1401073?dopt=AbstractPlus

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.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1874707&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/6847752?dopt=AbstractPlus

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.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1796258&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/5556053?dopt=AbstractPlus

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.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1341115&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/3091170?dopt=AbstractPlus

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. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1386190&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/3593625?dopt=AbstractPlus

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.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1587044&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/4742454?dopt=AbstractPlus

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.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1336391&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/1521215?dopt=AbstractPlus

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.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1401849&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/7306436?dopt=AbstractPlus

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.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1547150&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/6403102?dopt=AbstractPlus

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. Drug Intell Clin Pharm. 1982; 16:881-2. Letter. http://www.ncbi.nlm.nih.gov/pubmed/6756852?dopt=AbstractPlus

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. Reply. 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 pharmacodynamics 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) tablets 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. http://www.ncbi.nlm.nih.gov/pubmed/6641100?dopt=AbstractPlus

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.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1679237&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/8251784?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/8554200?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/8554204?dopt=AbstractPlus

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.

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

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.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1113869&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/9732334?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.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=28660&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/9732338?dopt=AbstractPlus

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.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=28659&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/9732337?dopt=AbstractPlus

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

234. Aurobindo Pharma USA. Glyburide and metformin hydrochloride tablet, film coated prescribing information. East Windsor, NJ; 2019 Feb.

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

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.

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

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/pdf/rosiglitazonehta.pdf

254. Heritage Pharmaceuticals. Glipizide and metformin hydrochloride tablets prescribing information. East Brunswick, NJ; 2017 Oct.

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.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2622728&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/12020338?dopt=AbstractPlus

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

257. Ranbaxy Laboratories Inc. Riomet (metformin hydrochloride) oral solution prescribing information. Jacksonville, FL; 2017 Apr.

258. Shionogi Pharma Inc. Fortamet (metformin hydrochloride) extended-release tablets prescribing information. Atlanta, GA; 2010 Feb..

260. Takeda Pharmaceuticals America. Actoplus Met (pioglitazone hydrochloride and metformin hydrochloride) tablets for oral use prescribing information. Deerfield, IL; 2017 Dec.

261. Depomed. Glumetza (metformin hydrochloride) extended release tablets prescribing information. Menlo Park, CA; 2008 Dec.

262. Depomed. Technology: diffusional. Accessed 2006 Aug 7. http://www.depomedinc.com/technology_diffusional.htm

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 practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes. 2003; 27(Suppl 2):S1-152.

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.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=27454&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/10938048?dopt=AbstractPlus

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.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2606812&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/19092168?dopt=AbstractPlus

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.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4551392&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/18539917?dopt=AbstractPlus

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.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2637991&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/16371630?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/19405411?dopt=AbstractPlus

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.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2495076&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/18550055?dopt=AbstractPlus

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

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.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2571051&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/18782901?dopt=AbstractPlus

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.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3400073&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/22798258?dopt=AbstractPlus

335. American College of Radiology (ACR) Committee on Drugs and Contrast Media. ACR manual on contrast media: metformin. Available at ACR website. Accessed 2021 Mar 1. https://www.acr.org/-/media/ACR/Files/Clinical-Resources/2021_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

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.

380. Deutsch JC, Santhosh-Kumar CR, Kolhouse JF. Efficacy of metformin in non-insulin-dependent diabetes mellitus. Letter. N Engl J Med. 1996; 334:269.

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

615. World Health Organization. Classification of diabetes mellitus 2019. Geneva: World Health Organization; 2019.

616. Handelsman Y, Bloomgarden ZT, Grunberger G et al. American Association of Clinical Endocrinologists and American College of Endocrinology—Clinical practice guidelines for developing a diabetes mellitus comprehensive care plan—2015. Endocr Pract. 2015; 21(Suppl 1):1-87.

617. Tamborlane WV, Barrientos-Pérez M, Fainberg U et al. Liraglutide in children and adolescents with type 2 diabetes. N Engl J Med. 2019; http://www.ncbi.nlm.nih.gov/pubmed/31034184?dopt=AbstractPlus

618. Wiviott SD, Raz I, Bonaca MP et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019; 380:347-357. http://www.ncbi.nlm.nih.gov/pubmed/30415602?dopt=AbstractPlus

619. Neal B, Perkovic V, Mahaffey KW et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017; 377:644-657. http://www.ncbi.nlm.nih.gov/pubmed/28605608?dopt=AbstractPlus

620. Mahaffey KW, Neal B, Perkovic V et al. Canagliflozin for primary and secondary prevention of cardiovascular events: results from the CANVAS program (canagliflozin cardiovascular assessment study). Circulation. 2018; 137:323-334. http://www.ncbi.nlm.nih.gov/pubmed/29133604?dopt=AbstractPlus

621. Trujillo JM, Nuffer WA. Impact of sodium-glucose cotransporter 2 inhibitors on nonglycemic outcomes in patients with type 2 diabetes. Pharmacotherapy. 2017; 37:481-491. http://www.ncbi.nlm.nih.gov/pubmed/28102030?dopt=AbstractPlus

622. Inzucchi SE, Zinman B, Wanner C et al. SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res. 2015; 12:90-100. http://www.ncbi.nlm.nih.gov/pubmed/25589482?dopt=AbstractPlus

623. Zinman B, Wanner C, Lachin JM et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015; 373:2117-28. http://www.ncbi.nlm.nih.gov/pubmed/26378978?dopt=AbstractPlus

624. American Diabetes Association. 11. Microvascular complications and foot care: standards of medical care in diabetes-2019. Diabetes Care. 2019; 42:S124-S138. http://www.ncbi.nlm.nih.gov/pubmed/30559237?dopt=AbstractPlus

698. Garber AJ, Handelsman Y, Grunberger G et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm 2020 executive summary. Endocr Pract. 2020; 26:107-139. http://www.ncbi.nlm.nih.gov/pubmed/32022600?dopt=AbstractPlus

699. Zelniker TA, Wiviott SD, Raz I et al. Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus. Circulation. 2019; 139(17):2022-2031. http://www.ncbi.nlm.nih.gov/pubmed/30786725?dopt=AbstractPlus

702. American Diabetes Association. 6. Glycemic targets: Standards of Medical Care in Diabetes-2020. Diabetes Care. 2020; 43:S66-S76. http://www.ncbi.nlm.nih.gov/pubmed/31862749?dopt=AbstractPlus

704. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes-2020. Diabetes Care. 2020; 43:S98-S110. http://www.ncbi.nlm.nih.gov/pubmed/31862752?dopt=AbstractPlus

705. American Diabetes Association. 10. Cardiovascular disease and risk management: Standards of Medical Care in Diabetes-2020. Diabetes Care. 2020; 43:S111-S134. http://www.ncbi.nlm.nih.gov/pubmed/31862753?dopt=AbstractPlus

706. American Diabetes Association. 11. Microvascular complications and foot care: Standards of Medical Care in Diabetes-2020. Diabetes Care. 2020; 43:S135-S151. http://www.ncbi.nlm.nih.gov/pubmed/31862754?dopt=AbstractPlus

709. American Diabetes Association. 14. Management of diabetes in pregnancy: Standards of Medical Care in Diabetes-2020. Diabetes Care. 2020; 43:S183-S192. http://www.ncbi.nlm.nih.gov/pubmed/31862757?dopt=AbstractPlus

Frequently asked questions

View more FAQ

Medical Disclaimer