Class: Biguanides
ATC Class: A10BA02
VA Class: HS502
Chemical Name: 1,1-Dimethylbiguanide monohydrochloride
Molecular Formula: C4H11N5 • HCl
CAS Number: 1115-70-4
Brands: Fortamet, Glucophage, Glucophage XR, Glumetza, Riomet
Medically reviewed by Drugs.com. Last updated on Nov 18, 2019.
Warning
- Lactic Acidosis
-
Lactic acidosis rare but potentially fatal.6 18 20 27 29 30 62 89 96 158 Increased risk of lactic acidosis in patients with renal impairment and advanced age.1 2 62 96 119
-
Generally has occurred in diabetic patients with severe renal insufficiency who frequently had concomitant medical and/or surgical problems and were receiving multiple drugs; metformin plasma concentrations >5 mcg/mL often found in patients with lactic acidosis.1 2 3 20 50 62 64 76 96 123 158 164 165
-
Periodically monitor renal function and use the minimum effective dosage.1 32 62 63 65 76 85 91 93 96 123 124 158 164 165 247 258 313 314 Withhold metformin promptly in patients with any condition associated with hypoxemia, sepsis, or dehydration.1 2 62 63 93 313 Avoid use in patients with clinical or laboratory evidence of hepatic impairment.1 2 63 65 85 91 93 156 158 313 314 Manufacturers state to temporarily discontinue metformin therapy before or at the time of an iodinated contrast imaging procedure in patients with eGFR of 30–60 mL/minute per 1.73 m2 and in patients with a history of liver disease, alcoholism, or heart failure.1 330 336 Withhold metformin temporarily in patients undergoing surgery or receiving intra-arterial iodinated contrast agents. 1 2 30 62 63 93 158 234 247 254 261 313 314 330 336 Drugs that may affect renal function or alter metformin elimination should be used with caution.1
However, the American College of Radiology states that in patients with no evidence of acute kidney injury and eGFR ≥30 mL/minute per 1.73 m2, there is no need to discontinue metformin either before or following the administration of iodinated contrast media, nor is there a need to reassess the patient's renal function after the test or procedure.335
-
Advise patients not to consume excessive amounts of alcohol.1 2 63 76 91 93 158
-
If lactic acidosis occurs, discontinue metformin.1 30 313 314 Treat as medical emergency; immediate hospitalization and treatment required; hemodialysis recommended.1 23 32 62 117 119 313 314
Introduction
Antidiabetic agent; a biguanide, chemically and pharmacologically unrelated to sulfonylurea antidiabetic agents.1 2 3 4 18 20 22 23 27 28 29 30 33 72 146 243 245 246
Uses for metFORMIN
Type 2 Diabetes Mellitus
Used as an adjunct to diet and exercise for the management of type 2 diabetes mellitus.1 3 4 6 8 15 16 17 18 19 20 27 29 95 166 243 245 246
May be used in combination with a sulfonylurea, repaglinide, a thiazolidinedione antidiabetic agent, a dipeptidyl peptidase-4 [DPP-4] inhibitor, a glucagon-like peptide-1 (GLP-1) agonist, or a sodium-glucose cotransporter-2 [SGLT2] inhibitor for the management of type 2 diabetes mellitus in patients who do not achieve adequate glycemic control on monotherapy with metformin or any of these drugs.1 3 6 15 18 20 22 27 29 30 48 59 78 88 95 97 99 112 134 166 191 234 237 238 239 241 242 243 245 246 249 250 260 352 355 362 368 370 372 374 376 378 598 604 610 Also used concomitantly with nateglinide.248
May be used with insulin to improve glycemic control and/or decrease the required dosage of insulin.1 3 6 88 90 94 95 146
Commercially available in fixed combination with glyburide or glipizide for use as an adjunct to diet and exercise in adults with type 2 diabetes mellitus.234 254 May add a thiazolidinedione antidiabetic agent if patient has inadequate glycemic control with fixed-combination metformin/glyburide therapy.234
Commercially available in fixed combination with rosiglitazone for use when treatment with both rosiglitazone and metformin is appropriate.247
Commercially available in fixed combination with pioglitazone (as immediate- or extended-release tablets) for use as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who have inadequate glycemic control with pioglitazone or metformin monotherapy or in those who are already receiving pioglitazone and metformin concurrently as separate components.260
Commercially available in fixed combination with repaglinide for use as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who are already receiving repaglinide and metformin concurrently as separate components or in those who have inadequate glycemic control with repaglinide or metformin monotherapy.313
Commercially available in fixed combination with the DPP-4 inhibitors alogliptin, linagliptin, saxagliptin, or sitagliptin for use as an adjunct to diet and exercise when treatment with both drug components is appropriate.314 352 368 376 378 610
Commercially available in fixed combinations with the SGLT2 inhibitors canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin for use when treatment with both drugs components is appropriate.355 362 372 370
Metformin generally is the preferred initial oral antidiabetic agent for patients with type 2 diabetes mellitus.264 Potential advantages of metformin compared with sulfonylureas or insulin include minimal risk of hypoglycemia, more favorable effects on serum lipids, reduction of hyperinsulinemia, and weight loss or lack of weight gain.1 2 3 6 16 17 18 19 20 27 30 42 60 68 102 134 146 166 264
Not effective as sole therapy in patients with diabetes mellitus complicated by acidosis, ketosis, or coma.1 6 30 146 191 192
Polycystic Ovary Syndrome
Has been used in the management of metabolic and reproductive abnormalities associated with polycystic ovary syndrome†.289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312
metFORMIN Dosage and Administration
General
-
When therapy is transferred from most sulfonylurea antidiabetic agents to metformin, sulfonylurea agent may be abruptly discontinued (no transition period generally required).1 2
-
Patients whose therapy is transferred from chlorpropamide to metformin should be monitored closely for hypoglycemia during the initial 2 weeks following transfer.1 2 30
-
Goal of therapy should be to reduce both fasting glucose and HbA1c values to normal or near normal using the lowest effective dosage of metformin hydrochloride, either when used as monotherapy or combined with another antidiabetic agent.1 8 13 14 78 85 88 105 134 146 166 234 235 243 245 246
Administration
Oral Administration
Administer orally with meals to reduce adverse GI effects.1 2 3 18 53 85 243 245 246
Administer immediate-release tablets 2 or 3 times daily.1 243 245 246 Administer in 2 divided doses if total dosage ≤2 g daily or in 3 divided doses if total dosage is >2 g daily.1
Administer extended-release tablets once daily with the evening meal; swallow whole and do not chew, cut, or crush.1 258 259 260 261 In addition, administer Fortamet extended-release tablets with a full glass of water.258
Administer immediate-release metformin hydrochloride in fixed combination with canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, pioglitazone, rosiglitazone, repaglinide, alogliptin, linagliptin, or sitagliptin in divided doses daily with meals to reduce the GI effects of the metformin hydrochloride component.247 260 313 314 355 362 370 372 376 610
Administer metformin/repaglinide fixed-combination tablets within 15 minutes before meals.313 If a meal is skipped, omit dose for that meal.313
Administer extended-release metformin hydrochloride in fixed combination with canagliflozin, dapagliflozin, or empagliflozin once daily with the morning meal.362 370 374
Administer the fixed combination of extended-release metformin hydrochloride and linagliptin once daily with a meal.378 Administer the fixed combination of extended-release metformin hydrochloride and sitagliptin once daily with a meal, preferably the evening meal.352 Administer extended-release metformin hydrochloride in fixed combination with saxagliptin once daily with the evening meal.368
Dosage
Available as metformin hydrochloride; dosage expressed in terms of the salt.1
Individualize dosage carefully based on patient’s glycemic response and tolerance.1 4 243 245 246
Pediatric Patients
Type 2 Diabetes Mellitus
Oral
Immediate-release tablets or oral solution in children 10–16 years of age: Initially, 500 mg twice daily with meals.1 257 Increase daily dosage in increments of 500 mg at weekly intervals to a maximum of 2 g daily given in divided doses.1 257
Adults
Type 2 Diabetes Mellitus
Metformin Hydrochloride Monotherapy
OralImmediate-release tablets or oral solution: Initially, 500 mg twice daily or 850 mg once daily with meals.1 257 Increase daily dosage by 500 mg at weekly intervals or by 850 mg at biweekly (every 2 week) intervals up to a maximum of 2 g daily given in divided doses.1 257 May increase dosage from 500 mg twice daily to 850 mg twice daily after 2 weeks.1 257 Clinically important responses generally not observed at dosages <1.5 g daily.1 257
Initial dosage of 500 mg once daily suggested by some experts.264
For additional glycemic control, increase dosage (as immediate-release tablets or oral solution) up to a maximum daily dosage of 2.55 g given in divided doses.1 257
Extended-release tablets (Glucophage XR) in patients ≥17 years of age: Initially, 500 mg once daily with the evening meal.1 259 Increase daily dosage by 500 mg at weekly intervals to a maximum of 2 g daily.1 259 If glycemic control is not achieved with 2 g once daily, consider administering 1 g twice daily.1 259 If >2 g daily is required, switch to immediate-release tablet formulation and increase dosage up to 2.55 g daily in divided doses (preferably 3 doses per day for daily dosages >2 g).1 259
Extended-release tablets (Fortamet) in patients ≥17 years of age: Initially, 1 g once daily with the evening meal; 500 mg once daily may be used when clinically appropriate.258 Increase daily dosage by 500 mg at weekly intervals to a maximum of 2.5 g daily with the evening meal.258
Immediate-release Metformin Hydrochloride in Fixed Combination with Glipizide (e.g., Metaglip)
OralPatients with inadequate glycemic control on diet and exercise alone: Initially, 250 mg of metformin hydrochloride and 2.5 mg of glipizide once daily with a meal.254 For more severe hyperglycemia (fasting plasma glucose concentrations of 280–320 mg/dL), 500 mg of metformin hydrochloride and 2.5 mg of glipizide twice daily.254 Increase daily dosage in increments of one tablet (using the tablet strength at which therapy was initiated) at 2-week intervals until adequate glycemic control is achieved or maximum daily dosage of 2 g of metformin hydrochloride and 10 mg of glipizide is reached.254 256
Efficacy of metformin hydrochloride and glipizide in fixed combination not established in patients with fasting plasma glucose concentrations >320 mg/dL.254 No experience with total initial daily dosages exceeding 2 g of metformin hydrochloride and 10 mg of glipizide.254
Patients with inadequate glycemic control on either a sulfonylurea or metformin alone: Initially, 500 mg of metformin hydrochloride and 2.5 or 5 mg of glipizide twice daily with the morning and evening meals.254 Initial dosage of the fixed combination should not exceed the patient's current daily dosage of metformin hydrochloride or glipizide (or equivalent dosage of another sulfonylurea).254 Titrate daily dosage in increments not exceeding 500 mg of metformin hydrochloride and 5 mg of glipizide until adequate glycemic control achieved or maximum daily dosage of 2 g of metformin hydrochloride and 20 mg of glipizide is reached.254
Patients currently receiving combined therapy with separate metformin and glipizide (or another sulfonylurea) preparations: May switch to 500 mg of metformin hydrochloride and 2.5 or 5 mg of glipizide; initial dosage of the fixed-combination preparation should not exceed the patient's current daily dosage of metformin hydrochloride and glipizide (or equivalent dosage of another sulfonylurea).254 Use clinical judgment regarding whether to switch to the nearest equivalent dosage or to titrate dosage.254 Titrate daily dosage in increments not exceeding until adequate glycemic control is achieved or maximum daily dosage of 2 g of metformin hydrochloride and 20 mg of glipizide is reached.254
Immediate-release Metformin Hydrochloride in Fixed Combination with Glyburide (e.g., Glucovance)
OralPatients with inadequate glycemic control on diet and exercise alone: Initially, 250 mg of metformin hydrochloride and 1.25 mg of glyburide once daily with a meal.234 For more severe hyperglycemia (i.e., fasting plasma glucose concentrations >200 mg/dL or HbA1c >9%), may consider initial dosage of 250 mg of metformin hydrochloride and 1.25 mg of glyburide twice daily with the morning and evening meals.234 Titrate daily dosage in increments of 250 mg of metformin hydrochloride and 1.25 mg of glyburide at 2-week intervals until adequate glycemic control is achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 10 mg of glyburide is reached.234
Do not use the fixed combination of metformin hydrochloride 500 mg and glyburide 5 mg as initial therapy due to an increased risk of hypoglycemia.234
Patients with inadequate glycemic control on a sulfonylurea and/or metformin: Initially, 500 mg of metformin hydrochloride and 2.5 or 5 mg of glyburide twice daily.234 Initial dosage of the fixed combination should not exceed the patient's current daily dosage of glyburide (or equivalent dosage of another sulfonylurea antidiabetic agent) and metformin hydrochloride.234 Increase daily dosage in increments not exceeding 500 mg of metformin hydrochloride and 5 mg of glyburide until adequate glycemic control is achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 20 mg of glyburide is reached.234
Patients currently receiving combined therapy with separate metformin and glyburide (or another sulfonylurea agent) preparations: Initial dosage of the fixed combination should not exceed the previous dosage of metformin hydrochloride and glyburide (or the equivalent dosage of the other sulfonylurea).234 Titrate daily dosage in increments not exceeding 500 mg of metformin hydrochloride and 5 mg of glyburide until adequate glycemic control is achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 20 of mg glyburide is reached.234
For patients whose hyperglycemia is not adequately controlled on the fixed combination, may add a thiazolidinedione (e.g., pioglitazone, rosiglitazone) at its recommended initial dosage and continue same dosage of the fixed combination.234 In patients requiring further glycemic control, increase thiazolidinedione dosage as recommended.234
Immediate-release Metformin Hydrochloride in Fixed Combination with Rosiglitazone (Avandamet)
OralDosage of the fixed combination is based on the patient’s current dosages of metformin hydrochloride and/or rosiglitazone.247 (See Table 1.) In rosiglitazone-naive patients, initiate rosiglitazone component at the lowest recommended dosage.247
In patients currently receiving metformin monotherapy, the usual initial dosage of rosiglitazone is 4 mg daily given in divided doses with patient's existing dosage of metformin hydrochloride.247
In patients currently receiving rosiglitazone monotherapy, the usual initial dosage of metformin hydrochloride is 1 g daily given in divided doses with patient's existing dosage of rosiglitazone.247
Individualize therapy in patients already receiving metformin hydrochloride at doses not available in the fixed combination (i.e., doses other than 1 or 2 g).247
Prior Therapy |
Usual Initial Dosage of Avandamet |
|
---|---|---|
Total Daily Dosage |
Tablet Strength |
Number of Tablets |
Metformin Hydrochloride |
||
1 g |
2 mg/500 mg |
1 tablet twice daily |
2 g |
2 mg/1 g |
1 tablet twice daily |
Rosiglitazone |
||
4 mg |
2 mg/500 mg |
1 tablet twice daily |
8 mg |
4 mg/500 mg |
1 tablet twice daily |
For patients switching from combined therapy with separate metformin and rosiglitazone preparations, the usual initial dosage of the fixed combination is the same as the patient's existing dosage of the individual drugs.247
If additional glycemic control is needed following transfer, increase daily dosage in increments of 500 mg of metformin hydrochloride and/or 4 mg of rosiglitazone until adequate glycemic control is achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 8 mg of rosiglitazone is reached.247 Following increase in dosage of metformin hydrochloride, further dosage adjustment recommended if adequate glycemic control not achieved in 1–2 weeks. 247 Following increase in dosage of rosiglitazone, further dosage adjustment recommended if adequate glycemic control not achieved in 8–12 weeks.247
Immediate-release Metformin Hydrochloride in Fixed Combination with Pioglitazone (Actoplus Met)
OralIndividualize dosage based on the patient’s current dosage regimen, effectiveness, and tolerability.260
Usual initial dosage is 500 or 850 mg of metformin hydrochloride and 15 mg of pioglitazone given once or twice daily.260
Gradually titrate dosage as needed based on therapeutic response.260 Allow sufficient time (e.g., 8–12 weeks) to assess response.260
Safety and efficacy of transferring from therapy with other oral antidiabetic agents to Actoplus Met not established; undertake any such change with caution and appropriate monitoring.260
Extended-release Metformin Hydrochloride in Fixed Combination with Pioglitazone (Actoplus Met XR)
OralIndividualize dosage based on the patient’s current dosage regimen, effectiveness, and tolerability.260
Usual initial dosage is 1 g of metformin hydrochloride and 15 or 30 mg of pioglitazone given once daily.260
Gradually titrate dosage as needed based on therapeutic response.260 Allow sufficient time (e.g., 8–12 weeks) to assess response.260
Safety and efficacy of transferring from therapy with other oral antidiabetic agents to Actoplus Met XR not established; undertake any such change with caution and appropriate monitoring.260
Immediate-release Metformin Hydrochloride in Fixed Combination with Repaglinide (PrandiMet)
OralIndividualize dosage based on the patient’s current dosage regimen, effectiveness, and tolerability.313
Patients with inadequate glycemic control on metformin monotherapy: Initially, 500 mg of metformin hydrochloride and 1 mg of repaglinide twice daily with meals; gradually increase dosage as needed.313
Patients with inadequate glycemic control on repaglinide monotherapy: Initially, 500 mg of the metformin hydrochloride component (given in fixed combination with repaglinide) twice daily; gradually increase dosage as needed.313
Patients switching from combined therapy with separate metformin and repaglinide preparations: Initiate with dosages that are similar to (but do not exceed) patient's existing dosages of the individual drugs.313
Safety and efficacy of transferring to PrandiMet from therapy with other oral antidiabetic agents not established; undertake any such change with caution and appropriate monitoring.313
Immediate-release Metformin Hydrochloride in Fixed Combination with Alogliptin (Kazano)
OralIndividualize 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)
OralIndividualize 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)
OralIndividualize 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)
OralPatients 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)
OralPatients 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)
OralPatients 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)
OralIndividualize 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)
OralIndividualize dosage of based on patient's current antidiabetic regimen.370 May increase dosage gradually based on effectiveness and tolerability.370
Patients not currently receiving either canagliflozin or metformin hydrochloride: Initially, 1 g of metformin hydrochloride and 100 mg of canagliflozin once daily.370
Patients currently receiving metformin hydrochloride: Initially, a total daily metformin hydrochloride dosage similar to the patient's existing dosage and 100 mg of canagliflozin, administered once daily.370 In patients currently receiving an evening dose of extended-release metformin hydrochloride, skip last dose of extended-release metformin hydrochloride prior to initiating therapy with the fixed combination of metformin hydrochloride and canagliflozin the following morning.370
Patients currently receiving canagliflozin: Initially, 1 g of metformin hydrochloride and same daily dosage of canagliflozin administered once daily.370
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)
OralInitial 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)
OralIndividualize 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)
OralIndividualize 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)
OralInitial dosage based on patient's current regimen with metformin hydrochloride and/or ertugliflozin.355 May increase dosage gradually based on effectiveness and tolerability.355
Patients currently receiving metformin hydrochloride: Initially, total daily metformin hydrochloride dosage similar to patient's existing dosage and total daily dosage of 5 mg of ertugliflozin (administered as fixed combination with 2.5 mg of ertugliflozin), given in 2 divided doses daily.355
Patients currently receiving ertugliflozin: Initially, total daily dosage of 1 g of metformin hydrochloride (administered as fixed combination with 500 mg of metformin hydrochloride) and a total daily ertugliflozin dosage similar to the patient's existing dosage, given in 2 divided doses daily.355
Patients currently receiving metformin hydrochloride and ertugliflozin (administered as separate tablets): Initially, give fixed combination containing a total daily metformin hydrochloride dosage similar to patient's existing dosage and same total daily dose of ertugliflozin, in 2 divided doses daily.355
Metformin Hydrochloride Dosage in Patients Transferred from Insulin
OralInitially, 500 mg once daily; increase dosage by 500 mg daily at weekly intervals until adequate glycemic control is achieved or a maximum daily dosage of 2.5 g (immediate-release tablets) or 2 g (extended-release tablets) is reached.1 Concurrent insulin dosage initially remains unchanged.1 When fasting plasma glucose concentration decreases to <120 mg/dL, decrease insulin dosage by 10–25%.1
Polycystic Ovary Syndrome†
Oral
In general, 1.5–2.25 g daily in divided doses.291 292 294 296 299 300 301 302 303 305 306 307
Prescribing Limits
Pediatric Patients
Type 2 Diabetes Mellitus
Oral
Children 10–16 years of age: Maximum 2 g daily as immediate-release tablets or oral solution.1 257
Adults
Type 2 Diabetes Mellitus
Metformin Hydrochloride Monotherapy
OralMaximum 2.55 g daily as immediate-release tablets or oral solution, 2.5 g daily as Fortamet extended-release tablets, or 2 g daily as certain other extended-release tablets (e.g., Glucophage XR).1 2 3 4 14 18 22 85 257 258 259 Switch to immediate-release tablets for further dosage titration if required dosage exceeds 2 g daily.1 259
Metformin Hydrochloride in Fixed Combination with Glyburide (e.g., Glucovance)
OralMaximum daily dosage as second-line therapy is 2 g of metformin hydrochloride and 20 mg of glyburide.234
No experience with total daily dosages exceeding 2 g of metformin hydrochloride and 10 mg of glipizide in clinical trials in patients receiving the fixed combination as initial therapy.234
Metformin Hydrochloride in Fixed Combination with Glipizide (e.g., Metaglip)
OralMaximum 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)
OralMaximum daily dosage is 2 g of metformin hydrochloride and 5 mg of linagliptin.376 378
Metformin Hydrochloride in Fixed Combination with Saxagliptin (Kombiglyze XR)
OralMaximum daily dosage is 2 g of metformin hydrochloride and 5 mg of saxagliptin.368
Metformin Hydrochloride in Fixed Combination with Sitagliptin (Janumet, Janumet XR)
OralMaximum 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)
OralPatients 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)
OralMaximum daily dosage is 2 g of metformin hydrochloride and 10 mg of dapagliflozin.362
Metformin Hydrochloride in Fixed Combination with Empagliflozin (Synjardy, Synjardy XR)
OralMaximum daily dosage is 2 g of metformin hydrochloride and 25 mg of empagliflozin.372 374
Metformin Hydrochloride in Fixed Combination with Ertugliflozin (Segluromet)
OralMaximum daily dosage is 2 g of metformin hydrochloride and 15 mg of ertugliflozin.355
Special Populations
Renal Impairment
eGFR 30–45 mL/minute per 1.73 m2: Do not initiate metformin; assess benefits and risks of continued treatment in patients already receiving metformin.330 336 350
eGFR <30 mL/minute per 1.73 m2: Use contraindicated; discontinue in patients already receiving metformin.330 336 350
National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) states that the exact GFR cutoff for metformin use is controversial.341 NKF-KDOQI suggests reviewing use of metformin in GFR <45 mL/minute per 1.73 m2.341 NKF-KDOQI and other clinicians suggest avoiding metformin therapy if GFR <30 mL/minute but suggest considering risk-benefit of such therapy if GFR stable.340 341
Hepatic Impairment
Avoid use in those with hepatic disease.1
Geriatric Patients
In general, do not titrate to the maximum dosage recommended for younger adults;1 2 3 4 165 243 245 246 314 limited data suggest reducing initial dosage by approximately 33% in geriatric patients.30 174
Monitor renal function regularly to determine appropriate dosage.1 2 3 4 164 165 243 245 246 314
Cautions for metFORMIN
Contraindications
-
Acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma.1 2 234 247
-
Severe renal impairment (eGFR <30 mL/minute per 1.73 m2),1 234 247 330 which may result from conditions such as cardiovascular collapse (shock), acute MI, or septicemia.1 234
-
Known hypersensitivity to metformin hydrochloride or any ingredient in the formulations.1 2 234 247 254
Warnings/Precautions
Warnings
Lactic Acidosis
See Boxed Warning.
General Precautions
Hypoglycemia
Uncommon in patients receiving metformin as monotherapy.1 15 30 78 94 99 Debilitated, malnourished, or geriatric patients and patients with renal or hepatic impairment or adrenal or pituitary insufficiency may be particularly susceptible.1 2 Strenuous exercise, alcohol ingestion, insufficient caloric intake, or use in combination with other antidiabetic agents may increase risk.1 2 Hypoglycemia may be difficult to recognize in geriatric patients or in those receiving β-adrenergic blocking agents.1 83 91 128 143 153 159 (See Specific Drugs under Interactions.)
Hematologic Effects
Decreased serum vitamin B12 concentrations, 1 18 with or without clinical manifestations (e.g., anemia).1
Symptoms rapidly reversible following discontinuation of metformin or supplementation with vitamin B12.1 3 6 20 30 70 77 82 134 Monitor hematologic parameters (e.g., hemoglobin, serum vitamin B12 concentrations)1 82 114 122 134 148 prior to initiation of therapy and at least annually during treatment and any abnormality properly investigated.1 350
Consider periodic supplementation with parenteral vitamin B12 in patients at high risk for developing subnormal serum vitamin B12 concentrations (e.g., alcoholics, patients with low calcium or vitamin B12 intake or absorption).1 82 114 122 134 148 598
Cardiovascular Effects
Possible increased cardiovascular mortality associated with other biguanide antidiabetic agents (i.e., phenformin).1 191 192 200 The American Diabetes Association (ADA) and other clinicians do not recommend changing current guidelines regarding the use of metformin as monotherapy or in combination with sulfonylureas pending the results of further studies of metformin alone or in combination with sulfonylureas.220 221 224
Use of metformin in combination with rosiglitazone and insulin is not recommended; adverse cardiovascular events (e.g., edema, CHF) have occurred with combined rosiglitazone and insulin therapy.247
Concurrent Illness
Evaluate serum electrolytes and ketones, blood glucose, and if indicated, blood pH, lactate, pyruvate, and metformin concentrations for evidence of ketoacidosis or lactic acidosis.1 88 134 156 169
Temporary withdrawal of metformin therapy and administration of insulin may be required to maintain glycemic control during periods of stress.1
Use of Fixed Combinations
When used in fixed combination with other drugs, consider the cautions, precautions, contraindications, and interactions associated with the concomitant agent(s).234 237 247 254 260 313 314 352 355 362 368 370 372 374 376 378 610
Specific Populations
Pregnancy
Category B.1
Most clinicians recommend use of insulin during pregnancy in diabetic patients to maintain optimum control of blood glucose concentrations.1 3 4 18 72 88 92
Lactation
Distributed into milk in rats; small amounts distributed into human milk.1 284 285 286 Discontinue nursing or the drug.1 3 4
Pediatric Use
Safety and efficacy of metformin as immediate-release tablets or oral solution in children <10 years of age have not been established.1 257
Safety and efficacy of metformin as extended-release tablets in children <17 years of age have not been established.1 258 259
Safety and efficacy of metformin in fixed combination with glipizide, pioglitazone, repaglinide, rosiglitazone, or sitagliptin in children have not been established.1 3 4 30 134 247 254 260 313 314 Data from a clinical trial in children 9–16 years of age comparing combined therapy with metformin and glyburide (Glucovance) with each drug as monotherapy did not reveal unexpected safety findings.234
Geriatric Use
Insufficient number of geriatric patients in controlled clinical trials of metformin hydrochloride immediate-release (Glucophage) and extended-release tablets (Glucophage XR, Glumetza) to determine if such patients respond differently than younger adults.1 261 314 With another extended-release preparation of metformin hydrochloride (Fortamet), no overall differences in safety or efficacy in geriatric patients were observed compared with younger adults.258
Use with caution, since renal function declines with age.1 3 4 30 85 174 234 247 254 314
Monitor renal function periodically.1 2 3 4 164 165 314
Do not initiate in patients ≥80 years of age without confirmation of adequate renal function as measured by Clcr.1 209 214 313 314
Geriatric patients particularly susceptible to hypoglycemia,1 2 which may be difficult to recognize.1 83 91 128 143 153 159
Renal Impairment
Do not use in patients with severe renal disease or dysfunction.1 330 (See Contraindications.)
Evaluate renal function prior to initiation of therapy and at least annually thereafter.1 2 77 85 234
Monitor more frequently if development of impaired renal function is anticipated (e.g., those with blood glucose concentrations >300 mg/dL, those who may develop renal dysfunction as a result of polyuria and volume depletion).156
Discontinue metformin if patient's eGFR <30 mL/minute per 1.73 m2; contraindicated in such patients.330
Hepatic Impairment
Generally avoid use in patients with clinical or laboratory evidence of hepatic disease.1 165 Elimination of lactate may be substantially reduced.1 (See Boxed Warning.)
Common Adverse Effects
Diarrhea,1 31 48 49 53 78 109 118 122 135 nausea,1 31 53 78 109 118 122 vomiting,1 118 122 abdominal bloating, abdominal cramping or pain,1 31 35 42 53 118 122 flatulence,1 anorexia.1 3 6 18
Interactions for metFORMIN
Cationic Agents Secreted by Proximal Renal Tubules
Pharmacokinetic interaction with cimetidine (decreased excretion of metformin).1 75
Potential pharmacokinetic interaction with other cationic drugs that undergo substantial tubular secretion (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, vancomycin).1 30
Monitor carefully; consider dosage adjustment of either agent.1
Protein-bound Drugs
Pharmacokinetic interaction unlikely.1
Drugs That May Antagonize Hypoglycemic Effects
Calcium-channel blocking agents, corticosteroids, thiazide diuretics, estrogens and progestins (e.g., oral contraceptives), isoniazid, niacin, phenothiazines, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline); observe patient closely for evidence of altered glycemic control when such drugs are added to or withdrawn from therapy.1 30 80 85 91 120 121 134 139 143 151 152 153 154 159 160
Specific Drugs or Foods
Drug |
Interaction |
Comments |
---|---|---|
Acarbose |
Acute decrease in metformin bioavailability in single-dose study138 201 |
|
ACE inhibitors |
Potential risk of hypoglycemia/hyperglycemia when ACE inhibitor therapy is initiated/withdrawn131 132 134 152 155 160 |
Monitor blood glucose concentrations during dosage adjustments with either agent130 131 132 134 152 155 160 |
Alcohol |
Increased risk of hypoglycemia and lactic acidosis1 2 18 33 63 72 76 91 93 107 143 |
Avoid excessive alcohol intake1 |
Antidiabetic agents (e.g., sulfonylureas, meglitinides, insulin) |
May need to reduce dosage of concomitant antidiabetic agent1 |
|
β-Adrenergic blocking agents |
May impair glucose tolerance; 73 143 152 153 159 may increase frequency or severity of hypoglycemia and hypoglycemia-induced complications91 127 153 159 |
If concomitant therapy necessary, a β1-selective adrenergic blocking agent or β-adrenergic blocking agents with intrinsic sympathomimetic activity preferred36 143 152 160 173 |
Cimetidine |
Possible decreased excretion of metformin1 Increased peak concentrations and AUC of metformin; negligible effects on cimetidine pharmacokinetics1 |
Carefully monitor patient; consider need for dosage adjustment1 |
Clomiphene |
Possible resumption of ovulation in premenopausal patients with polycystic ovary syndrome210 |
|
Furosemide |
Increased peak concentrations of metformin and decreased peak concentrations and terminal half-life of furosemide in single-dose study1 |
|
Glyburide |
Pharmacokinetics and pharmacodynamics of metformin not altered in single-dose study1 260 261 314 Variable decreases in AUC and peak blood concentration of glyburide1 260 314 |
Clinical importance uncertain1 |
Guar gum |
||
Nifedipine |
Enhanced absorption and increased urinary excretion of metformin; minimal effects on nifedipine pharmacokinetics1 |
|
Thiazide diuretics |
May exacerbate diabetes mellitus1 91 139 143 151 152 153 154 159 160 |
Consider using less diabetogenic diuretic (e.g., potassium-sparing diuretic), reducing dosage of or discontinuing diuretic, or increasing dosage of oral antidiabetic agent73 134 152 153 154 159 160 |
metFORMIN Pharmacokinetics
Absorption
Bioavailability
Approximately 50–60% (absolute) with dosages of 0.5–1.5 g.1 2 3 4 18 33 43 50 65 72 85 89
Fixed-combination preparation containing 500 mg of metformin hydrochloride and 4 mg of rosiglitazone is bioequivalent to mg-equivalent dosages of individual components administered separately under fasted conditions.247
Onset
Therapeutic response usually apparent within a few days to 1 week.18 53 72 98 134 Maximal glycemic response within 2 weeks.18 53 72 98 134
Duration
Blood glucose concentrations increase within 2 weeks following discontinuance of metformin therapy.53 134
Food
Food decreases and slightly delays absorption of immediate-release tablets.1 2 3 4 18 208 314
Food increases the extent of absorption of extended-release tablets (Glucophage XR, Fortamet).1 258 Peak plasma concentrations and time to achieve peak plasma concentrations not altered by administration of one extended-release preparation (Glucophage XR) with food; 1 food increases peak plasma concentrations and prolongs time to peak plasma concentrations of another extended-release tablet preparation (Fortamet).258
Peak concentrations and AUC of the extended-release metformin hydrochloride component increased by approximately 98 and 85%, respectively, when Actoplus Met XR was given with food.260 Time to peak concentration prolonged by approximately 3 hours for pioglitazone and 2 hours for extended-release metformin hydrochloride under fed conditions.260
Food increases the extent of absorption and delays the time to peak plasma concentrations of the oral solution.257 Fat content of meals does not appreciably affect the pharmacokinetics of metformin hydrochloride oral solution.257
Distribution
Extent
Rapidly distributed into peripheral body tissues and fluids, particularly GI tract.30 50 65 72 89 134 162 167
Slowly distributed into erythrocytes and a deep tissue compartment (probably GI tissue).30 50 65 72 89 134 162 167
Plasma Protein Binding
Negligible.1 18 50 51 65 85 89
Elimination
Metabolism
Not metabolized in the liver or GI tract and not excreted into bile.1 50 51 89 No metabolites identified in humans.1 50 51 89 314
Elimination Route
Excreted in urine (approximately 35–52%)50 51 89 and feces (20–33%).6 33 43 50 72 89 Eliminated as unchanged drug.1 2 6 33 50 63 65 75 85 89 314
Half-life
Approximately 6.2 hours.1 2 6 18 33 38 50 51 65 85 89 125 134 314
Special Populations
Renal impairment may reduce clearance, including in geriatric patients with age-related decline in renal function.1 33 51 174 Renal impairment results in increased peak plasma concentrations, prolonged time to peak plasma concentration and half-life, and decreased volume of distribution.1 3 51 174
Stability
Storage
Oral
Tablets
Immediate-release tablets: Tight, light-resistant containers at 20–25°C (may be exposed to 15–30°C).1
Extended-release tablets: Tight, light resistant containers at 20–25° C (may be exposed to 15–30°C).1 258
Metformin/glyburide fixed combination: Light-resistant containers at 25°C.234
Metformin/glipizide fixed combination: 20–25° C (may be exposed to 15–30°C).254
Metformin/rosiglitazone fixed combination: Tight, light-resistant containers at 25°C (may be exposed to 15–30°C).247
Metformin/pioglitazone fixed combination: Tight (Actoplus Met) or tight, light-resistant (Actoplus Met XR) containers at 25°C (may be exposed to 15–30°C).260
Metformin/repaglinide fixed combination: Tight containers at temperatures not exceeding 25°C.313
Metformin/linagliptin fixed combination: 25°C (may be exposed to 15–30°C); protect from exposure to high humidity.376 378
Metformin/saxagliptin fixed combination: 20–25°C (may be exposed to 15–30°C).368
Metformin/sitagliptin fixed combination: 20–25°C (may be exposed to 15–30°C).314
Metformin/canagliflozin fixed combination: 20–25°C (may be exposed to 15–30°C).370 Store and dispense in original container.370 May store in pillbox for ≤30 days.370
Metformin/dapagliflozin: 20–25°C (may be exposed to 15–30°C).362
Metformin/empagliflozin: 25°C (may be exposed to 15–30°C).372 374
Metformin/ertugliflozin: 20–25°C (may be exposed to 15–30°C); protect from moisture and store in a dry place.355
Solution
15–30°C.257
Actions
-
Lowers blood glucose concentrations in patients with type 2 (non-insulin-dependent) diabetes mellitus (NIDDM) without increasing insulin secretion from pancreatic β cells.1 2 3 4 18 20 27 31 40 60 134 Ineffective in the absence of some endogenous or exogenous insulin.18 27 40 71 122
-
Usually does not lower glucose concentrations below euglycemia, but hypoglycemia occasionally may occur with overdosage.1 2 18 20 27 28 29 72 102 103 111
-
Lowers both basal (fasting) and postprandial glucose concentrations in patients with type 2 diabetes mellitus.1 2 18 22 Improves insulin sensitivity by decreasing hepatic glucose production and enhancing insulin-stimulated uptake and utilization of glucose by peripheral tissues (e.g., skeletal muscle, adipocytes).18 31 40 41 42 44 60 81 146 149 Insulin secretion usually remains unchanged.1 2 3 18 20 42 60 68 102 166
Advice to Patients
-
Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs, dietary or herbal supplements, and alcohol consumption, as well as any concomitant illnesses (e.g., renal disease).1 Importance of avoiding excessive alcohol consumption.1
-
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1
-
Importance of adherence to diet and exercise regimens.1
-
Possibility of primary and secondary failure with metformin therapy.1
-
Risks of hypoglycemia, symptoms and treatment of hypoglycemic reactions, and conditions that predispose to the development of such reactions.1
-
Importance of regular laboratory evaluations, including fasting blood (or plasma) glucose determinations.1 2 85
-
Risks of lactic acidosis and conditions that predispose to its development.1
-
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Oral |
Solution |
500 mg/5 mL* |
metFORMIN Hydrochloride Solution |
|
Riomet |
Ranbaxy |
|||
Tablets, extended-release |
500 mg* |
Fortamet |
Shionogi Pharma |
|
Glucophage XR |
Bristol-Myers Squibb |
|||
Glumetza |
Depomed |
|||
metFORMIN Hydrochloride Extended-Release Tablets |
||||
750 mg* |
Glucophage XR |
Bristol-Myers Squibb |
||
metFORMIN Hydrochloride Extended-Release Tablets |
||||
1 g* |
Fortamet |
Shionogi Pharma |
||
Glumetza |
Depomed |
|||
Tablets, film-coated |
500 mg* |
Glucophage |
Bristol-Myers Squibb |
|
metFORMIN Hydrochloride Tablets |
||||
625 mg* |
metFORMIN Hydrochloride Tablets |
|||
750 mg* |
metFORMIN Hydrochloride Tablets |
|||
850 mg* |
Glucophage |
Bristol-Myers Squibb |
||
metFORMIN Hydrochloride Tablets |
||||
1 g* |
Glucophage |
Bristol-Myers Squibb |
||
metFORMIN Hydrochloride Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Oral |
Tablets, extended-release |
500 mg with Immediate-release Canagliflozin (anhydrous) 50 mg |
Invokamet XR |
Janssen |
500 mg with Immediate-release Canagliflozin (anhydrous) 150 mg |
Invokamet XR |
Janssen |
||
500 mg with Immediate-release Dapagliflozin Propanediol 5 mg (of dapagliflozin) |
Xigduo XR |
AstraZeneca |
||
500 mg with Immediate-release Dapagliflozin Propanediol 10 mg (of dapagliflozin) |
Xigduo XR |
AstraZeneca |
||
500 mg with Immediate-release Saxagliptin 5 mg |
Kombiglyze XR |
AstraZeneca |
||
500 mg with Immediate-release Sitagliptin 50 mg |
Janumet XR |
Merck |
||
1 g with Immediate-release Canagliflozin 50 mg (anhydrous) |
Invokamet XR |
Janssen |
||
1 g with Immediate-release Canagliflozin (anhydrous) 150 mg |
Invokamet XR |
Janssen |
||
1 g with Immediate-release Dapagliflozin Propanediol 2.5 mg (of dapagliflozin) |
Xigduo XR |
AstraZeneca |
||
1 g with Immediate-release Dapagliflozin Propanediol 5 mg (of dapagliflozin) |
Xigduo XR |
AstraZeneca |
||
1 g with Immediate-release Dapagliflozin Propanediol 10 mg (of dapagliflozin) |
Xigduo XR |
AstraZeneca |
||
1 g with Immediate-release Empagliflozin 5 mg |
Synjardy XR |
Boehniger Ingelheim |
||
1 g with Immediate-release Empagliflozin 10 mg |
Synjardy XR |
Boehniger Ingelheim |
||
1 g with Immediate-release Empagliflozin 12.5 mg |
Synjardy XR |
Boehniger Ingelheim |
||
1 g with Immediate-release Empagliflozin 25 mg |
Synjardy XR |
Boehniger Ingelheim |
||
1 g with Immediate-release Linagliptin 2.5 mg |
Jentadueto XR |
Boehringer Ingelheim |
||
1 g with Immediate-release Linagliptin 5 mg |
Jentadueto XR |
Boehringer Ingelheim |
||
1 g with Immediate-release Pioglitazone Hydrochloride 15 mg (of pioglitazone) |
Actoplus Met XR |
Takeda |
||
1 g with Immediate-release Pioglitazone Hydrochloride 30 mg (of pioglitazone) |
Actoplus Met XR |
Takeda |
||
1 g with Immediate-release Saxagliptin 2.5 mg |
Kombiglyze XR |
AstraZeneca |
||
1 g with Immediate-release Saxagliptin 5 mg |
Kombiglyze XR |
AstraZeneca |
||
1 g with Immediate-release Sitagliptin 50 mg |
Janumet XR |
Merck |
||
1 g with Immediate-release Sitagliptin 100 mg |
Janumet XR |
Merck |
||
Tablets, film-coated |
250 mg with Glipizide 2.5 mg* |
Metaglip |
Bristol-Myers Squibb |
|
metFORMIN Hydrochloride and Glipizide Tablets |
||||
250 mg with Glyburide 1.25 mg* |
Glucovance |
Bristol-Myers Squibb |
||
metFORMIN Hydrochloride and Glyburide Tablets |
||||
500 mg with Alogliptin Benzoate 12.5 mg (of alogliptin) |
Kazano |
Takeda |
||
500 mg with Canagliflozin (anhydrous) 50 mg |
Invokamet |
Janssen |
||
500 mg with Canagliflozin (anhydrous) 150 mg |
Invokamet |
Janssen |
||
500 mg with Empagliflozin 5 mg |
Synjardy |
Boehringer Ingelheim |
||
500 mg with Empagliflozin 12.5 mg |
Synjardy |
Boehringer Ingelheim |
||
500 mg with Ertugliflozin L-pyroglutamic Acid 2.5 mg (of ertugliflozin) |
Segluromet |
Merck |
||
500 mg with Ertugliflozin L-pyroglutamic Acid 7.5 mg (of ertugliflozin) |
Segluromet |
Merck |
||
500 mg with Glipizide 2.5 mg* |
Metaglip |
Bristol-Myers Squibb |
||
metFORMIN Hydrochloride and Glipizide Tablets |
||||
500 mg with Glipizide 5 mg* |
Metaglip |
Bristol-Myers Squibb |
||
metFORMIN Hydrochloride and Glipizide Tablets |
||||
500 mg with Glyburide 2.5 mg* |
Glucovance |
Bristol-Myers Squibb |
||
metFORMIN Hydrochloride and Glyburide Tablets |
||||
500 mg with Glyburide 5 mg* |
Glucovance |
Bristol-Myers Squibb |
||
MetFORMIN Hydrochloride and Glyburide Tablets |
||||
500 mg with Linagliptin 2.5 mg |
Jentadueto |
Boehringer Ingelheim |
||
500 mg with Pioglitazone Hydrochloride 15 mg (of pioglitazone) |
Actoplus Met |
Takeda |
||
500 mg with Repaglinide 1 mg |
Prandimet |
Novo Nordisk |
||
500 mg with Repaglinide 2 mg |
Prandimet |
Novo Nordisk |
||
500 mg with Rosiglitazone Maleate 2 mg (of rosiglitazone) |
Avandamet |
GlaxoSmithKline |
||
500 mg with Rosiglitazone Maleate 4 mg (of rosiglitazone) |
Avandamet |
GlaxoSmithKline |
||
500 mg with Sitagliptin Phosphate 50 mg (of sitagliptin) |
Janumet |
Merck |
||
850 mg with Linagliptin 2.5 mg |
Jentadueto |
Boehringer Ingelheim |
||
850 mg with Pioglitazone Hydrochloride 15 mg (of pioglitazone) |
Actoplus Met |
Takeda |
||
1 g with Alogliptin Benzoate 12.5 mg (of alogliptin) |
Kazano |
Takeda |
||
1 g with Canagliflozin (anhydrous) 50 mg |
Invokamet |
Janssen |
||
1 g with Canagliflozin (anhydrous) 150 mg |
Invokamet |
Janssen |
||
1 g with Empagliflozin 5 mg |
Synjardy |
Boehringer Ingelheim |
||
1 g with Empagliflozin 12.5 mg |
Synjardy |
Boehringer Ingelheim |
||
1 g with Ertugliflozin L-pyroglutamic Acid 2.5 mg (of ertugliflozin) |
Segluromet |
Merck |
||
1 g with Ertugliflozin L-pyroglutamic Acid 7.5 mg (of ertugliflozin) |
Segluromet |
Merck |
||
1 g with Linagliptin 2.5 mg |
Jentadueto |
Boehringer Ingelheim |
||
1 g with Rosiglitazone Maleate 2 mg (of rosiglitazone) |
Avandamet |
GlaxoSmithKline |
||
1 g with Rosiglitazone Maleate 4 mg (of rosiglitazone) |
Avandamet |
GlaxoSmithKline |
||
1 g with Sitagliptin Phosphate 50 mg (of sitagliptin) |
Janumet |
Merck |
AHFS DI Essentials™. © Copyright 2021, Selected Revisions November 18, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
References
1. Bristol-Myers Squibb Company. Glucophage (metformin hydrochloride) tablets and Glucophage XR (metformin hydrochloride) extended-release tablets prescribing information. Princeton, NJ; 2009 Jan.
2. Bristol-Myers Squibb Company. Product information form for American Hospital Formulary Service: Glucophage (metformin hydrochloride). Princeton, NJ; 1995 Mar.
3. Bristol-Myers Squibb Company. Executive summary (product information) on Glucophage (metformin hydrochloride). Princeton, NJ; 1995 Mar.
4. Bristol-Myers Squibb Company. Glucophage (metformin hydrochloride) tablets product monograph. Princeton, NJ; 1995 Apr.
5. Marchetti P, Benzi L, Cecchetti P et al. Plasma biguanide levels are correlated with metabolic effects in diabetic patients. Clin Pharmacol Ther. 1987; 41:450-4. http://www.ncbi.nlm.nih.gov/pubmed/3829580?dopt=AbstractPlus
6. Bailey CJ. Biguanides and NIDDM. Diabetes Care. 1992; 15:755-72. http://www.ncbi.nlm.nih.gov/pubmed/1600835?dopt=AbstractPlus
7. National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes. 1979; 28:1039-57. http://www.ncbi.nlm.nih.gov/pubmed/510803?dopt=AbstractPlus
8. Henry R R. Glucose control and insulin resistance in non-insulin-dependent diabetes mellitus. Ann Intern Med. 1996; 124:97-103. http://www.ncbi.nlm.nih.gov/pubmed/8554221?dopt=AbstractPlus
9. DeFronzo RA. The triumvirate: β-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988; 37:667-87. http://www.ncbi.nlm.nih.gov/pubmed/3289989?dopt=AbstractPlus
10. Scientific Advisory Panel of the Executive Committee, American Diabetes Association. Policy statement: the UGDP controversy. Diabetes. 1979; 28:168-70.
11. Polonsky KS, Sturis J, Bell GI. Non-insulin-dependent diabetes mellitus—a genetically programmed failure of the beta cell to compensate for insulin resistance. N Engl J Med. 1996; 334:777-83. http://www.ncbi.nlm.nih.gov/pubmed/8592553?dopt=AbstractPlus
12. American Diabetes Association. Office guide to diagnosis and classification of diabetes mellitus and other categories of glucose intolerance. Diabetes Care. 1995; 18(Suppl 1):4.
13. Lebovitz HE. Stepwise and combination drug therapy for the treatment of NIDDM. Diabetes Care. 1994; 17:1542-4. http://www.ncbi.nlm.nih.gov/pubmed/7882832?dopt=AbstractPlus
14. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care. 2003; 26(Suppl 1):S33-50.
15. Hermann LS, Scherstén B, Bitzén PO et al. Therapeutic comparison of metformin and sulfonylurea, alone and in various combinations. Diabetes Care. 1994; 17:1100-9. http://www.ncbi.nlm.nih.gov/pubmed/7821128?dopt=AbstractPlus
16. Clarke BF, Campbell IW. Comparison of metformin and chlropropamide in non-obese, maturity-onset diabetics uncontrolled by diet. Br Med J. 1977; 2:1576-8. http://www.ncbi.nlm.nih.gov/pubmed/589351?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1632725&blobtype=pdf
17. Clarke BF, Duncan LJP. Comparison of chlorpropamide and metformin treatment on weight and blood-glucose response of uncontrolled obese diabetics. Lancet. 1968; 1:123-6. http://www.ncbi.nlm.nih.gov/pubmed/4169605?dopt=AbstractPlus
18. Dunn CJ, Peters DH. Metformin: a review of its pharmacological properties and therapeutic use in non-insulin-dependent diabetes mellitus. Drugs. 1995; 49:721-49. http://www.ncbi.nlm.nih.gov/pubmed/7601013?dopt=AbstractPlus
19. United Kingdom Prospective Diabetes Study Group. United Kingdom prospective diabetes study (UKPDS) 13: relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years. BMJ. 1995; 310:83-8. http://www.ncbi.nlm.nih.gov/pubmed/7833731?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2548496&blobtype=pdf
20. Bailey CJ, Nattrass M. Treatment—metformin. Baillieres Clin Endocrinol Metab. 1988; 2:455-76. http://www.ncbi.nlm.nih.gov/pubmed/3075902?dopt=AbstractPlus
21. Haupt E, Knick B, Koschinsky T et al. Oral antidiabetic combination therapy with sulphonylureas and metformin. Diabetes Metab. 1991; 17:224-31.
22. Reaven GM, Johnston P, Hollenbeck CB et al. Combined metformin-sulfonylurea treatment of patients with noninsulin-dependent diabetes in fair to poor glycemic control. J Clin Endocrinol Metab. 1992; 74:1020-6. http://www.ncbi.nlm.nih.gov/pubmed/1569149?dopt=AbstractPlus
23. Krentz AJ, Ferner RE, Bailey CJ. Comparative tolerability profiles of oral antidiabetic agents. Drug Saf. 1994; 11:223-41. http://www.ncbi.nlm.nih.gov/pubmed/7848543?dopt=AbstractPlus
24. Anon. Diabetes mellitus. NIH Cons Dev Conf Statement. 1986; 6:1-7.
25. Blake GH. Control of type II diabetes: reaping the rewards of exercise and weight loss. Postgrad Med. 1992; 92:129-32. http://www.ncbi.nlm.nih.gov/pubmed/1437899?dopt=AbstractPlus
26. Kerr CP. Improving outcomes in diabetes: a review of the outpatient care of NIDDM patients. J Fam Pract. 1995; 40:63-75. http://www.ncbi.nlm.nih.gov/pubmed/7807040?dopt=AbstractPlus
27. Gerich JE. Oral hypoglycemic agents. N Engl J Med. 1989; 321:1231-45. http://www.ncbi.nlm.nih.gov/pubmed/2677730?dopt=AbstractPlus
28. Kahn CR, Shechter Y. Insulin, oral hypoglycemic agents, and the pharmacology of the endocrine pancreas. In: Gilman AG, Rawl TW, Nies AS et al, eds. Goodman and Gilman’s pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press; 1990:1463-95.
29. Anon. Metformin for noninsulin-dependent diabetes mellitus. Med Lett Drugs Ther. 1995; 37:41-2. http://www.ncbi.nlm.nih.gov/pubmed/7739421?dopt=AbstractPlus
30. Bristol-Myers Squibb, Princeton, NJ: personal communication.
31. DeFronzo RA, Barzilai N, Simonson DC. Mechanism of metformin action in Obese and Lean Noninsulin-Dependent Diabetic Subjects. J Clin Endocrinol Metab. 1991; 73:1294-1300. http://www.ncbi.nlm.nih.gov/pubmed/1955512?dopt=AbstractPlus
32. Gan SC, Barr J, Arieff AI et al. Biguanide-associated lactic acidosis. Arch Intern Med. 1992; 152:2333-36. http://www.ncbi.nlm.nih.gov/pubmed/1444694?dopt=AbstractPlus
33. Anon. Metformin. Phase III Drug Profiles. 1994; 4:1-15.
34. Nagi DK, Yudkin JS. Effects of metformin on insulin resistance, risk factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects. Diabetes Care. 1993; 16:621-629. http://www.ncbi.nlm.nih.gov/pubmed/8462390?dopt=AbstractPlus
35. Jeppesen J, Chen YDI, Zhou M et al. Effect of metformin on postprandial lipemia in patients with fairly to poorly controlled NIDDM. Diabetes Care. 1994; 17:1093-99. http://www.ncbi.nlm.nih.gov/pubmed/7821127?dopt=AbstractPlus
36. Hoffman BB, Lefkowitz RJ. Catecholamines, sympoathomimetic drugs, and adrenergic receptor antagonists. In: Hardman JG, Limbird LE, Molinoff PB et al, eds. Goodman and Gilman’s the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill; 1995:207-48.
37. Klip A, Leiter LA. Cellular mechanism of action of metformin.. Diabetes Care. 1990; 13:696-704. http://www.ncbi.nlm.nih.gov/pubmed/2162756?dopt=AbstractPlus
38. Caille G, Lacassw Y, Raymond M et al. Bioavailability of metformin in tablet form using a new high pressure liquid chromatography assay method. Biopharmaceutics & Drug Disposition. 1993; 14:257-63.
39. Widen EI, Eriksson JG, Groop LC. Metformin normalizes nonoxidative glucose metabolism in insulin-resistant. Diabetes. 1992; 41:354-58. http://www.ncbi.nlm.nih.gov/pubmed/1551495?dopt=AbstractPlus
40. Matthaei S, Reibold JP, Hamann A et al. In vivo metformin treatment ameliorates insulin resistance: evidence for potentiation of insulin-induced translocation and increased functional activity of glucose transporters in obese (fa/fa) zucker rat adipocytes. Ednocrinology. 1993; 133:304-11.
41. Nosadini R, Avogaro A, Trevisan R et al. Effect of metformin on insulin-stimulated glucose turnover and insulin binding to receptors in type II diabetes. Diabetes Care. 1987; 10:62-67. http://www.ncbi.nlm.nih.gov/pubmed/3552515?dopt=AbstractPlus
42. Wu MS, Johnston P, Hollenbeck CB et al. Effect of metformin on carbohydrate and lipoprotein metabolism in NIDDM patients. Diabetes Care. 1990; 13:1-8. http://www.ncbi.nlm.nih.gov/pubmed/2404714?dopt=AbstractPlus
43. Vidon N, Chaussade S, Noel M et al. Metformin in the digestive tract. Diabetes Res and Clin Practice. 1988; 4:223-29.
44. Jackson RA, Hawa MI, Jaspan JB et al. Mechanism of metformin action in non-insulin-dependent diabetes. Diabetes. 1987; 36:632-40. http://www.ncbi.nlm.nih.gov/pubmed/3552795?dopt=AbstractPlus
45. Hermann LS, Karlsson JE, Sjostrand A. Prospective comparative study in NIDDM patients of metformin and glibenclamide with special reference to lipid profiles. Eur J Clin Pharmacol. 1991; 41:263-265. http://www.ncbi.nlm.nih.gov/pubmed/1748145?dopt=AbstractPlus
46. Rains SGH, Wilson GA, Richmond W et al. The effect of glibenclamide and metformin on serum lipoproteins in type II diabetes. Diabetic Medicine. 1988; 5:653-59. http://www.ncbi.nlm.nih.gov/pubmed/2975549?dopt=AbstractPlus
47. Sarabia V, Lam L, Leiter LA et al. Glucose transport in human skeletal muscle cells in culture. J Clin Invest. 1992; 90:1386-95. http://www.ncbi.nlm.nih.gov/pubmed/1401073?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=443184&blobtype=pdf
48. Lim P, Khoo OT. Metformin compared to tolbutamide in the treatment of maturity-onset diabetes mellitus. Med J Aust. 1970; 1:271-273. http://www.ncbi.nlm.nih.gov/pubmed/5440868?dopt=AbstractPlus
49. Sirtori CR, Tremoli E, Sirtori M et al. Treatment of hypertriglyceridemia with metformin. Atherosclerosis. 1977; 26:583-592. http://www.ncbi.nlm.nih.gov/pubmed/193525?dopt=AbstractPlus
50. Pentikainen PJ, Neuvonen PJ, Penttila A. Pharmacokinetics of metformin after intravenous and oral administration to man. Eur J Clin Pharmacol. 1979; 16:195-202. http://www.ncbi.nlm.nih.gov/pubmed/499320?dopt=AbstractPlus
51. Sirtori CR, Franceschini G, Galli-Kienle M et al. Disposition of metformin (N,N-dimethylbiguanide) in man. Clin Pharmacol and Ther. 1978; 24:683-93.
52. Hundal H, Ramlal T, Reyes R et al. Cellular mechanism of metformin actioninvolves glucose transporter translocation from an intracellular pool to the plasma membrane in L6 muscle cells. Endocrinology. 1992; 131:1165-73. http://www.ncbi.nlm.nih.gov/pubmed/1505458?dopt=AbstractPlus
53. Campbell IW, Duncan C, Patton NW et al. The effect of metformin on glycaemic control, intermediary metabolism and blood pressure in non-insulin-dependent diabetes mellitus. Diabetic Medicine. 1987; 4:337-41. http://www.ncbi.nlm.nih.gov/pubmed/2956047?dopt=AbstractPlus
54. Fantus IG, Brosseau R. Mechanism of action of metformin: insulin receptor and postreceptor effects in vitro and in vivo. J Clin Endocrinol Metab. 1986; 63:898-905. http://www.ncbi.nlm.nih.gov/pubmed/3745404?dopt=AbstractPlus
55. Grant PJ. The effects of metformin on the fibrinolytic system in diabetic and non-diabetic subjects. Diabete et Metabolisme. 1991; 17:168-73. http://www.ncbi.nlm.nih.gov/pubmed/1936471?dopt=AbstractPlus
56. Chakrabarti R, Hocking ED, Fearnley GR. Fibrinolytic effect of metformin in cornorary-artery disease. Lancet. 1965; 2:256-259. http://www.ncbi.nlm.nih.gov/pubmed/14330058?dopt=AbstractPlus
57. Chan JCN, Cockram CS, Tomlinson B et al. Metabolic and hemodynamic effects of metformin and glibenclamide in normotensive NIDDM patients. Diabetes Care. 1993; 16:1035-38. http://www.ncbi.nlm.nih.gov/pubmed/8359098?dopt=AbstractPlus
58. Landin K, Tengborn L, Smith U. Treating insulin resistance in hypertension with metformin reduces both blood pressure and metabolic risk factors. J Int Med. 1991; 229:181-87.
59. Giugliano D, Quatraro A, Consoli G et al. Metformin for obese, insulin-treated diabetic patients: improvement in glycaemic control and reduction of metabolic risk factors. Eur J Clin Pharmacol. 1993; 44:107-12. http://www.ncbi.nlm.nih.gov/pubmed/8453955?dopt=AbstractPlus
60. Hother-Nielsen O, Schmitz O, Andersen PH et al. Metformin improves peripheral but not hepatic insulin action in obese patients with type II diabetes. Acta Endocrinol. 1989; 120:257-65. http://www.ncbi.nlm.nih.gov/pubmed/2648723?dopt=AbstractPlus
61. Nattrass M, Todd PG, Hinks L et al. Comparative effects of phenformin, metformin and glibenclamide on metabolic rhythms in maturity-onset diabetics. Diabetologia. 1977; 13:145-52. http://www.ncbi.nlm.nih.gov/pubmed/404205?dopt=AbstractPlus
62. Assan R, Heuclin C, Ganeval D et al. Metformin-induced lactic acidosis in the presence of acute renal failure. Diabetologia. 1977; 13:211-17. http://www.ncbi.nlm.nih.gov/pubmed/406158?dopt=AbstractPlus
63. Alberti KGMM, Nattrass M. Lactic acidosis. Lancet. 1977; 2:25-9. http://www.ncbi.nlm.nih.gov/pubmed/69109?dopt=AbstractPlus
64. Waters AK, Morgan DB, Wales JK. Blood lactate and pyruvate levels in diabetic patients treated with biguanides with and without sulphonylureas. Diabetologia. 1978; 14:95-100. http://www.ncbi.nlm.nih.gov/pubmed/631461?dopt=AbstractPlus
65. Lucis OJ. The status of metformin in Canada. Can Med Assoc J. 1983; 128:24-6. http://www.ncbi.nlm.nih.gov/pubmed/6847752?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1874707&blobtype=pdf
66. Lefkowitz RJ, Hoffman BB, Taylor P. Neuotransmission: the autonomic and somatic motor nervous systems. In: Goodman & Gilman’s The pharmacological basis of therapeutics. 9th ed. 1995:105-139.
67. Vigneri R, Pezzino V, Wong K et al. Comparison of the in vitro effect of biguanides and sulfonylureas on insulin binding to its receptors in target cells. J Clin Endocrinol Metab. 1982; 54:95-100. http://www.ncbi.nlm.nih.gov/pubmed/7033271?dopt=AbstractPlus
68. Riccio A, Del Prato S, Vigili De Kreutzenberg S et al. Glucose and lipid metabolism in non-insulin-dependent diabetes: effect of metformin. Diab Metab. 1991; 17:180-84.
69. McIntyre HD, Ma A, Bird DM et al. Metformin increases insulin sensitivity and basal glucose clearance in type 2 (non-insulin dependent) diabetes mellitus. Aust N Z J Med. 1991; 21:714-19. http://www.ncbi.nlm.nih.gov/pubmed/1759920?dopt=AbstractPlus
70. Tomkin GH, Hadden DR, Weaver JA et al. Vitamin-B12 status of patients on long-term metformin therapy. Br Med J. 1971; 2:685-87. http://www.ncbi.nlm.nih.gov/pubmed/5556053?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1796258&blobtype=pdf
71. Schernthaner G. Improvement of insulin action is an important part of the antidiabetic effect of metformin. Hormone Metab Res. 1985; 15:116-120.
72. Hermann LS, Melander A. Biguanides: basic aspects and clinical use. In: Alberti KGMM, DeFronzo RA, Keen H et al, eds. International textbook of diabetes mellitus. New York: John Wiley & Sons; 1992; 773-95.
73. Swislocki A. Insulin resistance and hypertension. Am J Med Sci. 1990; 300:104-15. http://www.ncbi.nlm.nih.gov/pubmed/2206054?dopt=AbstractPlus
74. Klapholz L, Leitersdorf E, Weinrauch L. Leucocytoclastic vasculitis and pneumonitis induced by metformin. BMJ. 1986; 293:483. http://www.ncbi.nlm.nih.gov/pubmed/3091170?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1341115&blobtype=pdf
75. Somogyi A, Stockley C, Keal J et al. Reduction of metformin renal tubular secretion by cimetidine in man. Br J Clin Pharmacol. 1987;23: 545-51.
76. Wiholm BE, Myrhed M. Metformin-associated lactic acidosis in Sweden 1977-1991. Eur J Clin Pharmacol. 1993; 44:589-91. http://www.ncbi.nlm.nih.gov/pubmed/8405019?dopt=AbstractPlus
77. Berger W. Incidence of severe side effects during therapy with sulfonylureas and giguanides. Hormone Metab Res. 1985;15: 11-15.
78. DeFronzo RA, Goodman AM, and the Multicenter Metformin Study Group. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. N Engl J Med. 1995; 333:541-49. http://www.ncbi.nlm.nih.gov/pubmed/7623902?dopt=AbstractPlus
79. Cigolini M, Bosello O, Zancanaro C et al. Influence of metformin on metabolic effect of insulin in human adipose tissue in vitro. Diab Metab. 1984; 10:311-15.
80. Cordingley FT, Crawford GPM. Diabetogenic effects of nifedipine. BMJ. 1984; 289:19.
81. Stumvoll M, Nurjahan N, Perriello G et al. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med. 1995; 333:550-54. http://www.ncbi.nlm.nih.gov/pubmed/7623903?dopt=AbstractPlus
82. Tomkin GH. Malabsorption of vitamin B12 in diabetic patients treated with phenformin: a comparison with metformin. Br Med J. 1973; 3:673-75. http://www.ncbi.nlm.nih.gov/pubmed/4742454?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1587044&blobtype=pdf
83. Bailey CJ, Flatt PR, Marks V. Drugs inducing hypoglycemia. Pharmacol Ther. 1989; 42:361-84. http://www.ncbi.nlm.nih.gov/pubmed/2672051?dopt=AbstractPlus
84. Pedersen O, Hother Nielsen, Bak J et al. The effects of metformin on adipocyte insulin action and metabolic control in obese subjects with type 2 diabetes. Diabet Med. 1989; 6:249-56. http://www.ncbi.nlm.nih.gov/pubmed/2523787?dopt=AbstractPlus
85. Johnston P, Rough T. Metformin: a newly approved oral hypoglycemic. Diabetologia. 1983; 24:351-54. http://www.ncbi.nlm.nih.gov/pubmed/6347782?dopt=AbstractPlus
86. Pagano G, Tagliaferro V, Caselle MT et al. Metformin reduces insulin requirement in type 1 (insulin-dependent) diabetes. Diabetologia. 1983; 24:351-54. http://www.ncbi.nlm.nih.gov/pubmed/6347782?dopt=AbstractPlus
87. Gin H, Messerchmitt C, Brottier E et al. Metformin improved insulin resistance in type 1, insulin-dependent, diabetic patients. Metab Clin Exp. 1985; 34:923-25. http://www.ncbi.nlm.nih.gov/pubmed/4046836?dopt=AbstractPlus
88. Expert Committee of the Canadian Diabetes Advisory Board. Clinical practice guidelines for treatment of diabetes mellitus. CMAJ. 1992; 147:697-712. http://www.ncbi.nlm.nih.gov/pubmed/1521215?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1336391&blobtype=pdf
89. Tucker GT, Casey C, Phillips PJ et al. Metformin kinetics in healthy subjects and in patients with diabetes mellitus. Br J Clin Pharmacol. 1981; 12:235-46. http://www.ncbi.nlm.nih.gov/pubmed/7306436?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1401849&blobtype=pdf
90. Yki-Jarvinen H, Esko N, Eero H et al. Clinical benefits and mechanisms of a sustained response to intermittent insulin therapy in type 2 diabetic patients with secondary drug failure. Am J Med. 1988; 84:185-192. http://www.ncbi.nlm.nih.gov/pubmed/3044067?dopt=AbstractPlus
91. Chan JCN, Cockram CS. Drug-induced disturbances of carbohydrate metabolism. Adv Drug React Toxicol Rev. 1991; 10:1-29.
92. Piacquadio K, Hollingsworth D, Murphy H. Effects of in-utero oral hypoglycaemic drugs. Lancet. 1991; 338:866-69. http://www.ncbi.nlm.nih.gov/pubmed/1681225?dopt=AbstractPlus
93. Campbell IW. Metformin and the sulphonylureas: the comparative risk. Horm Metab Res. 1985; 15(Suppl):105-11.
94. Chow CC, Tsang L, Sorensen J et al. Comparison of insulin with or without continuation of oral hypoglycemic agents in the treatment of secondary failure in NIDDM patients. Diabetes Care. 1995; 18:307-14. http://www.ncbi.nlm.nih.gov/pubmed/7555472?dopt=AbstractPlus
95. Zimmerman B, Espenshade J, Fujimoto W et al. The pharmacological treatment of hyperglycemia in NIDDM. Diabetes Care. 1995; 18:1510-18. http://www.ncbi.nlm.nih.gov/pubmed/8722084?dopt=AbstractPlus
96. Lalau J, Lacroix C, Compagnon P et al. Role of metformin accumulation in metformin-associated lactic acidosis. Diabetes Care. 1995; 18:779-84. http://www.ncbi.nlm.nih.gov/pubmed/7555503?dopt=AbstractPlus
97. Gregorio F, Ambrosi F, Marchetti P et al. Low dose metformin in the treatment of type II non-insulin-dependent diabetes: clinical and metabolic evaluations. Acta Diabetol Lat. 1990; 27:139-55. http://www.ncbi.nlm.nih.gov/pubmed/2198745?dopt=AbstractPlus
98. Lord JM, White SI, Bailey CJ et al. Effect of metformin on insulin receptor binding and glycaemic control in type II diabetes. BMJ. 1983; 286:830-31. http://www.ncbi.nlm.nih.gov/pubmed/6403102?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1547150&blobtype=pdf
99. Hermann L. Biguanides and sulfonylureas as combination therapy in NIDDM. Diabetes Care. 1990; 13:37-41. http://www.ncbi.nlm.nih.gov/pubmed/2209342?dopt=AbstractPlus
100. Klein W. Sulfonylurea-metformin-combination versus sulfonylurea-inslin-combination in secondary failures of sulfonylurea monotherapy. Diab Metab. 1991; 17(Suppl 1):235-40.
101. Groop L, Widen E. Treatment strategies for secondary sulfonylurea failure. Should we start insulin or add metformin? Is there a place for intermittent insulin therapy? Diab Metab. 1991; 17(Suppl 1):218-23.
102. Hollenbeck CB, Johnston P, Varasteh BB et al. Effects of metformin on glucose insulin and lipid metabolism in patients with mild hypertriglyceridaemia and non-insulin dependent diabetes by glucose tolerance test criteria. Diab Metab. 1991; 17:483-90.
103. Holman RR, Steemson J, Turner RC. Sulphonylurea failure in type 2 diabetes: treatment with a basal insulin supplement. Diabet Med. 1987; 4:457-62. http://www.ncbi.nlm.nih.gov/pubmed/2959438?dopt=AbstractPlus
104. Trischitta V, Italia S, Mazzarino S et al. Comparison of combined therapies in treatment of secondary failure to glyburide. Diabetes Care. 1992; 15:539-42. http://www.ncbi.nlm.nih.gov/pubmed/1499473?dopt=AbstractPlus
105. Dornan T, Heller S, Peck G et al. Double-blind evaluation of efficacy and tolerability of metformin in NIDDM. Diabetes Care. 1991; 14:342-44. http://www.ncbi.nlm.nih.gov/pubmed/2060439?dopt=AbstractPlus
106. Gin H, Orgerie MB, Aubertin J. The influence of guar gum on absorption of metformin from the gut in healthy volunteers. Horm Metab Res. 1989; 21:81-83. http://www.ncbi.nlm.nih.gov/pubmed/2722133?dopt=AbstractPlus
107. Schaffalitzky de Muckadell OB, Mortensen H, Lyngsoe J. Metabolic effects of glucocorticoid and ethanol administration in phenformin- and metformin-treated obese diabetics. ACTA Medica Scandinavica. 1979; 206:269-73. http://www.ncbi.nlm.nih.gov/pubmed/506799?dopt=AbstractPlus
108. Juhan-Vague I, Alessi MC, Badier C et al. Metformin decreases the high plasminogen activator inhibition capacity, plasma insulin and triglyceride levels in non-diabetic obese subjects. Thromb Haemost. 1987; 57:326-28. http://www.ncbi.nlm.nih.gov/pubmed/3310318?dopt=AbstractPlus
109. Collier A, Watson HHK, Patrick AW et al. Effect of glycaemic control, metformin and gliclazide on platelet density and aggregability in recently diagnosed type 2 (non-insulin-dependent) diabetic patients. Diab Metab. 1989; 15:420-25.
110. Gustafson A, Bjorntorp P, Fahlen M. Metformin administration in hyperlipidemic states. ACTA Medica Scandinavica. 1971; 190:491-494. http://www.ncbi.nlm.nih.gov/pubmed/5149092?dopt=AbstractPlus
111. Sambol NC, O’Connor MD, Lin ET et al. Pharmacokinetics (PK) and pharmacodynamics (PD) of metformin HCL (MET) in healthy individuals and individuals with noninsulin-dependent diabetes mellitus (NIDDM). Clin Pharmacol Ther. 1993; 53:211.
112. Chiasson J, Josse R, Hunt J et al. The efficacy of acarbose in the treatment of patients with non-insulin-dependent diabetes mellitus. Ann Intern Med. 1994; 121:929-935.
113. Bayer Corp. Precose™ (acarbose) tablets product information. West Haven, CT; 1995 Oct.
114. Wall R, Linford S, Akhter M. Megaloblastic anaemia due to vitamin B12 malabsorption associated with long-term metformin treatment. JAMA. 1963; 183:482-85.
115. Coretzee EJ, Jackson WPU. Pregnancy in established non-insulin-dependent diabetics. S Afr Med J. 1980; 58:795-802. http://www.ncbi.nlm.nih.gov/pubmed/6777880?dopt=AbstractPlus
116. Coscelli C, Palmari V, Saccardi F et al. Evidence that metformin addition to insulin induces an amelioration of glycaemic profile in type I (insulin-dependent) diabetes mellitus. Curr Ther Res. 1984; 35:1058-64.
117. Scapa E, Haagensen DE, Thomas P et al. Treatment of metformin-associated lactic acidosis with closed recirculation bicarbonate-buffered hemodialysis. Arch Intern Med. 1984; 144:203-5.
118. Josephkutty S, Potter JM. Comparison of tolbutamide and metformin in elderly diabetic patients. Diabet Med. 1990; 7:510-14. http://www.ncbi.nlm.nih.gov/pubmed/2142054?dopt=AbstractPlus
119. McLelland J. Recovery from metformin overdose. Diabet Med. 1985; 2:410-11. http://www.ncbi.nlm.nih.gov/pubmed/2951106?dopt=AbstractPlus
120. Giugliano D, Torella R, Cacciapuoti F et al. Impairment of insulin secretion in man by nifedipine. Eur J Clin Pharmacol. 1980; 18:395-8. http://www.ncbi.nlm.nih.gov/pubmed/7002569?dopt=AbstractPlus
121. Schauben J. Calcium channel blockers and insulin secretion. it/Drug Intell Clin Pharm. 1982; 16:881-2. Letter.
122. Melchior W, Jaber L. Metformin: an antihyperglycemic agent for treatment of type II diabetes. Ann Pharmacother. 1996; 30:158-63. http://www.ncbi.nlm.nih.gov/pubmed/8835050?dopt=AbstractPlus
123. DeFronzo RA, Goodman AM. Efficacy of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med. 1996; 334:269-70.
124. Bosisio E, Galli-Kienle M, Ciconali M et al. Defective hydroxylation of phenformin as a determinant of drug toxicity. Diabetes. 1981; 30:644-9. http://www.ncbi.nlm.nih.gov/pubmed/7250534?dopt=AbstractPlus
125. Arafat T, Kaddoumi A, Shami M et al. Pharmacokinetics and pharamcodynamics of two oral formulations of metformin hydrochloride. Adv Ther. 1994; 11:21-33.
126. Brookes LG, Sambol NC, Lin ET et al. Effect of dosage form, dose and food on the pharmacokinetics of metformin. Pharm Res. 1991; 8:S320. http://www.ncbi.nlm.nih.gov/pubmed/1905809?dopt=AbstractPlus
127. Holland B, Kaplan N. Propranolol in the treatment of hypertension. N Engl J Med. 1976; 294:930-6. http://www.ncbi.nlm.nih.gov/pubmed/1256484?dopt=AbstractPlus
128. Merck Sharp and Dohme. Blocardren (timolol maleate) tabelts prescribing information (dated 1993 Aug). In: Physicians’ desk reference. 50th ed. Montvale, NJ: Medical Economics Company Inc; 1996:1614-7.
129. Nicklin P, Keates AC, Page T et al. Transfer of metformin across monolayers of human intestinal Caco-2 cells and across rat intestine. Intl J Pharm. 1996; 128:155-62.
130. Rett K, Wickimayr M, Dietze G et al. Hypoglycemia in hypertensive diabetic patients treated with sulfonylureas, biguanides, and captopril. N Engl J Med. 1988; 319:1609. http://www.ncbi.nlm.nih.gov/pubmed/3059189?dopt=AbstractPlus
131. Ferriere M, Lachkar H, Richard J et al. Captopril and insulin sensitivity. Ann Intern Med. 1985; 102:134-5. http://www.ncbi.nlm.nih.gov/pubmed/3881067?dopt=AbstractPlus
132. McMurray J, Fraser DM. Captopril, enalapril, and blood glucose. Lancet. 1986; 1:1035. http://www.ncbi.nlm.nih.gov/pubmed/2871313?dopt=AbstractPlus
133. Passa Ph, Marre M, Leblanc H. Enalapril, captopril, and blood glucose. Lancet. 1986; 1:1447. http://www.ncbi.nlm.nih.gov/pubmed/2872551?dopt=AbstractPlus
134. Reviewers’ comments (personal observations).
135. Cusi K, Consoli A, DeFronzo RA. Metabolic effects of metformin on glucose and lactate metabolism in NIDDM. (unpublished observations).
136. GrantPJ. The effects of high- and medium-dose metformin therapy on cardiovascular risk factors in patients with type II diabetes. Diabetes Care. 1996; 19:64-6. http://www.ncbi.nlm.nih.gov/pubmed/8720537?dopt=AbstractPlus
137. Dachman AH. New contraindication to intravascular iodinated contrast material. Radiology. 1995; 197:545. http://www.ncbi.nlm.nih.gov/pubmed/7480710?dopt=AbstractPlus
138. Anon. Acarbose for diabetes mellitus. Med Lett Drugs Ther. 1996; 38:9-10. http://www.ncbi.nlm.nih.gov/pubmed/8559114?dopt=AbstractPlus
139. Jackson EK. Diuretics. In: Hardman JG, Limbird LE,Molinoff PB et al, eds. Goodman and Gilman’s the pharmacological basis of therapeutics. 9th ed. New York: McGraw Hill; 1996:685-713.
140. Molloy AM, Ardill J, Tomkin GH. The effect of metformin treatment on gastric acid secretion and gastrointestinal hormone levels in normal subjects. Diabetologia. 1980; 19:93-6. http://www.ncbi.nlm.nih.gov/pubmed/7418969?dopt=AbstractPlus
141. Adams JF, Clar JS, Ireland JT et al. Malabsorption of vitamin B12 and intrinsic factor secretion during giguanide therapy. Diabetologia. 1983; 24:16-8. http://www.ncbi.nlm.nih.gov/pubmed/6825978?dopt=AbstractPlus
142. Tomkin G. Metformin and B12 malabsorption. Ann Intern Med. 1972; 76:668. http://www.ncbi.nlm.nih.gov/pubmed/4640327?dopt=AbstractPlus
143. White Jr J, Harman J, Campbell K. Drug interactions in diabetic patients. Postgrad Med. 1993; 93:131-9.
144. Rotter A. New contraindication to intravascular iodinated contrast material. Radiology. 1995; 197:545-6. http://www.ncbi.nlm.nih.gov/pubmed/7480711?dopt=AbstractPlus
145. DeFronzo RA, Bonadonna RC, Ferannini E. Pathogenesis of NIDDM: a balanced overview. Diabetes Care. 1992; 15:318-68. http://www.ncbi.nlm.nih.gov/pubmed/1532777?dopt=AbstractPlus
146. Bailey C, Turner R. Metformin. N Engl J Med. 1996; 334:574-9. http://www.ncbi.nlm.nih.gov/pubmed/8569826?dopt=AbstractPlus
147. Oates NS, Shah RR, Idle JR et al. Influence of oxidation polymorphism on phenformin kinetics and dynamics. Clin Pharmacol Ther. 1983;34:827-34.
148. Shaw S, Jayatilleke E, Bauman W et al. The mechanism of B12 malabsorption and depletion due to metformin and its Reversal with Dietary Calcium. Diabetes. 1994; 43:167A.
149. Bailey CJ, Puah JA. Effect of metformin on glucose metabolism in mouse soleus muscle. Diabete Metabol (Paris). 1986; 12:212-8.
150. Frayn Kn, Adnitt PI. Effects of metformin on glucose uptake by isolated diaphragm from normal and diabetic rats. Biochem Pharmacol. 1972; 21:3153-62. http://www.ncbi.nlm.nih.gov/pubmed/4650637?dopt=AbstractPlus
151. Lant A. Diuretics clinical pharmacology and therapeutic use (Part II). Drugs. 1985; 29:162-88. http://www.ncbi.nlm.nih.gov/pubmed/3884320?dopt=AbstractPlus
152. Houston M. The effects of antihypertensive drugs on glucose intolerance in hypertensive nondiabetics and diabetics. Am Heart J. 1988; 115:640-56. http://www.ncbi.nlm.nih.gov/pubmed/3278578?dopt=AbstractPlus
153. Joseph J, Schuna A. Management of hypertension in the diabetic patient. Clin Pharm. 1990; 9:864-73. http://www.ncbi.nlm.nih.gov/pubmed/2272152?dopt=AbstractPlus
154. Antidiabetic drug interactions: thiazide diuretics. In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc; 1993:387.
155. Angiotensin-converting enzyme inhibitor drug interactions: antidiabetics. In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc; 1993:127.
156. Gueriguian J, Green L, Misbin RI et al. Efficacy of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med. 1996; 334:269. http://www.ncbi.nlm.nih.gov/pubmed/8532012?dopt=AbstractPlus
157. Bailey CJ. Hypoglycaemic, antihyperglycaemic and antidiabetic drugs. Diabetic Med. 1992; 9:482-3. http://www.ncbi.nlm.nih.gov/pubmed/1611838?dopt=AbstractPlus
158. Sirtori CR, Pasik C. Re-evaluation of a biguanide, metformin: mechanism of action and tolerability. Pharmacol Res. 1994; 30:187-228. http://www.ncbi.nlm.nih.gov/pubmed/7862618?dopt=AbstractPlus
159. Hurel S, Taylor R. Drugs and glucose tolerance. Adverse Drug Reaction Bulletin. 1995; 174:659-62.
160. Pandit M, Burke J, Gustafson A et al. Drug-induced disorders of glucose tolerance. Ann Intern Med. 1993; 118:529-39. http://www.ncbi.nlm.nih.gov/pubmed/8442624?dopt=AbstractPlus
161. Bailey CJ. Metformin-an update. Gen Pharmacol. 1993; 24:1299-309. http://www.ncbi.nlm.nih.gov/pubmed/8112499?dopt=AbstractPlus
162. Wilcock C, Bailey CJ. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica. 1994; 24:49-57. http://www.ncbi.nlm.nih.gov/pubmed/8165821?dopt=AbstractPlus
163. Anon. ASHP therapeutic position statement on strict glycemic control in selected patients with insulin-dependent diabetes mellitus. Am J Health-Syst Pharm. 1995; 52:2709-11. http://www.ncbi.nlm.nih.gov/pubmed/8601269?dopt=AbstractPlus
164. KhanIH, Catto GRD, MacLeod AM. Severe lactic acidosis in patient receiving continuous ambulatory peritoneal dialysis. BMJ. 1993; 307:1056-7. http://www.ncbi.nlm.nih.gov/pubmed/8251784?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1679237&blobtype=pdf
165. Anon. Fatal lactic acidosis with metformin. Aust Adv Drug React Bull. 1995; 14:6-7.
166. United Kingdom prospective diabetes study group. United Kingdom prospective diabetes study (UKPDS) 16: overview of 6 years’ therapy of type II diabetes: a progressive disease. Diabetes. 1995; 44:1240-58.
167. Scheen AJ. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 1996; 30:359-71. http://www.ncbi.nlm.nih.gov/pubmed/8743335?dopt=AbstractPlus
168. Stabler SP. Screening the older population for cobalamin (vitamin B12 deficiency. J Am Geriatrics Soc. 1995; 43:1295-6.
169. Anon. Urine glucose and ketone determinations. Diabetes Care. 1995; 18:.
170. Ferguson JE, Dyson DC, Holborok RH et al. Cardiovascular and metabolic effects associated with nifedipine and ritodrine tocolysis. Am J Obstet Gynecol. 1989; 161:788-95. http://www.ncbi.nlm.nih.gov/pubmed/2782362?dopt=AbstractPlus
171. Astra. Yutopar (ritodrine hydrochloride) injection prescribing information (dated 1995 Apr). In: Physicians’ desk reference. 50th ed. Montvale, NJ: Medical Economics Company Inc; 1996:570-2.
172. MacDonald IA, Bennett T, Fellows IW. Catecholamines and the control of metabolism in man. Clinical Science. 1985; 68:613-9. http://www.ncbi.nlm.nih.gov/pubmed/2485261?dopt=AbstractPlus
173. Kendall MJ. Impact of beta1 selectivity and intrinsic sympathomimetic activity on potential unwanted noncardiovascular effects of beta blockers. Am J Cardiol. 1987; 59:44-7.
174. Sambol NC, Chiang J, Kin ET et al. Kidney function and age are both predictors of pharmacokinetics of metformin. J Clin Pharmacol. 1995; 35:1094-102. http://www.ncbi.nlm.nih.gov/pubmed/8626883?dopt=AbstractPlus
175. Wollen N, Bailey CJ. Inhibition of hepatic gluconeogenesis by metformin. Clin Pharmacol. 1988; 37:4353-8.
176. Argaud D, Roth H, Wiernsperger N et al. Metformin decreases gluconeogenesis by enhancing the pyruvate kinase flux in isolated rat hepatocytes. Eur J Biochem. 1993; 213:1341-8. http://www.ncbi.nlm.nih.gov/pubmed/8504825?dopt=AbstractPlus
177. Alengrin F, Grossi G, Canivet B et al. Inhibitory effects of metformin on insulin and glucagon action in rat hepatocytes involve post-receptor alterations. Diabete Metabol (Paris). 1987; 13:591-7.
178. Scheen AJ, Letiexhe MR, Lefèbvre PJ. Effects of metformin in obese patients with impaired glucose tolerance. Diabetes/Metabolism Reviews. 1995; 11:S69-80.
179. Williams G. Management of non-insulin-dependent diabetes mellitus. Lancet. 1994; 95-100.
180. Genuth S. Exogenous insulin administration and cardiovascular risk in non-insulin-dependent and insulin-dependent diabetes mellitus. Ann Intern Med. 1996;124(1 Pt 2):104-9.
181. Ilarde A, Tuck M. Treatment of non-insulin-dependent diabetes mellitus and its complications. Drugs Aging. 1994; 4:470-91. http://www.ncbi.nlm.nih.gov/pubmed/8075474?dopt=AbstractPlus
182. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993; 329:977-86. http://www.ncbi.nlm.nih.gov/pubmed/8366922?dopt=AbstractPlus
183. Klein R, Klein BE, Moss SE. Relation of glycemic control to diabetic microvascular complications in diabetes mellitus. Ann Intern Med. 1996; 124(1 Pt 2):90-6. http://www.ncbi.nlm.nih.gov/pubmed/8554220?dopt=AbstractPlus
184. Turner R, Cull C, Holman R et al. United Kingdom Prospective Diabetes Study 17: a 9-year update of a randomized, controlled trial on the effect of improved metabolic control on complications in non-insulin-dependent diabetes mellitus. Ann Intern Med. 1996; 124(1 Pt 2):136-45. http://www.ncbi.nlm.nih.gov/pubmed/8554206?dopt=AbstractPlus
185. Clark CM Jr. Where do we go from here? Ann Intern Med. 1996; 124(1 Part 2):184-6. Editorial.
186. Ohkubo Y, Kishikawa H, Araki E et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus; a randomized prospective 6-year study. Diabetes Res Clin Pract. 1995; 28:103-17. http://www.ncbi.nlm.nih.gov/pubmed/7587918?dopt=AbstractPlus
187. Henry RR, Genuth S. Forum One: Current recommendations about intensification of metabolic control in non-insulin-dependent diabetes mellitus. Ann Intern Med. 1996; 124(1 Pt 2):175-7. http://www.ncbi.nlm.nih.gov/pubmed/8554214?dopt=AbstractPlus
188. Laakso M. Glycemic control and the risk for coronary heart disease in patients with non-insulin-dependent diabetes mellitus. The Finnish studies. Ann Intern Med. 1996;124(1 Pt 2):127-30.
189. Crofford OB. Metformin. N Engl J Med. 1995; 333:588-9. http://www.ncbi.nlm.nih.gov/pubmed/7623910?dopt=AbstractPlus
190. Reichard P, Nilsson B-Y, Rosenqvist U. The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med. 1993; 329:304-9. http://www.ncbi.nlm.nih.gov/pubmed/8147960?dopt=AbstractPlus
191. The Upjohn Company. Micronase (glyburide) prescribing information. Kalamazoo, MI; 2002 Mar.
192. Hoechst-Roussel Pharmaceuticals Inc. DiaBeta (glyburide) prescribing information. Somerville, NJ; 1987 Dec.
193. Calle-Pascual AL, Garcia-Honduvilla J, Martin-Alvarez PJ et al. Comparison between acarbose, metformin, and insulin treatment in type 2 diabetic patients with secondary failure to sulfonylurea treatment. Diabete & Metabolisme (Paris). 1995; 21:256-60.
194. Coniff RF, Shapiro JA, Seaton TB. Long-term efficacy and safety of acarbose in the treatment of obese subjects with non-insulin-dependent diabetes mellitus. Arch Intern Med. 1994; 154:2442-8. http://www.ncbi.nlm.nih.gov/pubmed/7979840?dopt=AbstractPlus
195. Balfour JA, McTavish D. Acarbose: an update of its pharmacology and therapeutic use in diabetes mellitus. Drugs. 1993; 46:1025-54. http://www.ncbi.nlm.nih.gov/pubmed/7510610?dopt=AbstractPlus
196. Zimmerman BR. Preventing long term complications: implicationsfor combination therapy with acarbose. Drugs. 1992; 44:54-9. http://www.ncbi.nlm.nih.gov/pubmed/1280578?dopt=AbstractPlus
197. Asmal AC, Marble A. Oral hypoglycaemic agents: an update. Drugs. 1984; 28:62-78. http://www.ncbi.nlm.nih.gov/pubmed/6378583?dopt=AbstractPlus
198. Jackson JE, Bressler R. Clinical pharmacology of sulphonylurea hypoglycaemic agents: part 1. Drugs. 1981; 22:211-45. http://www.ncbi.nlm.nih.gov/pubmed/7021124?dopt=AbstractPlus
199. Lebovitz HE. Clinical utility of oral hypoglycemic agents in the management of patients with noninsulin-dependent diabetes mellitus. Am J Med. 1983; 75(Suppl 5B):94-9. http://www.ncbi.nlm.nih.gov/pubmed/6369972?dopt=AbstractPlus
200. Food and Drug Administration. Labeling for oral hypoglycemic drugs of the sulfonylurea class. [Docet No. 75N-0062] Fed Regist. 1984; 49:14303-31.
201. Scheen AJ, Alves de Magalhaes F, Lefebvre ST et al. Reduction of metformin acute bioavailability by the alpha-glucosidase inhibitor acarbose in normal man. Eur J Clin Invest. 1993; 23(Suppl 1):A43.
202. Klein R, Klein BEK, Moss SE et al. Glycosylated hemoglobin predicts the incidence and progression of diabetic retinopathy. JAMA. 1988; 260:2864-71. http://www.ncbi.nlm.nih.gov/pubmed/3184351?dopt=AbstractPlus
203. Howanitz PJ, Howantiz JH. Carbohydrates. In: Henry JB, ed. Todd-Sanford-Davidsohn clinical diagnosis and management by laboratory methods. 17th ed. Philadelphia: WB Saunders Company; 1984:165-179.
204. USP DI: drug information for the health care provider. 20th ed. Englewood, CO: Micromedex, Inc; 2000;1:306.
205. Bayraktar M, Adalar N, Van Thiel DH. A comparison of acarbose versus metformin as an adjuvant therapy in sulfonylurea-treated NIDDM patients. Diabetes Care. 1996; 19:252-4. http://www.ncbi.nlm.nih.gov/pubmed/8742572?dopt=AbstractPlus
206. American Diabetes Association. Implications of the diabetes control and complications trial. Diabetes Care. 1996; 19:50-2S.
207. Sacher RA, McPherson RA, Campos JM. Glucose measurement. In: Sacher RA, McPherson RA, Campos JM, eds. Widman’s clinical interpretation of laboratory tests. 10th ed. Philadelphia: FA Davis Company; 1991:323-.
208. Saffar F, Aiache JM, Andre P. Influence of food on the disposition of the antidiabetic drug metformin in diabetic patients at steady-state. Meth Find Exp Clin Pharmacol. 1995; 17:483-7.
209. Misbin RI, Green L, Stadel BV et al. Lactic acidosis in patients with diabetes treated with metformin. New Engl J Med. 1998; 338:265-6. http://www.ncbi.nlm.nih.gov/pubmed/9441244?dopt=AbstractPlus
210. Nestler JE, Jakubowicz DA, Evans WS et al. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. New Engl J Med. 1998; 338:1876-80. http://www.ncbi.nlm.nih.gov/pubmed/9637806?dopt=AbstractPlus
211. Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17α activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. New Wngl J Med. 1996; 335:617-23.
212. Dunaif A, Scott D, Finegood D et al. The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metabol. 1996; 81:3299-306.
213. Babich MM, Pike I, Shiffman ML et al. Metformin-induced acute hepatitis. Am J Med. 1998; 104:490-2. http://www.ncbi.nlm.nih.gov/pubmed/9626034?dopt=AbstractPlus
214. Bristol-Myers Squibb Company. Glucophage (metformin hydrochloride) tablets and Glucophage XR (metformin hydrochloride) extended-release tablets patient information. Princeton, NJ; 2001 Jun.
215. Har SP, Walker JD. Is metformin contra-indicated in diabetic patients with chronic heart failure? Pract Diabetes Intern. 1996; 13:18-20.
216. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998; 352:854-65. http://www.ncbi.nlm.nih.gov/pubmed/9742977?dopt=AbstractPlus
217. Davis TM. United Kingdom Prospective Diabetes Study: the end of the beginning? Med J Aust. 1998; 169:511-2.
218. Nathan DM. Some answers, more controversy, from UKDS. Lancet. 1998; 352:832-3. http://www.ncbi.nlm.nih.gov/pubmed/9742972?dopt=AbstractPlus
219. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998; 352:837-53. http://www.ncbi.nlm.nih.gov/pubmed/9742976?dopt=AbstractPlus
220. American Diabetes Association. Position Statement: implications of the United Kingdom Prospective Diabetes Study. Diabetes Care. 1999; 22(Suppl. 1):S27-S31.
221. American Diabetes Association. The United Kingdom Prospective Diabetes Study (UKPDS) for type 2 diabetes: what you need to know about the results of a long-term study. Washington, DC; September 15, 1998. From American Diabetes Association web site (http://www.diabetes.org).
222. Genuth P. United Kingdom prospective diabetes study results are in J Fam Pract. 1998; 47:(Suppl.5):S27.
223. Matthews DR, Cull CA, Stratton RR et al. UKPDS 26: sulphonylurea failure in non-insulin-dependent diabetic patients over 6 years. Diabet Med. 1998; 15:297-303. http://www.ncbi.nlm.nih.gov/pubmed/9585394?dopt=AbstractPlus
224. Watkins PJ. UKPDS: a message of hope and a need for change. Diabet Med. 1998; 15:895-6. http://www.ncbi.nlm.nih.gov/pubmed/9827842?dopt=AbstractPlus
225. Bretzel RG, Voit K, Schatz H et al. The United Kingdom Prospective Diabetes Study (UKPDS): implications for the pharmacotherapy of type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes. 1998; 106:369-72. http://www.ncbi.nlm.nih.gov/pubmed/9831300?dopt=AbstractPlus
226. Morgensen CE. Combined high blood pressure and glucose in type 2 diabetes: double jeopardy. BMJ. 1998; 317:693-4. http://www.ncbi.nlm.nih.gov/pubmed/9732334?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1113869&blobtype=pdf
227. American Diabetes Association. Consensus statement: treatment of hypertension in diabetes. Diabetes Care. 1993; 16:1394-1401. http://www.ncbi.nlm.nih.gov/pubmed/8269800?dopt=AbstractPlus
228. UK Prospective Diabetes Study (UKPDS) Group. Efficacy of atenolol and captopril in reducing risk of macrovascular complications in type 2 diabetes mellitus: UKPDS 39. BMJ. 1998; 317:713-20. http://www.ncbi.nlm.nih.gov/pubmed/9732338?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=28660&blobtype=pdf
229. United Kingdom Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998; 317:703-13. http://www.ncbi.nlm.nih.gov/pubmed/9732337?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=28659&blobtype=pdf
230. Genuth S, Brownless MA, Kuller LH et al. Consensus development conference on insulin resistance: November 5-6 1997. Diabetes Care. 1998; 21:310-4. http://www.ncbi.nlm.nih.gov/pubmed/9540000?dopt=AbstractPlus
231. Turner RC, Cull CA, Frighi V et al. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirements for multiple therapies (UKPDS 49). JAMA. 1999; 281:2005-12. http://www.ncbi.nlm.nih.gov/pubmed/10359389?dopt=AbstractPlus
232. University Group Diabetes Program. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. Diabetes. 1970; 19(Suppl 2):747-830.
233. August K, Brooks L (California Department of Health and Human Services). State health director warns consumers about prescription drugs in herbal products. Rockville, MD; 2000 Feb 15. News release No. 09-00. News release from FDA web site (http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm171209.htm).
234. Bristol-Myers-Squibb Company. Glucovance(glyburide and metformin hydrochloride) tablets prescribing information. Princeton, NJ; 2010 May.
235. American Diabetes Association. Type 2 diabetes in children and adolescents. Pediatrics. 2000; 105:671-80. http://www.ncbi.nlm.nih.gov/pubmed/10699131?dopt=AbstractPlus
236. American Diabetes Association. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2000; 23(Suppl 1):S4-19.
237. Takeda Pharmaceuticals America. Actos (pioglitazone hydrochloride) tablets prescribing information. Deerfield, IL; 2011 Jul.
238. Moses R, Carter J, Slobodniuk R et al. Effect of repaglinide addition to metformin monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 1999; 22:119-24. http://www.ncbi.nlm.nih.gov/pubmed/10333912?dopt=AbstractPlus
239. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999; 131:281-303. http://www.ncbi.nlm.nih.gov/pubmed/10454950?dopt=AbstractPlus
240. Fonseca V,, Rosenstock J, Patwardhan R et al. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. JAMA. 2000; 283:1695-702. http://www.ncbi.nlm.nih.gov/pubmed/10755495?dopt=AbstractPlus
241. Aventis Pharmaceuticals Amaryl (glimepiride) tablets 1, 2, and 4 mg prescribing information. Kansas City, MO; 2000 Apr.
242. Pfizer. Glucotrol XL (glipizide) extended release tablets prescribing information. New York, NY; 1999 Aug.
243. Mylan Pharmaceuticals. Metformin hydrochloride tablets prescribing information. Morgantown, WV; 2002 Jan.
244. Bayer Corporation. Precose (acarbose) tablets prescribing information. West Haven, CT; 2003 Mar.
245. IVAX Pharmaceuticals. Metformin hydrochloride tablets prescribing information. Miami, FL; 2002 Jan.
246. PurePac Pharmaceutical Company. Metformin hydrochloride tablets prescribing information. Elizabeth, NJ; 2002 Feb.
247. GlaxoSmithKline. Avandamet(rosiglitazone maleate and metformin hydrochloride) tablets prescribing information. Research Triangle Park, NC; 2011 May.
248. Novartis. Starlix (nateglinide) tablets prescribing information. East Hanover, NJ; 2011 Aug.
249. Novo Nordisk. Prandin(repaglinide) tablets prescribing information. Princeton, NJ; 2009 Jun.
250. GlaxoSmithKline. Avandia (rosiglitazone maleate) tablets prescribing information. Research Triangle Park, NC; 2011 May.
251. Einhorn D, Rendell M, Rosenzweig J et al. Pioglitazone in combination with metformin in the treatment of type 2 diabetes mellitus: a randomized, placebo-controlled study. Clin Ther. 2000; 22:1395-409. http://www.ncbi.nlm.nih.gov/pubmed/11192132?dopt=AbstractPlus
252. Horton ES, Foley J, Clinkingbeard C et al. Nateglinide alone and in combination with metformin improves glycemic control by reducing mealtime glucose levels in type 2 diabetes. Diabetes Care. 2000; 23:1660-65. http://www.ncbi.nlm.nih.gov/pubmed/11092289?dopt=AbstractPlus
253. National Institute for Clinical Excellence, National Health Service. The clinical effectiveness and cost effectiveness of rosiglitazone for type 2 diabetes mellitus: health technology report. London, United Kingdom; 2000 Aug. From the NICE web site: http://www.nice.org.uk
254. Bristol-Myers Squibb Company. Metaglip (glipizide and metformin hydrochloride) prescribing information. Princeton, NJ; 2009 Feb.
255. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA. 2002; 287:2563-9. http://www.ncbi.nlm.nih.gov/pubmed/12020338?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2622728&blobtype=pdf
256. Bristol Myers Squibb, Princton, NJ: Personal communications.
257. Ranbaxy Laboratories Inc. Riomet (metformin hydrochloride) oral solution prescribing information. Jacksonville, FL; 2011 Jun.
258. Andrx Laboratories. Fortamet (metformin hydrochloride) extended-release tablets prescribing information. Weston, FL; 2005 May.
259. Teva Pharmaceutical USA. Metformin hydrochloride tablets 500 mg, 850 mg, and 1000 mg and metformin hydrochloride extended-release tablets 500 mg prescribing information. Sellersville, PA; 2004 Apr.
260. Takeda Pharmaceuticals America. Actoplus Met (pioglitazone hydrochloride and metformin hydrochloride) tablets prescribing information. Lincolnshire, IL; 2011 Jul.
261. Depomed. Glumetza (metformin hydrochloride) extended release tablets prescribing information. Menlo Park, CA; 2006 Apr.
262. Depomed. Technology: diffusional. Available at http://www.depomedinc.com. Accessed 2006 Aug 7.
263. American Diabetes Association. Preconception care of women with diabetes. Diabetes Care. 2004; 27(Suppl 1):S76-78.
264. Nathan DM, Buse JB, Davidson MB et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2006; 29:1963-72. http://www.ncbi.nlm.nih.gov/pubmed/16873813?dopt=AbstractPlus
265. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2003 clinical paractuce guidelines for the prevention and management of diabetes in Canada. Can J Diabetes. 2003; 27(Suppl 2):S1-152.
267. GlaxoSmithKline. Avandamet (rosiglitazone maleate and metformin hydrochloride) tablets prescribing information. Research Triangle Park, NC; 2007 Aug.
268. American Diabetes Association. Summary of revisions for the 2009 clinical practice recommendations. Diabetes Care. 2009; 32:S3-S5. http://www.ncbi.nlm.nih.gov/pubmed/19118287?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2613585&blobtype=pdf
269. Klein S, Allison DB, Heymsfield SB et al. Waist circumference and cardiometabolic risk: a consensus statement from shaping America's health: Association for Weight Management and Obesity Prevention; NAASO, the Obesity Society; the American Society for Nutrition; and the American Diabetes Association. Diabetes Care. 2007; 30:1647-52. http://www.ncbi.nlm.nih.gov/pubmed/17360974?dopt=AbstractPlus
270. Dluhy RG, McMahon GT. Intensive glycemic control in the ACCORD and ADVANCE trials. N Engl J Med. 2008; 358:2630-33. Editorial. http://www.ncbi.nlm.nih.gov/pubmed/18539918?dopt=AbstractPlus
271. Stratton IM, Adler AI, Neil HA et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000; 321:405-12. http://www.ncbi.nlm.nih.gov/pubmed/10938048?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=27454&blobtype=pdf
272. Henry RR. Glucose control and insulin resistance in non-insulin-dependent diabetes mellitus. Ann Intern Med. 1996; 124:97-103. http://www.ncbi.nlm.nih.gov/pubmed/8554221?dopt=AbstractPlus
273. Skyler JS, Bergenstal R, Bonow RO et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Diabetes Care. 2009; 32:187-92. http://www.ncbi.nlm.nih.gov/pubmed/19092168?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2606812&blobtype=pdf
274. , Patel A, MacMahon S et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008; 358:2560-72. http://www.ncbi.nlm.nih.gov/pubmed/18539916?dopt=AbstractPlus
275. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008; 358:2545-59. http://www.ncbi.nlm.nih.gov/pubmed/18539917?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4551392&blobtype=pdf
276. Duckworth W, Abraira C, Moritz T et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009; 360:129-39. http://www.ncbi.nlm.nih.gov/pubmed/19092145?dopt=AbstractPlus
277. American Diabetes Association. Aspirin therapy in diabetes: position statement. Diabetes Care. 2001; 24(Suppl.1):S62-3. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2663516&blobtype=pdf
278. Ismail-Beigi F, Moghissi ES. Glycemia management and cardiovascular risk in type 2 diabetes: an evolving perspective. Endocr Pract. 2008 Jul-Aug; 14:639-43.
279. Weiss IA, Valiquette G, Schwarcz MD. Impact of glycemic treatment choices on cardiovascular complications in type 2 diabetes. Cardiol Rev. 2009; 17(4):165-75. http://www.ncbi.nlm.nih.gov/pubmed/19525678?dopt=AbstractPlus
280. Holman RR, Paul SK, Bethel MA et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008; 359:1577-89. http://www.ncbi.nlm.nih.gov/pubmed/18784090?dopt=AbstractPlus
281. Nathan DM, Cleary PA, Backlund JY et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005; 353:2643-53. http://www.ncbi.nlm.nih.gov/pubmed/16371630?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2637991&blobtype=pdf
282. Skyler JS. Non-insulin-dependent diabetes mellitus: a clinical strategy. Diabetes Care. 1984; 7(Suppl 1):118-29. http://www.ncbi.nlm.nih.gov/pubmed/6376024?dopt=AbstractPlus
283. Defronzo RA, Ferrannini E, Koivisto V. New concepts in the pathogenesis and treatment of noninsulin-dependent diabetes mellitus. Am J Med. 1983; 74(Suppl 1A):52-81. http://www.ncbi.nlm.nih.gov/pubmed/6337486?dopt=AbstractPlus
284. Metformin. In: Briggs GG, Freeman RK, Yaffe SJ. Drug in pregnancy and lactation: a reference guide to fetal and neonatal risk. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2008:1155-9.
285. Hale TW, Kristensen JH, Hackett LP et al. Transfer of metformin into human milk. Diabetologia. 2002; 45(11):1509-14. http://www.ncbi.nlm.nih.gov/pubmed/12436333?dopt=AbstractPlus
286. Briggs GG, Ambrose PJ, Nageotte MP et al. Excretion of metformin into breast milk and the effect on nursing infants. Obstet Gynecol. 2005; 105(6):1437-41. http://www.ncbi.nlm.nih.gov/pubmed/15932841?dopt=AbstractPlus
287. Salpeter SR, Greyber E, Pasternak GA et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database of Systematic Reviews. 2010; Issue 1. Art. No.: CD002967.
288. Brown JB, Herson MK, Pedula K et al. Lactic acidosis rates in type 2 diabetes. Diabetes Care. 1998; 21:1659-63. http://www.ncbi.nlm.nih.gov/pubmed/9773726?dopt=AbstractPlus
289. Tso LO, Costello MF, Albuquerque LE et al. Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. Cochrane Database of Systematic Reviews. 2009, Issue 2. Art. No.: CD006105.
290. Costello MF, Shrestha B, Eden J et al. Insulin-sensitizing drugs versus the combined oral contraceptive pill for hirsutism, acne and risk of diabetes, cardiovascular disease, and endometrial cancer in polycystic ovary syndrome. Cochrane Database of Systematic Reviews. 2007, Issue 1. Art. No.: CD005552.
291. Fedorcsák P, Dale PO, Storeng R et al. The effect of metformin on ovarian stimulation and in vitro fertilization in insulin-resistant women with polycystic ovary syndrome: an open-label randomized cross-over trial. Gynecol Endocrinol. 2003; 17(3):207-14.
292. Practice Committee of the American Society for Reproductive Medicine. Use of insulin sensitizing agents in the treatment of polycystic ovary syndrome. Fertil Steril. 2004; 82 Suppl 1):S181-3. http://www.ncbi.nlm.nih.gov/pubmed/15363722?dopt=AbstractPlus
293. Ehrmann DA. Polycystic ovary syndrome. New Engl J Med. 2005; 352:1223-36. http://www.ncbi.nlm.nih.gov/pubmed/15788499?dopt=AbstractPlus
294. Tang T, Lord JM, Norman RJ et al. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro- inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database of Systematic Reviews. 2010, Issue 1. Art. No.: CD003053.
295. Meyer C, McGrath BP, Teede HJ. Effects of medical therapy on insulin resistance and the cardiovascular System in polycystic ovary syndrome. Diabetes Care. 2007; 30:471-8. http://www.ncbi.nlm.nih.gov/pubmed/17327307?dopt=AbstractPlus
296. Doldi N, Persico P, Di Sebastiano F et al. Gonadotropin-releasing hormone antagonist and metformin for treatment of polycystic ovary syndrome patients undergoing in vitro fertilization-embryo transfer. Gynecol Endocrinol. 2006; 22(5):235-8. http://www.ncbi.nlm.nih.gov/pubmed/16785142?dopt=AbstractPlus
297. Lobo RA. Choice of treatment for women with polycystic ovary syndrome. Fertil Steril. 2006; 86(suppl 1):S22-3. http://www.ncbi.nlm.nih.gov/pubmed/16798280?dopt=AbstractPlus
298. Teede HJ, Meyer C, Hutchison SK et al. Endothelial function and insulin resistance in polycystic ovary syndrome: the effects of medical therapy. Fertil Steril. 2010; 93:184-91. http://www.ncbi.nlm.nih.gov/pubmed/19019358?dopt=AbstractPlus
299. Practice Committee, American Society for Reproductive Medicine. Use of insulin sensitizing agents in the treatment of polycystic ovary syndrome. Fertil Steril. 2006; 86(Suppl 4):S221-3. http://www.ncbi.nlm.nih.gov/pubmed/17055827?dopt=AbstractPlus
300. Radosh L. Drug treatments for polycystic ovary syndrome. Am Fam Physician. 2009;79:671-6.
301. Creanga AA, Bradley HM, McCormick C et al. Use of metformin in polycystic ovary syndrome. Obstet Gynecol. 2008; 111:959-68. http://www.ncbi.nlm.nih.gov/pubmed/18378757?dopt=AbstractPlus
302. Nestler JE. Metformin for the treatment of the polycystic ovary syndrome. N Engl J Med. 2008; 358:47-54. http://www.ncbi.nlm.nih.gov/pubmed/18172174?dopt=AbstractPlus
303. Liu JH, Bill AH. Expanding applications for metformin in polycystic ovarian syndrome. J Pediatr. 2006; 148:573-4. Editorial. http://www.ncbi.nlm.nih.gov/pubmed/16737862?dopt=AbstractPlus
304. Urman B, Yahin K. Ovulatory disorders and infertility. J Reprod Med. 2006; 51:267-82. http://www.ncbi.nlm.nih.gov/pubmed/16737024?dopt=AbstractPlus
305. Siebert TI, Kruger, TF, Steyn DW et al. Is the addition of metformin efficacious in the treatment of clomiphene citrate-resistant patients with polycystic ovary syndrome? Fertil Steril. 2006; 86:1432-7.
306. Pillai AS, Bang H, Green C. Metformin & glitazones: Do they really help PCOS patients? J Fam Pract. 2007; 56:444-53.
307. Practice Committee of the American Society for Reproductive Medicine. Use of insulin-sensitizing agents in the treatment of polycystic ovary syndrome. Fertil Steril. 2008; 90(Suppl 3):S69-73. http://www.ncbi.nlm.nih.gov/pubmed/19007650?dopt=AbstractPlus
308. Nestler JE. Metformin in the treatment of infertility in polycystic ovarian syndrome: an alternative perspective. Fertil Steril. 2008; 90:14-6. Editorial. http://www.ncbi.nlm.nih.gov/pubmed/18550055?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2495076&blobtype=pdf
309. Legro RS, Barnhart HX, Schlaff WD et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007; 356:551-66. http://www.ncbi.nlm.nih.gov/pubmed/17287476?dopt=AbstractPlus
310. Guzick DS. Treating the polycystic ovary syndrome the old-fashioned way. N Engl J Med. 2007; 356:622-4. Editorial. http://www.ncbi.nlm.nih.gov/pubmed/17287483?dopt=AbstractPlus
311. Palomba S, Orio F Jr, Falbo A et al. Clomiphene citrate versus metformin as first-line approach for the treatment of anovulation in infertile patients with polycystic ovary syndrome. J Clin Endocrinol Metab. 2007; 92:3498-3503. http://www.ncbi.nlm.nih.gov/pubmed/17595241?dopt=AbstractPlus
312. Barbieri RL. Clomiphene versus metformin for ovulation induction in polycystic ovary syndrome: the winner is....J Clin Endocrinol Metab. 2007; 92:3399-3401. Editorial. http://www.ncbi.nlm.nih.gov/pubmed/17823274?dopt=AbstractPlus
313. Novo Nordisk A/S. Prandimet (repaglinide/metformin hydrochloride) tablets prescribing information. Princeton, NJ; 2011 Sept.
314. Merck. Janumet (sitagliptin/metformin hydrochloride) tablets prescribing information. Whitehouse Station, NJ; 2011 Apr.
315. Moses R, Carter J, Slobodniuk R et al. Effect of repaglinide addition to metformin monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 1999; 22:119-24. http://www.ncbi.nlm.nih.gov/pubmed/10333912?dopt=AbstractPlus
316. Stang M, Wysowski DK, Butler-Jones D. Incidence of lactic acidosis in metformin users. Diabetes Care. 1999; 22:925-7. http://www.ncbi.nlm.nih.gov/pubmed/10372243?dopt=AbstractPlus
317. Lalau JD, Race JM. Lactic acidosis in metformin therapy: searching for a link with metformin in reports of “metformin-associated lactic acidosis”. Diabetes Obes Metab. 2001; 3:195-201. http://www.ncbi.nlm.nih.gov/pubmed/11412284?dopt=AbstractPlus
318. Salpeter SR, Greyber E, Pasternak GA et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Arch Intern Med. 2003; 163:2594-2602. http://www.ncbi.nlm.nih.gov/pubmed/14638559?dopt=AbstractPlus
319. Bolen S, Feldman L, Vassy J et al. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med. 2007; 147:386-99. http://www.ncbi.nlm.nih.gov/pubmed/17638715?dopt=AbstractPlus
320. Tahrani AA, Varughese GI, Scarpello JH et al. Metformin, heart failure, and lactic acidosis: is metformin absolutely contraindicated? Br Med J. 2007; 335:508-12.
321. Misbin RI. The phantom of lactic acidosis due to metformin in patients with diabetes. Diabetes Care. 2004; 27:1791-3. Commentary. http://www.ncbi.nlm.nih.gov/pubmed/15220268?dopt=AbstractPlus
322. Bodmer M, Jick SS, Meier C et al. Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia. Diabetes Care. 2008; 31:2086-91. http://www.ncbi.nlm.nih.gov/pubmed/18782901?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2571051&blobtype=pdf
323. US Food and Drug Administration. FDA significantly restricts access to the diabetes drug Avandia. Rockville, MD; 2010 Sep 23. News release from FDA web site. Accessed 2010 Nov 15. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm226975
324. Woodcock J (US Food and Drug Administration). Decision on continued marketing of rosiglitazone (Avandia, Avandamet, Avandaryl). Rockville, MD; Available at FDA website. Accessed 2010 Nov 15. http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM226959.pdf
325. Food and Drug Administration. FDA drug safety communication: Updated risk evaluation and mitigation strategy (REMS) to restrict access to rosiglitazone-containing medicines including Avandia, Avandamet, and Avandaryl. Rockville, MD; 2011 May 18. Available from FDA website. Accessed 2011 Jun 20. http://www.fda.gov/Drugs/DrugSafety/ucm255005.htm
326. Avandia (rosiglitazone maleate), Avandamet (rosiglitazone maleate and metformin hydrochloride), and Avandaryl (rosiglitazone maleate and glimepiride) tablets risk evaluation and mitigation strategy (REMS). Available from FDA web site. Accessed 2011 Aug 25. http://www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm255624.pdf
327. Food and Drug Administration. FDA advisory committee meeting briefing document for NDA 21071 Avandia (rosiglitazone maleate). Rockville, MD; July 13 and 14, 2010. From FDA website. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM218493.pdf
328. Lipska KJ, Ross JS. Switching from rosiglitazone: thinking outside the class. JAMA. 2011; 305:820-1. http://www.ncbi.nlm.nih.gov/pubmed/21304068?dopt=AbstractPlus
330. Food and Drug Administration. FDA drug safety communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function. Silver Spring, MD; 2016 Apr 8. Available from FDA website. http://www.fda.gov/downloads/Drugs/DrugSafety/UCM494140.pdf
331. Rachmani R, Slavachevski I, Levi Z et al. Metformin in patients with type 2 diabetes mellitus: reconsideration of traditional contraindications. Eur J Intern Med. 2002; 13:428. http://www.ncbi.nlm.nih.gov/pubmed/12384131?dopt=AbstractPlus
332. Kamber N, Davis WA, Bruce DG et al. Metformin and lactic acidosis in an Australian community setting: the Fremantle Diabetes Study. Med J Aust. 2008; 188:446-9. http://www.ncbi.nlm.nih.gov/pubmed/18429709?dopt=AbstractPlus
333. Roussel R, Travert F, Pasquet B et al. Metformin use and mortality among patients with diabetes and atherothrombosis. Arch Intern Med. 2010; 170:1892-9. http://www.ncbi.nlm.nih.gov/pubmed/21098347?dopt=AbstractPlus
334. Ekström N, Schiöler L, Svensson AM et al. Effectiveness and safety of metformin in 51 675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register. BMJ Open. 2012; 2:. http://www.ncbi.nlm.nih.gov/pubmed/22798258?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3400073&blobtype=pdf
335. American College of Radiology (ACR) Committee on Drugs and Contrast Media. ACR manual on contrast media: metformin. 2016. Available at ACR website. Accessed 2016 Aug 4. http://www.acr.org/~/media/ACR/Documents/PDF/QualitySafety/Resources/Contrast%20Manual/2016_Contrast_Media.pdf
336. . In brief: New recommendations for use of metformin in renal impairment. Med Lett Drugs Ther. 2016; 58:51.
340. Inker LA, Astor BC, Fox CH et al. KDOQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for the Evaluation and Management of CKD. AM J Kidney Dis. 2014; 63(5):713-35. http://www.ncbi.nlm.nih.gov/pubmed/24647050?dopt=AbstractPlus
341. National Kidney Foundation. KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 update. AM J Kidney Dis. 2012; 60(5):850-86. http://www.ncbi.nlm.nih.gov/pubmed/23067652?dopt=AbstractPlus
350. Bristol-Myers Squibb Company. Glucophage (metformin hydrochloride) tablets and Glucophage XR (metformin hydrochloride) prescribing information. Princeton, NJ; 2018 May.
351. Bristol-Myers Squibb Company. Glucophage (metformin hydrochloride) tablets and Glucophage XR (metformin hydrochloride) patient information. Princeton, NJ; 2018 May.
352. Merck. Janumet XR (sitagliptin/extended-release metformin hydrochloride) tablets prescribing information. Whitehouse Station, NJ; 2018 Feb.
355. Merck. Segluromet (ertugliflozin and metformin hydrochloride) tablets prescribing information. Whitehouse Station, NJ; 2018 Oct.
360. Richy FF, Sabidó-Espin M, Guedes S et al. Incidence of lactic acidosis in patients with type 2 diabetes with and without renal impairment treated with metformin: a retrospective cohort study. Diabetes Care. 2014; 37:2291-5. http://www.ncbi.nlm.nih.gov/pubmed/24879835?dopt=AbstractPlus
361. Kraut JA, Madias NE. Lactic acidosis. N Engl J Med. 2014; 371:2309-19. http://www.ncbi.nlm.nih.gov/pubmed/25494270?dopt=AbstractPlus
362. AstraZeneca Pharmaceuticals. Xigduo XR (dapagliflozin and extended-release metformin hydrochloride) tablets prescribing information. Wilmington, DE; 2018 Oct.
363. AstraZeneca Pharmaceuticals. Xigduo XR (dapagliflozin and extended-release metformin hydrochloride) medication guide. Wilmington, DE; 2018 Oct.
368. AstraZeneca. Kombiglyze XR (saxagliptin and metformin HCl extended-release) tablets prescribing information. Wilmington, DE; 2014 Jun.
369. AstraZeneca. Kombiglyze XR (saxagliptin and metformin HCl extended-release) tablets medication guide. Wilmington, DE; 2014 Jun.
370. Janssen Pharmaceuticals, Inc. Invokamet/Invokamet XR (canagliflozin and immediate- or extended-release metformin hydrochloride) tablets prescribing information. Titusville, NJ; 2018 Oct.
371. Janssen Pharmaceuticals, Inc. Invokamet/Invokamet XR (canagliflozin and immediate- or extended-release metformin hydrochloride) medication guide. Titusville, NJ; 2018 Oct.
372. Boehringer Ingelheim Pharmaceuticals, Inc. Synjardy (empagliflozin and metformin hydrochloride) tablets prescribing information. Ridgefield, CT; 2018 Oct.
373. Boehringer Ingelheim Pharmaceuticals, Inc. Synjardy (empagliflozin and metformin hydrochloride) medication guide. Ridgefield, CT; 2018 Oct.
374. Boehringer Ingelheim Pharmaceuticals, Inc. Synjardy XR (empagliflozin and metformin hydrochloride extended-release) tablets prescribing information. Ridgefield, CT; 2018 Oct.
375. Boehringer Ingelheim Pharmaceuticals, Inc. Synjardy XR (empagliflozin and metformin hydrochloride extended-release) medication guide. Ridgefield, CT; 2018 Oct.
376. Boehringer Ingelheim Pharmaceuticals, Inc. Jentadueto (linagliptin and immediate-release metformin hydrochloride) tablets prescribing information. Ridgefield, CT; 2017 Aug.
377. Boehringer Ingelheim Pharmaceuticals, Inc. Jentadueto (linagliptin and immediate-release metformin hydrochloride) tablets medication guide. Ridgefield, CT; 2017 Aug.
378. Boehringer Ingelheim Pharmaceuticals, Inc. Jentadueto XR (linagliptin and extended-release metformin hydrochloride) tablets prescribing information. Ridgefield, CT; 2019 Jul.
379. Boehringer Ingelheim Pharmaceuticals, Inc. Jentadueto XR (linagliptin and extended-release metformin hydrochloride) tablets medication guide. Ridgefield, CT; 2019 Jul.
598. Garber AJ, Abrahamson MJ, Barzilay JI et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endorinology on the comprehensive type 2 diabetes management algorithm - 2019 executive summary. Endocr Pract. 2019; 25:69-100. http://www.ncbi.nlm.nih.gov/pubmed/30742570?dopt=AbstractPlus
602. American Diabetes Association. 6. Glycemic targets: standards of medical care in diabetes-2019. Diabetes Care. 2019; 42:S61-S70. http://www.ncbi.nlm.nih.gov/pubmed/30559232?dopt=AbstractPlus
604. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2019. Diabetes Care. 2019; 42:S90-S102. http://www.ncbi.nlm.nih.gov/pubmed/30559235?dopt=AbstractPlus
605. American Diabetes Association. 10. Cardiovascular disease and risk management: standards of medical care in diabetes-2019. Diabetes Care. 2019; 42:S103-S123. http://www.ncbi.nlm.nih.gov/pubmed/30559236?dopt=AbstractPlus
609. American Diabetes Association. 14. Management of diabetes in pregnancy: standards of medical care in diabetes-2019. Diabetes Care. 2019; 42:S165-S172. http://www.ncbi.nlm.nih.gov/pubmed/30559240?dopt=AbstractPlus
610. Takeda. Kazano (alogliptin and metformin hydrochloride) tablets, for oral use, prescribing information. Deerfield, IL; 2019 Jun.
611. Nauck MA, Ellis GC, Fleck PR et al. Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo-controlled study. Int J Clin Pract. 2009; 63:46-55. http://www.ncbi.nlm.nih.gov/pubmed/19125992?dopt=AbstractPlus
Frequently asked questions
- Is Invokana the same as metformin?
- How long does glucophage/Metformin stay in your system?
- What are the ingredient drugs contained in Qternmet XR?
More about metformin
- Side Effects
- During Pregnancy or Breastfeeding
- Dosage Information
- Patient Tips
- Drug Images
- Drug Interactions
- Compare Alternatives
- Support Group
- Pricing & Coupons
- 548 Reviews
- Drug class: non-sulfonylureas
- FDA Alerts (14)
Consumer resources
Professional resources
- MetFORMIN (Professional Patient Advice)
- Metformin (FDA)
- Metformin Extended Release Tablets (FDA)
- Metformin Oral Solution (FDA)
Other brands: Glucophage, Glumetza, Glucophage XR, Fortamet, Riomet