Metformin hydrochloride is a biguanide antidiabetic agent.1, 18, 20, 22, 23, 27, 29, 33, 146
Metformin hydrochloride is used as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.1, 6, 8, 15, 16, 17, 18, 19, 20, 27, 29, 95, 166, 234, 254, 711, 712 Metformin hydrochloride immediate-release tablets and oral solution are used for this indication in adult and pediatric patients ≥10 years of a metformin hydrochloride extended-release tablets are used in adult patients.1, 257, 258, 261
Metformin may also be used in combination with a glucagon-like peptide-1 (GLP-1) agonist, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, a dipeptidyl peptidase-4 (DPP-4) inhibitor, a thiazolidinedione, a sulfonylurea, or a meglitinide (repaglinide, nateglinide) antidiabetic agent 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 medications.1, 6, 15, 18, 20, 22, 27, 29, 48, 59, 78, 95, 97, 99, 112, 166, 191, 234, 237, 238, 239, 241, 242, 248, 249, 254, 260, 352, 355, 362, 368, 370, 372, 374, 376, 378, 610, 711, 712
Metformin is commercially available in fixed combination with glyburide or glipizide for use as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus; such fixed-combination preparations may be used as initial therapy in patients whose hyperglycemia cannot be controlled by diet and exercise alone, or as second-line therapy in patients who do not achieve adequate control of hyperglycemia with metformin or sulfonylurea monotherapy.234, 254
Immediate-release metformin is commercially available in fixed combination with pioglitazone for use as an adjunct to diet and exercise in adult patients with type 2 diabetes mellitus when treatment with both pioglitazone and metformin is appropriate and also in those who are already receiving pioglitazone and metformin concurrently as separate components.260, 710
Metformin is commercially available in fixed combination with a DPP-4 inhibitor (e.g., alogliptin, linagliptin, saxagliptin, sitagliptin) for use in adult patients when treatment with both medication components is appropriate.314, 352, 368, 376, 378, 610
Metformin is commercially available in fixed combination with the SGLT2 inhibitors canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin for use when treatment with both medication components is appropriate.355, 362, 370, 372, 374 Fixed-combination products containing canagliflozin, dapagliflozin, and empagliflozin are used in adult and pediatric patients ≥10 years of a the fixed-combination product containing ertugliflozin is used in adult patients.355, 362, 370, 372, 374
Metformin also may be used as adjunctive therapy in patients with type 2 diabetes mellitus receiving insulin therapy to improve glycemic control and/or decrease the dosage of insulin needed to obtain optimal glycemic control.6, 90, 94, 95, 146, 711, 712
The manufacturer states that metformin is not used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.1, 257, 258, 261
When given as monotherapy for the management of type 2 diabetes mellitus, metformin improves glycemic control as evidenced by reductions in both basal (fasting) and postprandial glucose concentrations in patients with type 2 diabetes mellitus.1, 18, 22, 257, 258, 261
In controlled studies of up to 8 months' duration in adults with type 2 diabetes mellitus, therapy with metformin hydrochloride (0.5-3 g daily) reduced fasting and postprandial glucose concentrations substantially more than placebo.15, 31, 34, 35, 42, 60, 78, 85, 105 and HbA1c15, 35, 42, 68, 78 The antihyperglycemic effect of metformin does not appear to correlate with duration of diabetes, age, obesity, race, fasting insulin concentrations, or baseline plasma lipid concentrations.6, 20, 78, 105 In a placebo-controlled study in pediatric (10-16 years of age) patients with type 2 diabetes mellitus, the mean net reduction at week 16 in fasting plasma glucose concentrations in patients receiving metformin hydrochloride (up to 2 g daily) or placebo for up to 16 weeks was 42.9 mg/dL, compared with an increase of 21.4 mg/dL in fasting plasma glucose concentrations in the placebo group.1 The mean reduction from baseline in body weight in patients receiving metformin (mean baseline body weight: 93 kg) or placebo (mean baseline body weight: 85.7 kg) in this study was approximately 1.5 or 0.9 kg, respectively.1 In a multicenter, randomized, controlled study in newly diagnosed, asymptomatic patients with type 2 diabetes mellitus, the efficacy of metformin therapy in reducing fasting plasma glucose (target value: less than 108 mg/dL) and HbA1c concentrations in a subgroup of obese patients was similar to that of therapy with a sulfonylurea (chlorpropamide, glyburide, or glipizide) or insulin in nonobese patients; all medication regimens improved glycemic control compared with conventional (diet only) therapy.19, 166, 184 However, unlike sulfonylurea or insulin therapy, metformin therapy generally decreased plasma insulin concentrations and was not associated with weight gain or an increased incidence of hypoglycemia.19, 166, 184 In this long-term study, gradual deterioration in glycemic control occurred with all therapies over the study period despite increases in drug dosage or combined drug therapy; glycosylated hemoglobin (hemoglobin A1c; HbA1c ) concentrations generally had increased to baseline levels after 4-5 years of therapy with any of the medication regimens.184 Such deterioration in glycemic control has been attributed to a progressive decline in pancreatic β-cell function94, 95, 146, 166, 184 rather than a reduction in insulin sensitivity.166
When given in combination with one or more antidiabetic agents, metformin hydrochloride improves glycemic control compared with monotherapy with these medications.234, 254, 314, 352, 355, 362, 368, 370, 372, 374, 376, 378, 610
Metformin is commercially available in fixed combination with glyburide or glipizide for use as initial therapy in the management of patients with type 2 diabetes mellitus whose hyperglycemia cannot be controlled by diet and exercise alone.234, 254 In several comparative trials in such patients, therapy with metformin in fixed combination with glyburide or glipizide was more effective in improving glycemic control (as determined by HbA1c values, fasting plasma glucose concentrations) than monotherapy with either component.234, 254 A greater percentage of patients receiving metformin in fixed combination with glyburide or glipizide achieved strict glycemic control (e.g., HbA1c values less than 7%) than patients receiving monotherapy with metformin, glyburide, or glipizide.234, 254
Metformin in fixed combination with glyburide or glipizide also is used to improve glycemic control in patients with type 2 diabetes mellitus who are inadequately controlled with either sulfonylurea or metformin monotherapy.234, 254 In several comparative studies in such patients, greater glycemic control (as determined by HbA1c values, fasting plasma glucose concentrations) was achieved with the fixed combination of metformin and glyburide or glipizide than with metformin, glyburide, or glipizide monotherapy.234, 254 Strict glycemic control (e.g., HbA1c values less than 7%) was achieved in a greater percentage of patients receiving fixed combinations of metformin with a sulfonylurea (glyburide or glipizide) than with sulfonylurea or metformin monotherapy.234, 254 In a comparative clinical trial in pediatric patients (9-16 years of age) with type 2 diabetes mellitus, therapy with metformin in fixed combination with glyburide (titrated to a final mean daily dosage of 3.1 mg of glyburide and 623 mg of metformin hydrochloride) was no more effective in improving glycemic control (as determined by reductions in HbA1c values) than monotherapy with either component (titrated to final mean daily dosages of 6.5 mg of glyburide or 1.5 g of metformin hydrochloride).234
Immediate-release metformin is used in fixed combination with pioglitazone 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 No clinical trials have evaluated the fixed combination of immediate-release metformin and pioglitazone; efficacy and safety of the fixed combination has been established based on concurrent administration of the 2 agents given separately.260 Safety and efficacy of the fixed combination of immediate-release metformin and pioglitazone in patients with type 2 diabetes mellitus are extrapolated from clinical trials evaluating pioglitazone as add-on therapy to metformin.260
A thiazolidinedione may be added to metformin in fixed combination with glyburide in patients with type 2 diabetes mellitus who have inadequate glycemic control with the fixed combination.234 In such patients, the addition of rosiglitazone to combined therapy with metformin and glyburide has reduced fasting glucose concentrations and HbA1c values.234 Strict glycemic control (e.g., HbA1c values less than 7%) was achieved in 42.4% of patients of receiving the triple combination of metformin, glyburide, and rosiglitazone compared with 13.5% of those receiving metformin and glyburide.234
In a double-blind, controlled trial in patients with type 2 diabetes mellitus who had inadequate glycemic control with metformin monotherapy, add-on therapy with repaglinide resulted in greater glycemic control (as determined by HbA1c values, fasting plasma glucose concentrations) than metformin or repaglinide monotherapy.315 Combined therapy with metformin and repaglinide resulted in a greater reduction in HbA1c and fasting plasma glucose concentrations at a lower repaglinide dosage than with repaglinide monotherapy.315 However, the incidence of hypoglycemia with combined metformin and repaglinide therapy was higher than with repaglinide monotherapy.315 In addition, body weight increased in patients receiving repaglinide alone or combined with metformin but remained stable in those receiving metformin monotherapy.315
In a clinical trial in patients who had inadequate glycemic control (HbA1c exceeding 7.1%) with metformin monotherapy, addition of repaglinide to metformin therapy produced reductions in fasting plasma glucose concentrations and HbA1c averaging 39.6 mg/dL and 1.4%, respectively, compared with reductions averaging 4.5 mg/dL and 0.33%, respectively, with metformin alone; patients receiving repaglinide therapy alone had an increase in fasting plasma glucose concentrations of 8.8 mg/dL and a reduction of 0.38% in HbA1c.238, 249 In a clinical trial in treatment-naïve patients or patients who had previously received antidiabetic therapy (followed by a washout period of at least 2 months), combined therapy with metformin hydrochloride and nateglinide resulted in greater reductions in HbA1c and fasting plasma glucose concentrations than metformin or nateglinide monotherapy.248, 252
In another clinical trial in patients with type 2 diabetes mellitus who had inadequate glycemic control with metformin, a sulfonylurea, or insulin, the combination of pioglitazone (30 mg daily) and metformin (and withdrawal of other antidiabetic therapy) reduced fasting plasma glucose concentrations and HbA1c values compared with metformin therapy alone, regardless of whether patients were receiving lower (less than 2 g daily) or higher (2 g daily or more) dosages of metformin hydrochloride.237, 251
In a multicenter, controlled study in patients whose hyperglycemia was inadequately controlled by diet and metformin therapy, the addition of acarbose produced appreciable improvement in postprandial plasma glucose concentrations and modest improvement in HbA1c.112, 244 Fasting plasma glucose concentrations generally are not reduced by the addition of acarbose to therapy with metformin since acarbose acts principally during a meal to delay carbohydrate absorption.112, 113 Limited data suggest that combined therapy with metformin and a sulfonylurea is as effective205 or more effective193 in reducing fasting blood glucose and HbA1c concentrations than combined therapy with acarbose and a sulfonylurea; however, acarbose may provide better control of postprandial blood glucose concentrations.205
Metformin (immediate-release) is used in fixed combination with alogliptin in patients with type 2 diabetes mellitus when treatment with both drugs is appropriate.610 Efficacy and safety of this fixed combination have been established based on concurrent administration of the 2 agents given separately.610, 611
Metformin (immediate- or extended-release) is used in fixed combination with linagliptin in patients with type 2 diabetes mellitus when treatment with both drugs is appropriate.376, 378 Efficacy and safety of these fixed combinations have been established based on concurrent administration of the 2 agents given separately.376, 378
Extended-release metformin is used in fixed combination with saxagliptin in patients with type 2 diabetes mellitus when treatment with both medications is appropriate.368 Efficacy and safety of this fixed combination have been established based on concurrent administration of metformin and saxagliptin given as separate tablets.368
Metformin (immediate- or extended-release) is used in fixed combination with sitagliptin in patients with type 2 diabetes mellitus when treatment with both medications is appropriate.314, 352 Efficacy and safety of these fixed combinations have been established based on concurrent administration of the 2 agents given separately and extrapolations from clinical trials evaluating sitagliptin as add-on therapy to metformin.314, 352
Metformin is used in fixed combinations with the SGLT2 inhibitors canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin.355, 362, 370, 372, 374 These fixed-combination preparations are used in patients with type 2 diabetes mellitus when treatment with both medications is appropriate.355, 362, 370, 372, 374 Efficacy and safety of these fixed combinations have been established based on concurrent administration of the 2 medications given separately.355, 362, 370, 372, 374 In clinical trials evaluating the efficacy of the combination of an SGLT2 inhibitor and metformin, patients who received both medications had substantially greater improvements in HbA1c than when either medication component was administered alone.355, 362, 370, 372, 374
Combined therapy with insulin and metformin with or without other oral antidiabetic agents is one of several options for the management of hyperglycemia in patients with type 2 diabetes mellitus not responding adequately to oral monotherapy with metformin.711, 712
The American Diabetes Association (ADA) publishes an annual guideline on diabetes management, which provides clinical recommendations for glucose-lowering therapies in patients with type 2 diabetes mellitus.711 The current 2025 ADA guidelines state in adults with type 2 diabetes mellitus, pharmacologic strategies that provide sufficient effectiveness to achieve and maintain the intended treatment goals should be used and guided by a person-centered, shared decision-making approach.711 In general, higher-efficacy approaches have a greater likelihood of achieving glycemic goals.711 Weight management should be included as a distinct treatment goal, and other healthy lifestyle behaviors should also be considered.711 When selecting an appropriate treatment regimen, clinicians should be guided by factors such as cardiovascular and renal comorbidities, drug efficacy and adverse effects, hypoglycemic risk, presence of overweight or obesity, cost, access, and patient preferences.711 In adults with type 2 diabetes mellitus, the ADA recommends metformin for those who require initiation or intensification of glucose-lowering therapy to meet glycemic goals and do not have additional needs beyond glucose lowering and for add-on therapy to maintain HbA1cgoals.711
The American Association of Clinical Endocrinology (AACE) also publishes a guideline for the management of type 2 diabetes.712 The principles of diabetes management outlined in the guidelines are similar to those recommended by the ADA.712 The AACE guidelines state that metformin should be considered as initial or add-on therapy when reduction of HbA1c is necessary and there is no contraindication.712
Metformin 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 However, adequate and well-controlled clinical trials evaluating metformin for polycystic ovary syndrome remain limited, particularly regarding long-term efficacy, and available data are conflicting regarding the benefits of the medication in ameliorating various manifestations of the condition.289, 290, 295, 300, 302, 306
Polycystic ovary syndrome is characterized by chronic anovulation (generally manifested as oligomenorrhea or amenorrhea) and hyperandrogenism (excessive production of male hormones in women) with clinical manifestations of irregular menstrual cycles, infertility, hirsutism, acne, and dyslipidemia.289, 290, 292, 293, 294, 298, 300, 301, 304, 306, 307 While the principal etiology is unknown, insulin resistance with compensatory hyperinsulinemia is a prominent manifestation of polycystic ovary syndrome.289, 290, 292, 298, 299, 301, 303, 304, 307 Hyperinsulinemia stimulates ovarian and adrenal androgen secretion, leading to hyperandrogenism and its associated clinical manifestations.289, 290, 292, 293, 299, 303, 307 In addition, cardiovascular risk factors such as obesity and impaired glucose tolerance, including metabolic syndrome and type 2 diabetes mellitus, are present in a substantial proportion of women with polycystic ovary syndrome, making the use of insulin-sensitizing medications such as metformin reasonable in the treatment of this condition.289, 290, 292, 293, 294, 295, 297, 298, 299, 306, 307
Estrogen-progestin oral contraceptives with or without an antiandrogen (e.g., spironolactone) traditionally have been used in the long-term management of polycystic ovary syndrome; however, such therapy may worsen preexisting insulin resistance and glucose tolerance and potentially increase cardiovascular risk.293, 298, 300, 302 In a meta-analysis based on a small number of randomized, controlled trials in patients with polycystic ovary syndrome, oral contraceptive therapy (ethinyl estradiol with cyproterone acetate [not commercially available in the US] or norgestimate) for up to 12 months was associated with improvement in menstrual pattern and serum androgen concentrations compared with metformin, while metformin was more effective than oral contraceptives in reducing fasting insulin and triglyceride concentrations.290 However, a preference for either medication as maintenance therapy for polycystic ovary syndrome could not be determined because of a lack of adequate trial data.290 Another meta-analysis was unable to determine clinically important effects of metformin or thiazolidinedione therapy on metabolic or hyperandrogenism parameters such as fasting insulin or glucose concentrations, hirsutism, or hormone levels.306 Because of a lack of adequate long-term clinical trials, the effects of therapy with oral contraceptives or metformin on long-term outcomes such as diabetes, cardiovascular disease, or endometrial cancer in women with polycystic ovary syndrome have not been established.290, 302, 307
Variable effects have been reported with metformin therapy used alone or in combination with fertility-enhancing drugs (e.g., clomiphene) for the treatment of infertility in women with polycystic ovary syndrome.294, 297, 300, 301, 304, 308, 309, 310, 311 Currently available evidence suggests that metformin hydrochloride dosages of 1.5-2.5 g daily in women with polycystic ovary syndrome increase the frequency of spontaneous ovulation, menstrual cyclicity, and ovulatory response after ovarian stimulation (e.g., with clomiphene, recombinant follicle-stimulating hormone).289, 291, 292, 293, 294, 296, 299, 301, 302, 303, 304, 305, 306, 307 However, improvement in the rate of live births with metformin therapy generally has not been comparable to that associated with clomiphene therapy in such women.289, 291, 292, 293, 294, 296, 301, 302, 308, 309, 310, 312 Results of a meta-analysis also indicated improvement in ovulation and clinical pregnancy rates with combined metformin and clomiphene treatment compared with clomiphene alone in women with polycystic ovary syndrome.294, 301 However, another meta-analysis found only minimal improvement in ovulation rate and no improvement in pregnancy rate with metformin therapy.306 Some clinicians suggest that metformin therapy may be useful for inducing ovulation in women with polycystic ovary syndrome who desire pregnancy at a more distant time (e.g., more than 6 months away), and that clomiphene therapy may be preferable in those who desire to become pregnant much sooner.308 A potential advantage of metformin therapy over clomiphene for infertility is a reduced chance of twin or triplet pregnancy with metformin.308, 309, 312 Additional large, randomized, well-controlled studies are needed to establish the effectiveness of metformin alone or in combination with other therapies for treatment of infertility associated with polycystic ovary syndrome.289, 292, 294, 306, 311, 713
Metformin and other insulin-sensitizing agents (e.g., thiazolidinedione antidiabetic agents) improve insulin resistance, which leads to a reduction in androgen production in ovarian theca cells and potential beneficial effects on metabolic and hormonal abnormalities associated with polycystic ovary syndrome.289, 290, 291, 292, 293, 298, 299, 300, 302, 303, 304 Although metformin therapy has not been shown specifically to reduce cardiovascular events in women with polycystic ovary syndrome, the medication's pharmacologic and clinical effects support its use as maintenance therapy to ameliorate insulin resistance and hyperinsulinemia in such women.293, 295, 298, 299, 302, 713 As with diabetes mellitus, lifestyle changes (e.g., diet, exercise, weight loss in obese patients) are strongly recommended for the initial management of polycystic ovary syndrome; however, long-term success with such measures alone is difficult to achieve and drug therapy, including metformin, often is used for symptomatic management of this condition.295, 299, 300, 302, 304, 306, 307, 310, 713
Dispensing and Administration Precautions
Metformin hydrochloride is administered orally.1, 18, 85, 257, 258, 261 In patients receiving metformin hydrochloride immediate-release tablets at a dosage of 2 g or less daily, the medication can usually be given as 2 divided doses daily; however, in patients who require more than 2 g daily, the medication may be better tolerated if administered in 3 divided doses daily.1 Although food decreases the extent and slightly delays absorption of metformin immediate-release tablets, the manufacturer recommends that the medication be taken with meals to decrease adverse GI effects.1, 18 Immediate-release metformin hydrochloride in fixed combination with alogliptin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, linagliptin, pioglitazone, or sitagliptin is administered in divided doses daily with meals to reduce the GI effects of the metformin hydrochloride component.260, 314, 355, 370, 372, 376, 610 See the full prescribing information for additional administration instructions for the combination products.260, 314, 355, 370, 372, 376, 610
Metformin hydrochloride oral solution is administered either once or twice daily with meals.257 Dosages above 2 g daily may be better tolerated if administered in 3 divided doses daily.257 Each dose should be measured using a metformin hydrochloride oral solution specific dosing cup.257
Metformin hydrochloride extended-release tablets usually are taken with the evening meal.261 Extended-release metformin hydrochloride in fixed combination with canagliflozin, dapagliflozin, or empagliflozin is administered once daily with the morning meal.362, 370, 374 The fixed combination of extended-release metformin hydrochloride and linagliptin should be administered once daily with a meal.378 The fixed combination of extended-release metformin hydrochloride and sitagliptin should be administered once daily with a meal, preferably with the evening meal.352 Extended-release metformin hydrochloride in fixed combination with saxagliptin should be administered once daily with the evening meal.368 Extended-release metformin hydrochloride tablets and fixed-combination preparations containing the extended-release form of the medication must be swallowed whole and not chewed, cut, or crushed; inactive ingredients occasionally may be eliminated in feces as a soft mass that may resemble the original tablet.1, 258, 261, 352, 362, 368, 370, 374, 378 See the full prescribing information for additional administration instructions for the combination products.352, 369, 362, 368, 370, 374, 378
Store metformin hydrochloride immediate- and extended-release tablets at 20—25°C in light-resistant containers; excursions permitted to 15—30°C.1, 258, 261 Store metformin hydrochloride oral solution at 15—30°C.257
Available as metformin hydrochloride; dosage expressed in terms of the salt.1
Dosage of metformin hydrochloride must be individualized carefully based on patient response and tolerance.1 The goal of therapy should be to reduce both fasting glucose and glycosylated hemoglobin (hemoglobin A1c [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, 78, 85, 105, 146, 166
Since adverse GI effects with metformin appear to be dose related, it is recommended that dosage of the medication be taken with meals and increased gradually.1, 18, 53, 85, 261
Metformin Hydrochloride Monotherapy
For the management of type 2 diabetes mellitus in adults, the usual initial dosage of metformin hydrochloride as immediate-release tablets or immediate-release oral solution is 500 mg twice daily or 850 mg once daily with meals.1, 257 The daily dosage may be increased by 500 mg at weekly intervals or by 850 mg every 2 weeks based on glycemic control and tolerability.1, 257 For patients requiring additional glycemic control with metformin hydrochloride, a maximum daily dosage of 2.55 g (administered in divided doses) as immediate-release tablets or the immediate-release oral solution may be used.1, 257 Total daily dosages above 2 g may be better tolerated if divided into 3 daily doses with meals.1, 257
When metformin hydrochloride is administered as an extended-release tablet preparation in adults, the usual initial dosage is 500 mg once daily with the evening meal.258, 261, 258 Subsequent dosage of metformin hydrochloride should be adjusted according to the patient's therapeutic response, using the lowest possible effective dosa the dosage may be increased by 500 mg at weekly intervals258 or every 1 to 2 weeks261 up to a maximum of 2 g once daily with the evening meal.258, 261 Although satisfactory control of blood glucose concentrations may be achieved within a few days after dosage adjustment, the full effects of the medication may not be observed for up to 2 weeks.18 If glycemic control is not achieved at a dosage of 2 g once daily, consideration may be given to dividing the dosage into 1 g twice daily.258
In adult patients transferring from immediate-release tablets to an extended-release preparation, glycemic control should be closely monitored and dosage adjustments made accordingly.258 Patients may be transferred to extended-release preparations at the same total daily dosage given once daily, up to 2 g once daily.258, 261
For the management of type 2 diabetes mellitus in pediatric patients ≥10 years of age, the usual initial dosage of metformin hydrochloride as immediate-release tablets or the immediate-release oral solution is 500 mg twice daily given in the morning and evening with meals.1, 257 The dosage may be increased by 500 mg at weekly intervals based on glycemic control and tolerability up to a maximum of 2 g per day, given in divided doses twice daily.1, 257 Safety and efficacy of extended-release tablet preparations of metformin hydrochloride have not been established in pediatric patients; refer to labeling of specific preparations for details.258, 261
Metformin Hydrochloride Fixed-combination Therapy with a Sulfonylurea Antidiabetic Agents
If the fixed combination of metformin hydrochloride and glipizide is used as initial therapy in adult patients who have inadequate glycemic control with diet and exercise alone, the recommended initial dosage is 250 mg of metformin hydrochloride and 2.5 mg of glipizide once daily with a meal.254 In patients with more severe hyperglycemia (fasting plasma glucose concentrations of 280-320 mg/dL), an initial dosage of 500 mg of metformin hydrochloride and 2.5 mg of glipizide twice daily should be considered.254 The efficacy of metformin in fixed combination with glipizide has not been established in patients whose fasting plasma glucose concentrations exceed 320 mg/dL.254 Daily dosage may be increased in increments of one tablet (using the tablet strength at which therapy was initiated, either 250 mg of metformin hydrochloride and 2.5 mg of glipizide or 500 mg of metformin hydrochloride and 2.5 mg of glipizide ) at 2-week intervals until the minimum effective dosage required to achieve adequate blood glucose control or to a maximum dosage of 1 or 2 g of metformin hydrochloride and 10 mg of glipizide in divided doses is reached; there is no experience in clinical trials with the fixed combination using total daily dosages exceeding 2 g of metformin hydrochloride and 10 mg of glipizide as initial therapy.254 In adult patients who have inadequate glycemic control on either metformin hydrochloride or glipizide (or another sulfonylurea) alone, the recommended starting dosage is 500 mg of metformin hydrochloride and either 2.5 or 5 mg of glipizide twice daily with morning and evening meals.254 To avoid hypoglycemia, the starting dosage should not exceed the daily dosages of metformin hydrochloride or glipizide already being taken.254 The daily dosage should be titrated in increments of no more than 500 mg of metformin hydrochloride and 5 mg of glipizide until the minimum effective dosage required to achieve adequate blood glucose control or a maximum dosage of 2 g of metformin hydrochloride and 20 mg of glipizide is reached.254
In adult patients not already receiving therapy with either metformin hydrochloride or glyburide (or another sulfonylurea), the fixed combination of metformin and glyburide should be initiated using a dosage of 250 mg of metformin hydrochloride and 1.25 mg of glyburide once or twice daily with a meal.234 For patients not adequately controlled on either glyburide (or another sulfonylurea) or metformin hydrochloride alone, the recommended initial dosage of the fixed combination is metformin hydrochloride 500 mg and glyburide 2.5 mg or metformin hydrochloride 500 mg and glyburide 5 mg orally twice daily with meals.234 For patients previously treated with the combination of metformin hydrochloride and glyburide (or another sulfonylurea), the initial dosage of metformin hydrochloride and glyburide should not exceed the daily dosage of glyburide (or equivalent dose of another sulfonylurea) and metformin hydrochloride already being taken.234 Dosage of the fixed combination may be increased gradually based on glycemic control and tolerability up to a maximum daily dosage of 2 g of metformin hydrochloride and 20 mg of glyburide.234
Metformin Hydrochloride/Alogliptin Fixed-combination Therapy
Dosage of the fixed combination of metformin hydrochloride and alogliptin should be individualized based on the patient's current antidiabetic regimen, effectiveness, and tolerability.610 The maximum recommended dosage of the fixed combination of metformin hydrochloride and alogliptin (Kazano®) in adults is 2 g of metformin hydrochloride and 25 mg of alogliptin daily.610
Metformin Hydrochloride/Canagliflozin Fixed-combination Therapy
When the commercially available fixed combination of immediate- or extended-release metformin hydrochloride and canagliflozin (Invokamet®, Invokamet® XR) is used in adult and pediatric patients ≥10 years of age with type 2 diabetes mellitus in whom treatment with both medications is appropriate, the initial dosage should be based on the patient's current regimen with metformin hydrochloride and canagliflozin.370 In patients with an eGFR of at least 60 mL/minute per 1.73 m2, the dosage of the fixed-combination preparation may be gradually increased based on effectiveness and tolerability up to a maximum of 2 g of metformin hydrochloride and 300 mg of canagliflozin daily.370
In patients not currently treated with either metformin hydrochloride or canagliflozin, the recommended initial total daily dosage is 1 g of metformin hydrochloride and 100 mg of canagliflozin, administered in 2 divided doses (when given as the fixed-combination preparation containing immediate-release metformin hydrochloride) or once daily (when given as the fixed-combination preparation containing extended-release metformin hydrochloride).370
In patients currently receiving metformin hydrochloride, the recommended initial total daily dosage of the fixed combination with canagliflozin is a metformin hydrochloride dosage similar to the patient's existing total daily dosage and 100 mg of canagliflozin, administered in 2 divided doses (when given as the fixed-combination preparation containing immediate-release metformin hydrochloride) or once daily (when given as the fixed-combination preparation containing extended-release metformin hydrochloride).370 Patients who are currently receiving an evening dose of extended-release metformin hydrochloride should skip their last dose prior to initiating therapy with the fixed combination of metformin hydrochloride and canagliflozin the following morning.370
In patients currently receiving canagliflozin, the recommended initial total daily dosage of the fixed combination is 1 g of metformin hydrochloride and the same daily dosage of canagliflozin, administered in 2 divided doses (when given as the fixed-combination preparation containing immediate-release metformin hydrochloride) or once daily (when given as the fixed-combination preparation containing extended-release metformin hydrochloride).370
In patients currently receiving metformin hydrochloride and canagliflozin as separate components, the recommended initial dosage of the fixed combination is a total daily metformin hydrochloride dosage similar to the patient's existing dosage and the same daily dosage of canagliflozin, administered in 2 divided doses (when given as the fixed-combination preparation containing immediate-release metformin hydrochloride) or once daily (when given as the fixed-combination preparation containing extended-release metformin hydrochloride).370
Additional dosage guidelines are available when the fixed combination of metformin hydrochloride and canagliflozin is used concomitantly with uridine diphosphate-glucuronosyltransferase (UGT) enzyme inhibitors (e.g., rifampin, phenytoin, phenobarbital, ritonavir); see full prescribing information for additional details.370
Metformin Hydrochloride/Dapagliflozin Fixed-combination Therapy
When the commercially available fixed combination of extended-release metformin hydrochloride and dapagliflozin (Xigduo® XR) is used in adult and pediatric patients ≥10 years of age with type 2 diabetes mellitus, the recommended initial dosage is based on the patient's current regimen of metformin hydrochloride and/or dapagliflozin.362 For patients not currently receiving metformin hydrochloride and/or dapagliflozin, the recommended initial dosage of the extended-release metformin hydrochloride component is 500 mg once daily and the recommended initial dosage of the dapagliflozin component is 5 mg once daily.362 Dosage should be titrated gradually based on effectiveness and tolerability up to a maximum daily dosage of 2 g of extended-release metformin hydrochloride and 10 mg of dapagliflozin.362 Patients who are already receiving extended-release metformin hydrochloride in the evening who are switching to the fixed combination of metformin hydrochloride and dapagliflozin should skip their last dose of metformin hydrochloride before initiating therapy with the fixed combination the following morning.362
Metformin Hydrochloride/Empagliflozin Fixed-combination Therapy
Dosage of metformin hydrochloride in fixed combination with empagliflozin (Synjardy®) should be individualized based on the patient's current antidiabetic regimen.372, 374 In adult and pediatric patients ≥10 years of age, the dosage of the fixed-combination preparation may be gradually increased based on effectiveness and tolerability up to a maximum of 2 g of metformin hydrochloride and 25 mg of empagliflozin daily.372, 374 In pediatric patients ≥10 years of age, the fixed-combination of immediate-release metformin hydrochloride and empagliflozin should be used; safety and efficacy of extended-release metformin hydrochloride have not been evaluated in this population.372, 374
In patients currently receiving metformin hydrochloride, the recommended initial total daily dosage of the fixed combination is a metformin hydrochloride dosage similar to the patient's existing total daily dosage and 10 mg of empagliflozin, administered in 2 divided doses (when given as the fixed-combination preparation containing immediate-release metformin hydrochloride) or once daily (when given as the fixed-combination preparation containing extended-release metformin hydrochloride).372, 374
In patients currently receiving empagliflozin, the recommended initial total daily dosage of the fixed combination is 1 g of metformin hydrochloride and the same daily dosage of empagliflozin administered in 2 divided doses (when given as the fixed-combination preparation containing immediate-release metformin hydrochloride) or once daily (when given as the fixed-combination preparation containing extended-release metformin hydrochloride).372, 374
In patients currently receiving metformin hydrochloride and empagliflozin as separate components, the recommended initial total daily dosage of the fixed combination is a metformin hydrochloride dosage similar to the patient's existing total daily dosage and the same daily dosage of empagliflozin, administered in 2 divided doses (when given as the fixed-combination preparation containing immediate-release metformin hydrochloride) or once daily (when given as the fixed-combination preparation containing extended-release metformin hydrochloride).372, 374
Metformin Hydrochloride/Ertugliflozin Fixed-combination Therapy
When the commercially available fixed-combination preparation containing immediate-release metformin hydrochloride and ertugliflozin (Segluromet®) is used in adult patients with type 2 diabetes mellitus, the recommended initial dosage is based on the patient's current regimen of metformin hydrochloride and/or ertugliflozin.355 The dosage of the fixed combination may be increased gradually based on effectiveness and tolerability up to a maximum of 2 g of metformin hydrochloride and 15 mg of ertugliflozin daily.355
In patients currently receiving metformin hydrochloride, the recommended initial total daily dosage of the fixed combination is a metformin hydrochloride dosage similar to the patient's existing total daily dosage and 5 mg of ertugliflozin, administered in 2 divided doses.355
In patients currently receiving ertugliflozin, the recommended initial total daily dosage of the fixed combination is 1 g of metformin hydrochloride and the same daily dosage of ertugliflozin, administered in 2 divided doses.355
For patients currently receiving metformin hydrochloride and ertugliflozin as separate components, the recommended initial total daily dosage of the fixed combination is a dosage of metformin hydrochloride similar to the patient's existing total daily dosage and the same daily dosage of ertugliflozin, administered in 2 divided doses.355
Metformin Hydrochloride/Linagliptin Fixed-combination Therapy
Dosage of the fixed combination of metformin hydrochloride and linagliptin (Jentadueto®) may be increased up to a maximum of 2 g of metformin hydrochloride and 5 mg of linagliptin daily.376, 378
In adult patients not currently receiving metformin hydrochloride, the recommended initial total daily dosage of the fixed combination is 1 g of metformin hydrochloride and 5 mg of linagliptin administered in 2 divided doses (when given as the fixed-combination preparation containing immediate-release metformin hydrochloride) or once daily (when given as the fixed-combination preparation containing extended-release metformin hydrochloride).376, 378
In adult patients currently receiving metformin hydrochloride, the recommended initial total daily dosage of the fixed combination is a total daily metformin hydrochloride dosage similar to what the patient is receiving and 5 mg of linagliptin, administered in 2 divided doses (when given as the fixed-combination preparation containing immediate-release metformin hydrochloride) or once daily (when given as the fixed-combination preparation containing extended-release metformin hydrochloride).376, 378
In adult patients currently receiving metformin hydrochloride and linagliptin, the recommended initial dosage of the fixed combination of immediate-release metformin hydrochloride and linagliptin is the same as the existing total daily dosage of each component administered in 2 divided doses daily.376 In patients already receiving metformin and linagliptin or the fixed combination of immediate-release metformin and linagliptin, the recommended initial dosage of the fixed combination of extended-release metformin hydrochloride and linagliptin is a total daily metformin hydrochloride dosage similar to the patient's existing dosage and 5 mg of linagliptin administered once daily.378
Metformin Hydrochloride/Pioglitazone Fixed-combination Therapy
Dosage of the fixed combination of immediate-release metformin hydrochloride and pioglitazone (Actoplus Met®) should be based on the patient's current dosages of metformin hydrochloride and/or pioglitazone and on effectiveness and tolerability.260, 710
For adult patients in whom combination therapy with metformin and pioglitazone is considered appropriate, the usual initial dosage of the fixed combination is metformin hydrochloride 850 mg and pioglitazone 15 mg once daily.260, 710
For adult patients inadequately controlled on metformin hydrochloride monotherapy, the usual initial dosage of the fixed combination is metformin hydrochloride 850 mg and pioglitazone 15 mg once or twice daily (depending on the dosage of metformin hydrochloride already being taken).260, 710
For adult patients inadequately controlled on pioglitazone monotherapy, the usual initial dosage of the fixed combination is metformin hydrochloride 850 mg and pioglitazone 15 mg once daily.260, 710
For patients switching from combination therapy with metformin hydrochloride and pioglitazone given as separate tablets, the dosage of the fixed combination should be as close as possible to the metformin hydrochloride and pioglitazone dosages already being taken.260, 710
For adult patients with New York Heart Association (NYHA) class I or II congestive heart failure, the recommended initial dosage of the fixed combination is metformin hydrochloride 850 mg and pioglitazone 15 mg once daily.260, 710 Initiation of the fixed combination of metformin and pioglitazone is contraindicated in patients with NYHA class III or IV congestive heart failure.260, 710
Dosage of the fixed combination should be titrated gradually as needed based on adequacy of therapeutic response and tolerability up to a maximum daily dosage of 2.55 g of metformin hydrochloride and 45 mg of pioglitazone.260, 710 When used concomitantly with gemfibrozil or other strong cytochrome P-450 2C8 inhibitors, the maximum recommended dosage is metformin hydrochloride 850 mg and pioglitazone 15 mg.260, 710 Metformin hydrochloride dosages exceeding 2 g daily may be better tolerated if given in 3 divided doses daily.260, 710
Metformin Hydrochloride/Saxagliptin Fixed-combination Therapy
Dosage of extended-release metformin hydrochloride in fixed combination with saxagliptin hydrochloride (Kombiglyze® XR) should be individualized based on the patient's current antidiabetic regimen, clinical response, and tolerability.368
When the fixed-combination preparation is used in patients who need 5 mg of saxagliptin and who are not currently treated with metformin, the recommended initial dosage of the fixed combination is 500 mg of extended-release metformin hydrochloride and 5 mg of saxagliptin once daily; dosage should be increased gradually to reduce adverse GI effects of metformin.368
In patients treated with metformin, the recommended starting dosage of the fixed-combination preparation should provide metformin at the dose already being taken, or the nearest therapeutically appropriate dose.368 Following a switch from immediate-release to extended-release metformin, glycemic control should be closely monitored and dosage adjustments made accordingly.368
In patients who need saxagliptin 2.5 mg daily in combination with metformin extended-release, the recommended dosage of the fixed combination is 1 g of extended-release metformin hydrochloride and 2.5 mg of saxagliptin daily.368 Patients who require 2.5 mg of saxagliptin who are either metformin naïve or require a dose of metformin hydrochloride exceeding 1 g should use the individual components.368
The maximum recommended dosages of extended-release metformin hydrochloride and saxagliptin in fixed combination are 2 g of extended-release metformin hydrochloride and 5 mg of saxagliptin daily.368
When the fixed-combination preparation containing extended-release metformin hydrochloride and saxagliptin is used concomitantly with a potent cytochrome P-450 isoenzyme 3A4/5 (CYP3A4/5) inhibitor (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin), dosage of saxagliptin should be limited to 2.5 mg once daily.368
Metformin Hydrochloride/Sitagliptin Fixed-combination Therapy
Dosage of the fixed-combination preparation containing immediate- or extended-release metformin hydrochloride and sitagliptin (Janumet® or Janumet® XR) should be individualized based on the patient's current antidiabetic regimen, effectiveness, and tolerability to a maximum total daily dosage of 2 g of metformin hydrochloride and 100 mg of sitagliptin.314, 352
When the fixed combination containing immediate-release metformin hydrochloride and sitagliptin is used in adult patients not currently receiving metformin hydrochloride, the recommended initial dosage is 500 mg of immediate-release metformin hydrochloride and 50 mg of sitagliptin twice daily.314 When the fixed combination containing extended-release metformin hydrochloride and sitagliptin is used in adult patients not currently receiving metformin hydrochloride, the recommended initial dosage is 1 g of extended-release metformin hydrochloride and 100 mg of sitagliptin once daily.352 The dosage should be increased gradually to reduce adverse GI effects associated with the metformin hydrochloride component.314, 352
When the fixed combination of immediate-release metformin hydrochloride and sitagliptin is used in adult patients currently receiving metformin hydrochloride, the recommended initial dosage is 500 mg of metformin hydrochloride and 50 mg of sitagliptin or 1 g of metformin hydrochloride and 50 mg of sitagliptin twice daily, depending on the patient's existing dosage of metformin hydrochloride.314
When the fixed combination of immediate-release metformin hydrochloride and sitagliptin is used in adult patients currently receiving immediate-release metformin hydrochloride 850 mg twice daily, the recommended initial dosage of the fixed combination is 1 g of immediate-release metformin hydrochloride and 50 mg of sitagliptin twice daily.314
When the fixed combination of extended-release metformin hydrochloride and sitagliptin is used in adult patients currently receiving metformin hydrochloride, the recommended initial dosage of the fixed combination is 1 g of extended-release metformin hydrochloride and 100 mg of sitagliptin or 2 g of extended-release metformin hydrochloride and 100 mg of sitagliptin once daily, depending on the patient's existing dosage of metformin hydrochloride.352
In adult patients currently receiving immediate-release metformin hydrochloride 850 or 1000 mg twice daily, the recommend initial dosage of the fixed combination containing extended-release metformin hydrochloride and sitagliptin is 2 g of extended-release metformin hydrochloride and 100 mg of sitagliptin once daily.352
The same total daily dosage of sitagliptin and metformin hydrochloride should be maintained when transitioning between the fixed combination of immediate-release metformin hydrochloride and sitagliptin and the fixed combination of extended-release metformin hydrochloride and sitagliptin.352
The safety and efficacy of transferring from therapy with other oral antidiabetic agents to the fixed combination of immediate- or extended-release metformin hydrochloride and sitagliptin have not been specifically established in clinical studies.314, 352 Any change in the therapy of patients with type 2 diabetes mellitus should be undertaken with caution and appropriate monitoring, as changes in glycemic control can occur.314, 352
In women with polycystic ovary syndrome†, metformin hydrochloride dosages of 1.5-2.25 g daily in divided doses have been used to ameliorate symptoms of insulin resistance and hyperinsulinemia and to increase the frequency of spontaneous ovulation, menstrual cyclicity, and ovulatory response after ovarian stimulation.289, 291, 292, 294, 296, 299, 300, 301, 302, 303, 305, 306, 307, 713
Avoid use of metformin hydrochloride, both as monotherapy and in fixed-combination products, in patients with clinical or laboratory evidence of hepatic disease or impairment.1, 234, 254, 257, 258, 260, 261, 314, 352, 355, 362, 368, 370, 372, 374, 376, 378, 610
Metformin Hydrochloride Monotherapy
The manufacturers and FDA state that initiation of metformin therapy is not recommended in patients with an eGFR between 30-45 mL/minute per 1.73 m2 and the benefits and risks of continuing the medication should be assessed in those already receiving metformin whose eGFR falls below 45 mL/minute per 1.73 m2.1, 257, 258, 261, 330, 336 The manufacturers and FDA state metformin is contraindicated in patients with an eGFR <30 mL/minute per 1.73 m2; discontinue use if eGFR falls below 30 mL/minute per 1.73 m2.1, 257, 258, 261, 330, 336
Initiation of the fixed-combination of metformin hydrochloride and a sulfonylurea (i.e., glipizide, glyburide) is not recommended in patients with an eGFR of 30—45 mL/minute per 1.73 m2; assess the benefit and risk of continuing therapy if the eGFR falls below 45 mL/minute per 1.73 m2.234, 254 Use is contraindicated in patients with an eGFR <30 mL/minute per 1.73 m2; discontinue use if eGFR falls below 30 mL/minute per 1.73 m2.234, 254
Metformin Hydrochloride/Alogliptin Fixed-combination Therapy
The fixed combination of metformin hydrochloride and alogliptin is not recommended in patients with an eGFR of 30—59 mL/minute per 1.73 m2 and is contraindicated in patients with an eGFR <30 mL/minute per 1.73 m2 ; discontinue use if eGFR drops below 30 mL/minute per 1.73 m2 during treatment.610
Metformin Hydrochloride/Canagliflozin Fixed-combination Therapy
In patients with an eGFR 45 to <60 mL/minute per 1.73 m2 , the maximum total daily dosage of canagliflozin is 100 mg.370 Initiation of the fixed combination of metformin hydrochloride and canagliflozin is not recommended in patients with an eGFR <45 mL/minute per 1.73 m2.370 Assess the benefit and risk of continuing the fixed combination of metformin hydrochloride and canagliflozin in patients with an eGFR 30 to <45 mL/minute per 1.73 m2; the maximum total daily dosage of canagliflozin is 100 mg in this population.370 Use is contraindicated is patients with an eGFR <30 mL/minute per 1.73 m2; discontinue use if eGFR drops below 30 mL/minute per 1.73 m2 during treatment.370
Metformin Hydrochloride/Dapagliflozin Fixed-combination Therapy
Initiation of the fixed-combination of metformin hydrochloride and dapagliflozin is not recommended in patients with an eGFR of 30—45 mL/minute per 1.73 m2; assess the benefit and risk of continuing therapy if the eGFR falls persistently below this level.362 Use is contraindicated in patients with an eGFR <30 mL/minute per 1.73 m2 due to the metformin component; discontinue use if eGFR drops below 30 mL/minute per 1.73 m2 during treatment.362
Metformin Hydrochloride/Empagliflozin Fixed-combination Therapy
Initiation of the fixed combination of metformin hydrochloride and empagliflozin is not recommended in patients with an eGFR <45 mL/minute per 1.73 m2; use is contraindicated in patients with an eGFR <30 mL/minute per 1.73 m2discontinue use if eGFR drops below 30 mL/minute per 1.73 m2 during treatment.372, 374
Metformin Hydrochloride/Ertugliflozin Fixed-combination Therapy
Use of the fixed combination of metformin hydrochloride and ertugliflozin is not recommended in patients with an eGFR < 45 mL/minute per 1.73 m2; use is contraindicated in patients with an eGFR <30 mL/minute per 1.73 m2, with end stage-renal disease, or on dialysis.355
Metformin Hydrochloride/Linagliptin Fixed-combination Therapy
Initiation of the fixed combination of metformin hydrochloride and linagliptin is not recommended in patients with an eGFR 30—45 mL/minute per 1.73 m2.376, 378 In patients whose eGFR falls below 45 mL/minute per 1.73 m2, assess the benefit and risk of continuing therapy.376, 378 Use of the fixed combination of metformin hydrochloride and linagliptin is contraindicated in patients with an eGFR <30 mL/minute per 1.73 m2; discontinue use if the eGFR falls below 30 mL/minute per 1.73 m2.376, 378
Metformin Hydrochloride/Pioglitazone Fixed-combination Therapy
Initiation of the fixed combination of metformin hydrochloride and pioglitazone is not recommended in patients with an eGFR 30—45 mL/minute per 1.73 m2.260, 710 In patients whose eGFR falls below 45 mL/minute per 1.73 m2, assess the benefit and risk of continuing therapy.260, 710 Use of the fixed combination of metformin hydrochloride and pioglitazone is contraindicated in patients with an eGFR <30 mL/minute per 1.73 m2; discontinue use if the eGFR falls below 30 mL/minute per 1.73 m2.260, 710
Metformin Hydrochloride/Saxagliptin Fixed-combination Therapy
No dosage adjustment is necessary in patients with an eGFR ≥45 mL/minute per 1.73 m2.368 In patients whose eGFR falls below 45 mL/minute per 1.73 m2, assess the benefit and risk of continuing therapy.368 Initiation of the fixed combination of metformin hydrochloride and saxagliptin is not recommended in patients with an eGFR 30—45 mL/minute per 1.73 m2.368 The fixed combination of metformin hydrochloride and saxagliptin is contraindicated in patients with an eGFR <30 mL/minute per 1.73 m2; discontinue use if the eGFR falls below 30 mL/minute per 1.73 m2.368
Metformin Hydrochloride/Sitagliptin Fixed-combination Therapy
Use of the fixed combination of immediate-release metformin hydrochloride and sitagliptin is not recommended in patients with an eGFR 30—45 mL/minute per 1.73 m2.314 Use of the fixed combination of immediate-release metformin hydrochloride and sitagliptin is contraindicated in patients with an eGFR <30 mL/minute per 1.73 m2.314
Initiation of the fixed combination of extended-release metformin hydrochloride and sitagliptin is not recommended in patients with an eGFR 30—45 mL/minute per 1.73 m2.352 In patients whose eGFR later falls below 45 mL/minute per 1.73 2, assess the benefit and risk of continuing therapy and limit the dosage of the sitagliptin component to 50 mg once daily.352 Use of the fixed combination of extended-release metformin hydrochloride and sitagliptin is contraindicated in patients with an eGFR <30 mL/minute per 1.73 m2; discontinue use if the eGFR falls below 30 mL/minute per 1.73 m2.352
Metformin should be used with caution in geriatric patients since aging is associated with a greater frequency of reduced renal, hepatic, and cardiac function, and of concomitant disease or other therapy, resulting in a higher risk of lactic acidosis.1, 165, 257, 258, 260, 261 Initial dosages of metformin hydrochloride in geriatric patients should be conservative (initiated at the low end of the dosage range) and should be titrated carefully;1, 165, 254, 257, 258, 261, 314 limited data suggest reducing dosage by approximately 33% in geriatric patients.174 In addition, renal function should be monitored more frequently in geriatric patients to determine the appropriate dosage of metformin hydrochloride.1, 164, 165, 257, 258, 260, 261 Any dosage adjustment in geriatric patients should be based on a careful assessment of renal function.1, 257, 258, 260, 261
Cases of metformin-associated lactic acidosis reported during postmarketing experience have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias.1, 254, 257, 258, 261 Lactic acidosis often has a subtle onset and may be accompanied by only nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific and unexplained abdominal distress with nausea and vomiting or diarrhea.1, 32, 62, 119, 234, 257, 258, 260, 261, 314 Associated hypothermia (e.g., cold hands or feet), hypotension (e.g., dizziness or lightheadedness), and resistant bradyarrhythmias with more marked acidosis also may occur.1, 62, 117, 260 Lactic acidosis constitutes a medical emergency requiring immediate hospitalization and treatment;1, 314, 352, 355 in such cases, metformin should be discontinued and general supportive therapy (e.g., volume expansion, diuresis) initiated immediately.1, 32, 62, 119, 260, 314, 352, 355, 361 Prompt hemodialysis is also recommended.1, 23, 32, 62, 117, 119, 257, 258, 260, 261, 314, 352, 355
Metformin-associated lactic acidosis has been characterized by elevated blood lactate concentrations (exceeding 45 mg/dL), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate/pyruvate ratio.1, 257, 258, 261 The manufacturer states when metformin has been implicated as the cause of lactic acidosis, plasma metformin concentrations exceeding 5 mcg/mL generally have been observed.1, 234, 254, 257, 258, 261, 314 However, plasma metformin concentrations may not be an accurate indication of tissue accumulation of the medication in patients with metformin-induced lactic acidosis, and increased plasma concentrations of lactic acid or lactic acidosis have been demonstrated during metformin therapy despite normal plasma concentrations of the medication.51, 64, 96, 146, 158, 320 Patients with lactic acidosis and normal plasma metformin concentrations also may have other conditions contributing to the development of lactic acidosis (e.g., hypoxia, dehydration).96, 158, 320 Some observational data suggest neither plasma metformin concentrations nor plasma lactate concentrations are related to mortality in patients with lactic acidosis receiving metformin.320, 322
The risk of lactic acidosis appears to increase with the degree of renal impairment and the patient's a therefore, the risk of this condition can be minimized by periodic monitoring of renal function and cautious dosage selection (i.e., initiating therapy at the low end of the dosage range).1, 32, 62, 63, 65, 76, 85, 91, 93, 96, 119, 123, 124, 158, 164, 165, 234, 258, 287 Other risk factors for lactic acidosis include concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years or older, undergoing radiological procedures with intravascular contrast agents, surgery and other procedures, hypoxic states, excessive alcohol consumption, and hepatic impairment.234, 254, 260 Metformin therapy should be withheld promptly in patients with any condition associated with hypoxemia, sepsis, or dehydration, or in any patient who becomes acutely unwell.1, 62, 63, 93, 234, 254, 257, 258, 261 Therapy with metformin alone or in fixed combinations should also be avoided in patients with clinical or laboratory evidence of hepatic impairment since elimination of lactate may be reduced substantially in such patients.1, 63, 65, 85, 91, 93, 156, 158, 234, 254, 257, 258, 260, 261, 314, 352, 355, 362, 368, 370, 372, 374, 378, 376, 610 Patients should be advised not to consume excessive amounts of alcohol, either acutely or chronically, since alcohol may potentiate the effects of metformin on lactate metabolism by decreasing hepatic gluconeogenesis.1, 63, 76, 91, 93, 158, 234, 254, 257, 258, 260, 261, 314, 352, 355
The manufacturers, FDA, and other clinicians state metformin-containing therapy should be discontinued before or at the time of an intravascular (e.g., IV, intra-arterial) iodinated contrast imaging procedure in patients with an eGFR of 30-60 mL/minute per 1.73 m2, history of liver disease, alcohol use disorder, or heart failure.1, 257, 258, 260, 261, 314, 352, 355, 362, 368, 370, 372, 374, 376, 378, 610 Therapy with metformin-containing preparations should be withheld temporarily in patients undergoing surgery.1, 62, 63, 93, 158, 254, 257, 258, 260, 261, 314, 330, 336, 352, 355, 610 Renal function should be evaluated 48 hours after the imaging procedure and metformin therapy may be reinstituted if renal function is stable.1, 257, 260, 314, 330, 352, 355, 610
Patients and clinicians should be aware of the importance of lactic acidosis symptoms (e.g., malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific and unexplained abdominal distress with nausea and vomiting or diarrhea), and patients should be instructed to notify their clinician immediately if these symptoms occur;1, 260 metformin should be discontinued until a clinician has evaluated the patient's condition.1, 257, 258, 261
Asymptomatic decreases in serum vitamin B12 concentration were reported in about 7-9% of patients receiving metformin alone,1, 18, 314 and in about 6% of those receiving metformin concomitantly with a sulfonylurea antidiabetic agent, during a 29-week controlled clinical trial.18 Such decreases may be related to interference with absorption of vitamin B12 from B12-intrinsic factor complex;1, 70, 314 however, they rarely are associated with anemia and are rapidly reversible following discontinuation of metformin or supplementation with vitamin B12.1, 6, 20, 70, 77, 82, 257, 258, 261 Some patients (i.e., those with an inadequate absorption or intake of vitamin B12 or calcium) appear to be predisposed to developing decreased vitamin B12 concentrations.1, 148, 168, 257, 260
Since decreases in serum vitamin B12 concentrations have been reported in some patients receiving metformin, hematologic parameters (e.g., hemoglobin, hematocrit, erythrocyte indices) should be evaluated prior to initiation of metformin therapy and at least annually during treatment..1, 85, 257, 261 Vitamin B12 concentrations should be monitored every 2-3 years in patients receiving metformin therapy and any abnormalities managed.1, 257, 258, 261
Serum folic acid concentrations do not appear to decrease substantially in patients receiving metformin therapy.70, 82 Megaloblastic anemia has been reported rarely in patients receiving metformin.18, 114, 314 No increased incidence of neuropathy has been observed in patients receiving the drug.18, 114, 123
Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
Insulin and insulin secretagogues (e.g., sulfonylurea antidiabetic agents) are known to cause hypoglycemia.1, 257, 258, 261 Metformin hydrochloride may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue.1, 257, 258, 261 A lower dosage of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with metformin hydrochloride.1, 257, 258, 261
The manufacturer states that there have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin.1, 257, 258, 261
When metformin hydrochloride is used in fixed combination with other medications (e.g., sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 [DPP-4] inhibitors, meglitinides, sodium-glucose cotransporter 2 [SGLT2] inhibitors), the cautions, precautions, contraindications, and drug interactions associated with these concomitant agents must be considered in addition to those associated with metformin.234, 254, 260, 314, 352, 355, 362, 368, 370, 372, 374, 376, 378
Limited data with metformin hydrochloride in pregnant females are not sufficient to determine a medication-associated risk for major birth defects or miscarriage.1, 257, 258, 261 Available studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes.1, 257, 258, 261 Limited data from uncontrolled or retrospective studies are conflicting with regard to the effects of long-term maternal therapy with metformin hydrochloride (1.5-3 g daily) on neonatal morbidity (e.g., congenital malformations) and mortality.92, 115
Reproduction studies in rats and rabbits given metformin hydrochloride dosages of 600 mg/kg daily (about twice the maximum recommended human daily dosage based on body surface area or about 3 and 6 times the maximum recommended human daily dosage of extended-release tablets [2 g] based on body surface area comparisons with rats and rabbits, respectively) have not revealed evidence of harm (e.g., teratogenicity) to the fetus.1, 234, 254, 314 Determination of fetal concentrations of metformin suggest that a partial placental barrier to the medication exists.1, 257, 258, 261, 314
Poorly controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications.234, 260 Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity.234, 254, 257, 258, 261 Since abnormal maternal blood glucose concentrations during pregnancy may be associated with a higher incidence of congenital abnormalities,1, 115 most experts recommend that insulin be used during pregnancy to maintain optimum control of blood glucose concentration.1, 18, 92
Metformin is distributed into milk in lactating rats.1 Limited data indicate that metformin is distributed into breast milk in humans.1, 257, 258, 260, 284, 261, 285, 286 However, there is insufficient information to determine the effects of metformin on the breast-fed infant and no available information on the effects of metformin on milk production.1, 257, 258, 261
Published clinical lactation studies report that metformin present in human milk resulted in infant doses approximately 0.11—1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1.1, 257, 258, 261 However, these studies were not designed to establish the risk of metformin use during lactation; limited adverse event data were collected in infants.1, 257, 258, 261 In a study in 7 nursing females who received metformin hydrochloride (median dosage 1500 mg daily), the mean milk-to-plasma ratio for metformin was 0.35 and the overall average concentration in milk over the dosing interval was 0.27 mg/L.284, 285 Metformin was present in low or undetectable amounts in the plasma of 4 breast-fed infants, and no adverse effects were noted in 6 infants that were evaluated.285 In another study, mean peak and trough metformin concentrations in 4 nursing women receiving metformin hydrochloride 500 mg twice daily were 1.06 and 0.42 mcg/mL, respectively, in serum and 0.42 and 0.39 mcg/mL, respectively, in breast milk.284, 286 The mean milk-to-serum ratio was 0.63 and the mean estimated infant dose as a percentage of the mother's weight-adjusted dose was 0.65%.284, 286 Blood glucose concentrations obtained in 3 infants 4 hours after breastfeeding were within normal limits (47-77 mg/dL).284, 286
The developmental and health benefits of breastfeeding should be considered along with mother's clinical need for the medication and potential adverse effects on the breast-fed child (e.g., hypoglycemia).234, 254 Breast-fed infants should be monitored for signs of hypoglycemia (e.g., jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, seizures).234, 254
Females and Males of Reproductive Potential
The potential for unplanned pregnancy should be discussed with premenopausal females since metformin-containing therapy may result in ovulation in some anovulatory females.1, 257, 258, 261
Safety and effectiveness of immediate-release metformin hydrochloride tablets and oral solution have been established in pediatric patients 10—16 years of age.1, 257 Safety and effectiveness of immediate-release metformin hydrochloride tablets and oral solution have not been established in pediatric patients <10 years of age.1, 257 Use of immediate-release metformin hydrochloride tablets and oral solution is supported by evidence from adequate and well-controlled studies in adults with additional data from a controlled clinical study in pediatric patients 10—16 years of age with type 2 diabetes mellitus, which demonstrated a similar response in glycemic control to that seen in adults.1, 257 In this study, adverse effects were similar to those described in adults.1, 257 A maximum daily dosage of 2 g of immediate-release metformin hydrochloride tablets or oral solution is recommended.1, 257
Safety and effectiveness of extended-release metformin hydrochloride tablets in pediatric patients have not been established.258, 261
Controlled clinical trials evaluating metformin hydrochloride immediate-release and extended-release tablets did not include sufficient numbers of geriatric patients to determine whether geriatric patients respond differently to metformin than younger patients, although other reported clinical experience has not identified any differences in response between geriatric and younger patients.1, 257, 258, 261, 314
In general, dosage selection for a geriatric patient should be cautious, usually starting at the low end of the dosage range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other medication therapy and the higher risk of lactic acidosis.1, 257, 258, 261 In addition, renal function should be monitored more frequently in geriatric patients and care should be taken in dosage selection;1 such patients generally should not receive the maximum recommended dosage of metformin hydrochloride.1, 85, 174, 234, 254, 257, 258, 261, 314
Use of metformin hydrochloride in patients with hepatic impairment has been associated with some cases of lactic acidosis.1, 257, 258, 261 This may be due to impaired lactate clearance resulting in higher lactate blood levels.1, 257, 258, 261 No pharmacokinetic studies have been performed in patients with hepatic impairment.1, 257, 258, 261 Use of metformin hydrochloride is not recommended in patients with clinical or laboratory evidence of hepatic disease/impairment.1, 257, 258, 261
Metformin hydrochloride is substantially excreted renally, and risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment.1, 257, 258, 261 In patients with decreased renal function, the half-life of metformin is prolonged and renal clearance is decreased.1, 257 Following a single-dose administration of extended-release metformin hydrochloride in patients with mild and moderate renal impairment, the oral and renal clearance were decreased by 33% and 50% and 16% and 53%, respectively.261 Metformin peak and systemic exposure was 27% and 61% greater in patients with mild renal impairment and 74% and 2.36-fold greater in patients with moderate renal impairment, respectively, compared to healthy patients.261 Metformin hydrochloride is contraindicated in severe renal impairment (eGFR <30 mL/minute per 1.73 m2).1, 257, 258, 261
The most common adverse effects of immediate-release metformin hydrochloride tablets (>5%) are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.1
The most common adverse effects of metformin hydrochloride oral solution are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.257
The most common adverse effects of extended-release metformin hydrochloride tablets (>5%) are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.258
Drugs Affecting or Affected by Transport Systems
Concomitant use of medications (e.g., ranolazine, vandetanib, dolutegravir, cimetidine) that interfere with common renal tubular transport systems involved in the renal elimination of metformin hydrochloride (e.g., organic cationic transporter [OCT] 2/multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis.1, 257, 258, 261 Consider the benefits and risk of concomitant use of such medications with metformin.1, 257, 258, 261
Drugs That May Antagonize Hypoglycemic Effects
Medications that cause hyperglycemia and may lead to loss of glycemic control in patients with diabetes mellitus include thiazide and other diuretics, corticosteroids, phenothiazines, thyroid preparations, estrogens, oral contraceptives, phenytoin, niacin, sympathomimetics, calcium-channel blocking agents, and isoniazid.1, 80, 85, 91, 120, 121, 139, 143, 151, 152, 153, 154, 159, 160, 234, 254, 257, 258, 261 When such medications are added to or withdrawn from therapy in patients receiving oral antidiabetic agents, patients should be observed closely for evidence of altered glycemic control.1, 234, 254
Beta-Adrenergic Blocking Agents
In single-dose studies in healthy individuals, concomitant administration of metformin and propranolol did not alter the pharmacokinetics of either medication.1 However, several potential interactions between β-adrenergic blocking agents and oral antidiabetic agents (e.g., sulfonylureas, metformin) exist.91, 127, 143, 153, 159, 160, 198β-Adrenergic blocking agents may impair glucose tolerance;73, 143, 152, 153, 159 increase the frequency or severity of hypoglycemia;127 block hypoglycemia-induced tachycardia but not hypoglycemic sweating, which may actually be increased;91, 153, 159 delay the rate of recovery of blood glucose concentration following drug-induced hypoglycemia;91, 127, 153 alter the hemodynamic response to hypoglycemia, possibly resulting in an exaggerated hypertensive response;153 and possibly impair peripheral circulation.153 Nonselective β-adrenergic blocking agents (e.g., propranolol, nadolol) without intrinsic sympathomimetic activity are more likely to affect glucose metabolism than more selective β-adrenergic blocking agents (e.g., metoprolol, atenolol) or those with intrinsic sympathomimetic activity (e.g., acebutolol, pindolol).36, 73, 91, 143, 152, 159, 160, 173 Signs of hypoglycemia (e.g., tachycardia, blood pressure changes, tremor, feelings of anxiety) mediated by catecholamines may be masked by either nonselective or selective β-adrenergic blocking agents.143, 153, 159 These drugs should be used with caution in patients with type 2 diabetes mellitus who are receiving antidiabetic agents, especially in those with labile disease or in those prone to hypoglycemia.36, 83, 91, 127, 153 Use of low-dose, selective β1-adrenergic blockers (e.g., metoprolol) or β-adrenergic blocking agents with intrinsic sympathomimetic activity in patients receiving oral antidiabetic agents may theoretically decrease the risk of affecting glycemic control.36, 143, 152, 160, 173
Combined use of alcohol and metformin can increase the risk of hypoglycemia and lactic acidosis, since alcohol decreases lactate clearance and hepatic gluconeogenesis and may increase insulin secretion.1, 18, 33, 63, 91, 93, 107, 143, 314 Excessive alcohol intake, on an acute or chronic basis, should be avoided in patients receiving metformin therapy.1, 314
Angiotensin-converting Enzyme Inhibitors
Angiotensin-converting enzyme (ACE) inhibitors (e.g., captopril, enalapril) may reduce fasting blood glucose concentrations in nondiabetic individuals132 and have been associated with unexplained hypoglycemia in patients whose diabetes had been controlled with insulin or oral antidiabetic agents, including combined therapy with glyburide and metformin.73, 130, 131, 132, 155, 159, 160 Testing in some of these patients indicated that the ACE inhibitor (e.g., captopril) apparently increased insulin sensitivity; the mechanism of this effect is not known.131, 152, 159, 160 Other investigators have reported no alterations in glycemic control with concomitant use of an ACE inhibitor and oral antidiabetic agents or insulin in diabetic patients.133 The potential risk of precipitating hypoglycemia or hyperglycemia appears to be low but should be considered when therapy with an ACE inhibitor is initiated or withdrawn in diabetic patients; blood glucose concentrations should be monitored during dosage adjustments with either agent.130, 131, 132, 152, 155, 160
Although hypoglycemia occurs infrequently in patients receiving metformin therapy alone,1, 19, 62, 78, 166 hypoglycemia may occur when the medication is used concomitantly with an insulin secretagogue such as a sulfonylurea antidiabetic agent (e.g., glyburide), a meglitinide (e.g., repaglinide), or insulin.1, 15, 78, 94, 99, 257, 258, 261 In a single-dose study in patients with type 2 diabetes mellitus, concomitant administration of glyburide with metformin did not alter the pharmacokinetics or pharmacodynamics of metformin.1, 260, 261, 314 In a single-dose study, administration of metformin concomitantly with an α-glucosidase inhibitor (acarbose) resulted in an acute decrease in the bioavailability of metformin.138, 201 Coadministration of guar gum (10 g) and metformin hydrochloride (1.7 g) with a standard meal in healthy individuals reduced and delayed the absorption of metformin from the GI tract.18, 85, 99, 106
Topiramate and other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide, dichlorphenamide) frequently cause a reduction in serum bicarbonate concentrations and induce non-anion gap, hyperchloremic metabolic acidosis.1, 257, 258, 261 Concomitant use of these medications with metformin may increase the risk for lactic acidosis; consider more frequent monitoring in patients receiving these medications in combination.1, 257, 258, 261
Cimetidine may reduce the urinary excretion of metformin by competing for renal tubular organic cationic transport systems.1, 75, 234, 254, 260, 314 In single- and multiple-dose studies in healthy individuals, concomitant administration of cimetidine and metformin increased the peak plasma and whole blood concentrations of metformin by approximately 60-81% and the area under the plasma or whole blood concentration-time curve (AUC) of metformin by approximately 40-50%.75, 314 Metformin has negligible effects on cimetidine pharmacokinetics, possibly because cimetidine has a higher affinity for renal tubular transport sites.75, 314 The manufacturer states that the possibility of other cationic drugs that undergo substantial tubular secretion (e.g., amiloride, digoxin, dolutegravir, morphine, procainamide, quinidine, quinine, ranolazine, ranitidine, triamterene, trimethoprim, vancomycin, vandetanib) decreasing the urinary excretion of metformin and increasing systemic exposure to the medication should be considered.254, 260, 314
In premenopausal patients with polycystic ovary syndrome, therapy with certain oral antidiabetic agents, including metformin, may result in the resumption of ovulation in a modest number of women.210, 211, 212, 234 Ovulatory response is further increased in patients pretreated with metformin hydrochloride (500 mg 3 times daily for 35 days) receiving additional low-dose clomiphene (50 mg daily for 5 days); ovulation was associated with decreased insulin secretion and increased serum progesterone concentrations.210
Thiazide diuretics can exacerbate diabetes mellitus, resulting in increased requirements of oral antidiabetic agents, temporary loss of diabetic control, or secondary failure of the antidiabetic agent.1, 91, 139, 143, 151, 152, 153, 154, 159, 160 If control of diabetes is impaired by a thiazide diuretic, clinicians may consider substituting a less diabetogenic diuretic (e.g., potassium-sparing diuretic), reducing the dosage of or discontinuing the diuretic if clinically appropriate to do so, or increasing the dosage of the oral antidiabetic agent.73, 152, 153, 154, 159, 160
In a single-dose study in healthy individuals, administration of furosemide concomitantly with metformin increased peak plasma and blood concentrations of metformin by approximately 22% and AUC of metformin by approximately 15%.314 Administration of metformin concomitantly with furosemide decreased peak plasma furosemide concentrations by approximately 31% and AUC by approximately 12%.314 The renal clearance of both medications remained unchanged during such concomitant use, but the half-life of furosemide was decreased by 32%.314 The manufacturer states that no information is available on potential interactions between metformin and furosemide during long-term administration.314
Concomitant administration of single doses of metformin and nifedipine in healthy individuals resulted in enhanced absorption of metformin, as indicated by increases of 20 and 9% in the peak plasma concentration and AUC, respectively, of metformin.314 Nifedipine also increased the urinary excretion of metformin; half-life and time to peak plasma concentration of metformin remained unchanged.314 Metformin appears to have minimal effects on the pharmacokinetics of nifedipine.314
Metformin a biguanide antidiabetic agent, lowers both basal (fasting) and postprandial glucose concentrations in patients with type 2 diabetes mellitus.1, 18, 22 Biguanides usually do not produce hypoglycemia in patients with diabetes and do not affect normal blood glucose concentrations in nondiabetic individuals; metformin, even in excessive dosage, normally does not lower glucose concentrations below euglycemia, although hypoglycemia occasionally may occur with overdosage.18, 20, 102, 103, 111 Although the precise mechanism(s) by which metformin exerts its antihyperglycemic effect has not been fully established, current evidence suggests that the medication improves both peripheral and hepatic sensitivity to insulin.18, 31, 33, 40, 41, 42, 44, 52, 58, 60, 81, 146 Improved insulin sensitivity occurs principally as a result of decreased hepatic glucose production and enhanced 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 the relative contribution of these mechanisms to the antihyperglycemic effect of metformin has not been fully elucidated.18, 42, 44, 71, 135, 146, 161 The apparent improvement in peripheral glucose disposal with metformin therapy has been attributed principally to improved metabolism of glucose via nonoxidative (anaerobic) pathways (e.g., glycogen formation in skeletal muscle, postprandial lactate production in splanchnic tissues, lipogenesis in adipose tissue).6, 18, 27, 31, 39, 68, 71, 79, 146, 149 Metformin reduces basal hepatic glucose production by decreasing gluconeogenesis and possibly glycogenolysis, thereby lowering fasting plasma glucose concentrations.6, 20, 23, 31, 37, 39, 61, 81, 135 Although some investigators have suggested that reduction of hepatic glucose production may be the medication's principal antihyperglycemic mechanism,18, 27, 44, 61, 81 this effect has not been demonstrated in all studies.18, 41, 60, 69 In vitro studies in hepatocytes indicate that metformin, at concentrations similar to or higher than those observed with therapeutic dosages, enhances insulin-induced suppression of gluconeogenesis and decreases glucagon-stimulated gluconeogenesis.6, 146, 175, 176, 177 Insulin secretion usually remains unchanged during metformin therapy; fasting insulin concentrations and day-long plasma insulin response remain the same or may even decrease.1, 18, 20, 42, 60, 68, 102, 166 The magnitude of the decrease in fasting blood glucose concentrations generally is proportional to the level of fasting baseline hyperglycemia.146 Metformin also may decrease plasma glucose concentrations by enhancing basal glucose disposal through insulin-independent mechanisms (e.g., a decrease in free fatty acid oxidation), but such effects appear to be modest.18, 42, 68, 146
Metformin is slowly and incompletely absorbed from the GI tract, mainly from the small intestine; absorption is complete within 6 hours.6, 18, 43, 50, 51, 65, 89 The absolute oral bioavailability of the medication under fasting conditions is reported to be approximately 50-60% with metformin hydrochloride doses of 0.5-1.5 g;1, 18, 33, 43, 50, 65, 85, 89, 314 binding of the medication to the intestinal wall may explain the difference between the amount of medication absorbed (as determined by the urinary and fecal excretion of unchanged drug) and the amount bioavailable in some studies.6, 18, 51, 89, 129 In single-dose studies with metformin hydrochloride immediate-release tablets at doses of 0.5-1.5 g1, 89 or 0.85-2.55 g,1, 111 plasma metformin concentrations did not increase in proportion to increasing doses, suggesting an active saturable absorption process.1, 18, 65, 89, 111, 126, 1 Food decreases and slightly delays the absorption of metformin immediate-release tablets; the clinical importance of these effects is unknown.1, 18, 208, 314 Administration of metformin hydrochloride immediate-release tablets with food reportedly has decreased peak plasma concentrations of the medication by 35-40%, reduced area under the plasma concentration-time curve (AUC) by 20-25%, and delayed time to peak plasma concentration by 35-40 minutes compared with these parameters in fasting individuals receiving this metformin preparation.1, 126, 314 However, in one study, concomitant administration of the medication as immediate-release tablets with food had a less pronounced effect (average reduction in bioavailability of 10%) on absorption.208 Following oral administration of metformin hydrochloride as an extended-release tablet preparation with food, the extent of absorption (as measured by AUC) increased by approximately 50%, but peak plasma concentrations and time to achieve peak plasma concentrations were not altered.258, 1 However, following administration of another metformin hydrochloride extended-release preparation (Glumetza®) with low-fat and high-fat meals, the AUCs increased by 38 and 73%, respectively, compared with those in the fasting state.261 Following oral administration of metformin hydrochloride as an immediate-release oral solution with food, the extent of absorption (as measured by AUC) increased by approximately 17-21% compared with administration in the fasted state.257 Food delayed the time to achieve peak plasma concentrations by 1.4 hours compared with administration in the fasted state.257 The pharmacokinetics of immediate-release metformin oral solution were not appreciably affected by the fat content of meals.257 Following administration of a single 500-mg dose of metformin hydrochloride as immediate-release tablets with food in pediatric patients (12-16 years of age) with type 2 diabetes mellitus, mean peak plasma concentrations and AUC differed less than 5% compared with those values in healthy adults; all patients had normal renal function.234 In pediatric patients 11-16 years of age receiving a single dose of metformin in fixed combination with glyburide, mean dose-normalized glyburide peak plasma concentration and AUC differed less than 6% from historical values in healthy adults.234
Following oral administration of 0.5-1.5 g of metformin hydrochloride as immediate-release tablets in healthy individuals or in patients with type 2 diabetes mellitus, peak plasma drug concentrations usually are attained within 2-4 hours.6, 18, 33, 38, 43, 44, 50, 85, 125 Following oral administration of a single dose of metformin hydrochloride as extended-release tablets, peak plasma drug concentrations usually are attained within a median of 7 hours.1 Following administration of a single dose (0.5-2.5 g) of another extended-release preparation (Glumetza®), peak plasma drug concentrations usually are attained within 7-8 hours.261 Peak plasma concentrations following administration of metformin extended-release tablets are approximately 20% lower than those following administration of the same dose as immediate-release tablets.1 The extent of absorption of metformin hydrochloride 2 g once daily as extended-release tablets is similar to that following administration of 1 g of the drug twice daily as immediate-release tablets.1, 258 Steady-state plasma concentrations with usual dosages of metformin hydrochloride as immediate-release tablets (e.g., 1.5-2.55 g daily in 1 to 3 divided doses) are attained within 24-48 hours.1, 38, 51 Satisfactory control of blood or plasma glucose concentration may occur within a few days to 1 week following initiation of metformin therapy in patients with type 2 diabetes mellitus, but the maximum antihyperglycemic effect may be delayed for up to 2 weeks.18, 53, 98 Following discontinuance of metformin therapy, blood glucose concentration increases within 2 weeks.53
Bioequivalence has been demonstrated between the fixed combination of metformin and sitagliptin and each agent given concurrently.314 Bioequivalence also has been demonstrated between the fixed combination of immediate-release metformin and pioglitazone (ActoPlus Met®) and each agent (immediate-release metformin [Glucophage®] and pioglitazone [Actos®]) given concurrently.260 Results of a bioequivalence study indicate that the fixed-combination tablets of immediate-release metformin hydrochloride and canagliflozin are bioequivalent to the corresponding doses of metformin hydrochloride and canagliflozin given as individual tablets under fed conditions.370 Bioequivalence between the fixed combination of extended-release metformin hydrochloride and dapagliflozin (Xigduo® XR) and each agent (extended-release metformin hydrochloride and dapagliflozin) given concurrently as separate tablets has been demonstrated; however, the relative bioavailability of the fixed combination of extended-release metformin hydrochloride and dapagliflozin (Xigduo® XR) and concomitantly administered dapagliflozin and immediate-release metformin hydrochloride has not been established.362 Bioequivalence between the fixed-combination tablets of immediate-release metformin hydrochloride and empagliflozin and the corresponding doses of metformin hydrochloride and empagliflozin as individual tablets also has been established.372 In healthy individuals who received the extended-release metformin hydrochloride preparation (Glumetza®) in a single-dose crossover study, a 1-g tablet has been shown to be bioequivalent to two 500-mg tablets based on peak plasma concentrations and AUC.261
Metformin is distributed rapidly in animals and humans into peripheral body tissues and fluids, particularly the GI tract; the medication also appears to distribute slowly into erythrocytes and into a deep tissue compartment (probably GI tissues).50, 65, 89, 162, 167 The highest tissue concentrations of metformin (at least 10 times the plasma concentration) occur in the GI tract (e.g., esophagus, stomach, duodenum, jejunum, ileum), with lower concentrations (twice the plasma concentration) occurring in kidney, liver, and salivary gland tissue.6, 18, 44, 50, 51, 65, 162 The medication distributes into salivary glands with a half-life of about 9 hours.50, 65 Metformin concentrations in saliva are 10-fold lower than those in plasma and may be responsible for the metallic taste reported in some patients.50, 65 Any local effect of metformin on glucose absorption in the GI tract may be associated with the relatively high GI concentrations of the medication compared with those in other tissues.6, 18, 43 Limited data indicate that metformin is distributed into breast milk in humans.1, 257, 258, 260, 261, 285, 286 Metformin is negligibly bound to plasma proteins.1, 18, 50, 51, 65, 85, 89, 257, 258, 261
Following oral administration of metformin hydrochloride (0.5-1.5 g) as immediate-release tablets in healthy individuals or in patients with type 2 diabetes mellitus, plasma concentrations decline in a triphasic manner.50, 89 The principal plasma elimination half-life of metformin averages approximately 6.2 hours; 90% of the medication is cleared within 24 hours in patients with normal renal function.1, 6, 18, 33, 38, 50, 51, 65, 85, 89, 125, 258, 314 The decline in plasma metformin concentrations is slower after oral than after IV administration, indicating that elimination is absorption rate-limited.18, 50, 89 Urinary excretion data and data from whole blood indicate a slower terminal-elimination phase half-life of 8-20 hours (e.g., 17.6 hours)1 suggesting that the erythrocyte mass may be a compartment of distribution.1, 18, 50, 65, 174, 314 Metformin is not metabolized in the liver or GI tract and is not excreted in bile; no metabolites of the medication have been identified in humans.1, 50, 51, 89, 314 Renal elimination of metformin involves glomerular filtration and secretion by the proximal convoluted tubules as unchanged drug.6, 33, 50, 63, 65, 75, 85, 89, 314 Renal clearance is approximately 3.5 times greater than creatinine clearance, indicating that tubular secretion is the principal route of metformin elimination.1, 314 Renal impairment results in increased peak plasma concentrations of metformin, a prolonged time to peak plasma concentration, and a decreased volume of distribution.1, 51, 174 Renal clearance is decreased in patients with renal impairment (as measured by decreases in creatinine clearance) and, because of reduced renal function with age, in geriatric individuals.1, 33, 51, 174, 314 In geriatric individuals, decreased renal and plasma clearance of metformin results in increased plasma concentrations of metformin; volume of distribution remains unaffected.1, 174, 314 The pharmacokinetics of metformin in patients with normal renal function do not appear to be affected by sex, race, or the presence of diabetes mellitus.1, 18, 89, 260, 314
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Solution | 500 mg/5 mL* | ||
850 mg/8.5 mL* | metFORMIN Hydrochloride Solution | |||
Tablets, extended-release | 500 mg* | Salix Pharmaceuticals | ||
750 mg* | metFORMIN Hydrochloride Extended-Release Tablets | |||
1 g* | Glumetza® | Salix Pharmaceuticals | ||
metFORMIN Hydrochloride Extended-Release Tablets | ||||
Tablets, film-coated | 500 mg* | |||
625 mg* | metFORMIN Hydrochloride Tablets | |||
750 mg* | metFORMIN Hydrochloride Tablets | |||
850 mg* | metFORMIN Hydrochloride Tablets | |||
1 g* | metFORMIN Hydrochloride Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, extended-release | 500 mg with Immediate-release Canagliflozin (anhydrous) 50 mg | Invokamet® XR | |
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 | |||
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 Sharp & Dohme | ||
1 g with Immediate-release Canagliflozin (anhydrous) 50 mg | Invokamet® XR | Janssen | ||
1 g with Immediate-release Canagliflozin (anhydrous) 150 mg | Invokamet® XR | Janssen | ||
1 g with Immediate-release Dapagliflozin Propanediol 2.5 mg (of dapagliflozin) | Xigduo® XR | AstraZeneca | ||
1 g with Immediate-release Dapagliflozin Propanediol 5 mg (of dapagliflozin) | Xigduo® XR | AstraZeneca | ||
1 g with Immediate-release Dapagliflozin Propanediol 10 mg (of dapagliflozin) | Xigduo® XR | AstraZeneca | ||
1 g with Immediate-release Empagliflozin 5 mg | Synjardy® XR | |||
1 g with Immediate-release Empagliflozin 10 mg | Synjardy® XR | Boehringer Ingelheim | ||
1 g with Immediate-release Empagliflozin 12.5 mg | Synjardy® XR | Boehringer Ingelheim | ||
1 g with Immediate-release Empagliflozin 25 mg | Synjardy® XR | Boehringer Ingelheim | ||
1 g with Immediate-release Linagliptin 2.5 mg | Jentadueto® XR | Boehringer Ingelheim | ||
1 g with Immediate-release Linagliptin 5 mg | Jentadueto® XR | Boehringer Ingelheim | ||
1 g with Immediate-release Saxagliptin 2.5 mg | Kombiglyze® XR | AstraZeneca | ||
1 g with Immediate-release Saxagliptin 5 mg | Kombiglyze® XR | AstraZeneca | ||
1 g with Immediate-release Sitagliptin 50 mg | Janumet® XR | Merck Sharp & Dohme | ||
1 g with Immediate-release Sitagliptin 100 mg | Janumet® XR | Merck Sharp & Dohme | ||
Tablets, film-coated | 250 mg with Glipizide 2.5 mg* | metFORMIN Hydrochloride and Glipizide Tablets | ||
250 mg with Glyburide 1.25 mg* | metFORMIN Hydrochloride and Glyburide Tablets | |||
500 mg with Alogliptin Benzoate 12.5 mg (of alogliptin) | ||||
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) | Merck Sharp & Dohme | |||
500 mg with Ertugliflozin L-pyroglutamic Acid 7.5 mg (of ertugliflozin) | Segluromet® | Merck Sharp & Dohme | ||
500 mg with Glipizide 2.5 mg* | metFORMIN Hydrochloride and Glipizide Tablets | |||
500 mg with Glipizide 5 mg* | metFORMIN Hydrochloride and Glipizide Tablets | |||
500 mg with Glyburide 2.5 mg* | metFORMIN Hydrochloride and Glyburide Tablets | |||
500 mg with Glyburide 5 mg* | MetFORMIN Hydrochloride and Glyburide Tablets | |||
500 mg with Linagliptin 2.5 mg | Jentadueto® | Boehringer Ingelheim | ||
500 mg with Pioglitazone Hydrochloride 15 mg (of pioglitazone) | Takeda | |||
500 mg with Sitagliptin Phosphate 50 mg (of sitagliptin) | Janumet® | Merck Sharp & Dohme | ||
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 Sharp & Dohme | ||
1 g with Ertugliflozin L-pyroglutamic Acid 7.5 mg (of ertugliflozin) | Segluromet® | Merck Sharp & Dohme | ||
1 g with Linagliptin 2.5 mg | Jentadueto® | Boehringer Ingelheim | ||
1 g with Sitagliptin Phosphate 50 mg (of sitagliptin) | Janumet® | Merck Sharp & Dohme |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
1. Time-Cap Laboratories, Inc. Metformin hydrochloride tablets, film coated and prescribing information. Farmingdale, NY; 2025 Feb.
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. [PubMed 3829580]
6. Bailey CJ. Biguanides and NIDDM. Diabetes Care . 1992; 15:755-72. [PubMed 1600835]
8. Henry RR. Glucose control and insulin resistance in non-insulin-dependent diabetes mellitus. Ann Intern Med . 1996; 124:97-103. [PubMed 8554221]
13. Lebovitz HE. Stepwise and combination drug therapy for the treatment of NIDDM. Diabetes Care . 1994; 17:1542-4. [PubMed 7882832]
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. [PubMed 7821128]
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. [PubMed 589351]
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. [PubMed 4169605]
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. [PubMed 7601013]
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. [PubMed 7833731]
20. Bailey CJ, Nattrass M. Treatment—metformin. Baillieres Clin Endocrinol Metab . 1988; 2:455-76. [PubMed 3075902]
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. [PubMed 1569149]
23. Krentz AJ, Ferner RE, Bailey CJ. Comparative tolerability profiles of oral antidiabetic agents. Drug Saf . 1994; 11:223-41. [PubMed 7848543]
27. Gerich JE. Oral hypoglycemic agents. N Engl J Med . 1989; 321:1231-45. [PubMed 2677730]
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. [PubMed 7739421]
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. [PubMed 1955512]
32. Gan SC, Barr J, Arieff AI et al. Biguanide-associated lactic acidosis. Arch Intern Med . 1992; 152:2333-36. [PubMed 1444694]
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. [PubMed 8462390]
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. [PubMed 7821127]
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. [PubMed 2162756]
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. [PubMed 1551495]
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. [PubMed 3552515]
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. [PubMed 2404714]
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. [PubMed 3552795]
48. Lim P, Khoo OT. Metformin compared to tolbutamide in the treatment of maturity-onset diabetes mellitus. Med J Aust . 1970; 1:271-273. [PubMed 5440868]
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. [PubMed 499320]
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. [PubMed 1505458]
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. [PubMed 2956047]
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. [PubMed 8453955]
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. [PubMed 2648723]
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. [PubMed 404205]
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. [PubMed 406158]
63. Alberti KGMM, Nattrass M. Lactic acidosis. Lancet . 1977; 2:25-9. [PubMed 69109]
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. [PubMed 631461]
65. Lucis OJ. The status of metformin in Canada. Can Med Assoc J . 1983; 128:24-6. [PubMed 6847752]
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. [PubMed 1759920]
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. [PubMed 5556053]
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. [PubMed 2206054]
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. [PubMed 3593625]
76. Wiholm BE, Myrhed M. Metformin-associated lactic acidosis in Sweden 1977-1991. Eur J Clin Pharmacol . 1993; 44:589-91. [PubMed 8405019]
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. [PubMed 7623902]
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. [PubMed 7623903]
82. Tomkin GH. Malabsorption of vitamin B12 in diabetic patients treated with phenformin: a comparison with metformin. Br Med J . 1973; 3:673-75. [PubMed 4742454]
83. Bailey CJ, Flatt PR, Marks V. Drugs inducing hypoglycemia. Pharmacol Ther . 1989; 42:361-84. [PubMed 2672051]
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. [PubMed 2523787]
85. Johnston P, Rough T. Metformin: a newly approved oral hypoglycemic. Diabetologia . 1983; 24:351-54. [PubMed 6347782]
88. Expert Committee of the Canadian Diabetes Advisory Board. Clinical practice guidelines for treatment of diabetes mellitus. CMAJ . 1992; 147:697-712. [PubMed 1521215]
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. [PubMed 7306436]
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. [PubMed 3044067]
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. [PubMed 1681225]
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. [PubMed 7555472]
95. Zimmerman B, Espenshade J, Fujimoto W et al. The pharmacological treatment of hyperglycemia in NIDDM. Diabetes Care . 1995; 18:1510-18. [PubMed 8722084]
96. Lalau J, Lacroix C, Compagnon P et al. Role of metformin accumulation in metformin-associated lactic acidosis. Diabetes Care . 1995; 18:779-84. [PubMed 7555503]
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. [PubMed 2198745]
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. [PubMed 6403102]
99. Hermann L. Biguanides and sulfonylureas as combination therapy in NIDDM. Diabetes Care . 1990; 13:37-41. [PubMed 2209342]
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. [PubMed 2959438]
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. [PubMed 2060439]
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. [PubMed 2722133]
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. [PubMed 506799]
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. Avet Pharmaceuticals, Inc. Acarbose tablets prescribing information. East Brunswick, NJ; 2024 Apr.
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. [PubMed 6777880]
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. [PubMed 2142054]
119. McLelland J. Recovery from metformin overdose. Diabet Med . 1985; 2:410-11. [PubMed 2951106]
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. [PubMed 7002569]
121. Schauben J. Calcium channel blockers and insulin secretion. Drug Intell Clin Pharm. 1982; 16:881-2. Letter. [PubMed 6756852]
122. Melchior W, Jaber L. Metformin: an antihyperglycemic agent for treatment of type II diabetes. Ann Pharmacother . 1996; 30:158-63. [PubMed 8835050]
123. DeFronzo RA, Goodman AM. Efficacy of metformin in non-insulin-dependent diabetes mellitus. Reply. N Engl J Med . 1996; 334:269-70.
124. Bosisio E, Galli-Kienle M, Ciconali M et al. Defective hydroxylation of phenformin as a determinant of drug toxicity. Diabetes . 1981; 30:644-9. [PubMed 7250534]
125. Arafat T, Kaddoumi A, Shami M et al. Pharmacokinetics and pharmacodynamics of two oral formulations of metformin hydrochloride. Adv Ther . 1994; 11:21-33.
126. Brookes LG, Sambol NC, Lin ET et al. Effect of dosage form, dose and food on the pharmacokinetics of metformin. Pharm Res . 1991; 8:S320. [PubMed 1905809]
127. Holland B, Kaplan N. Propranolol in the treatment of hypertension. N Engl J Med . 1976; 294:930-6. [PubMed 1256484]
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. [PubMed 3059189]
131. Ferriere M, Lachkar H, Richard J et al. Captopril and insulin sensitivity. Ann Intern Med . 1985; 102:134-5. [PubMed 3881067]
132. McMurray J, Fraser DM. Captopril, enalapril, and blood glucose. Lancet . 1986; 1:1035. [PubMed 2871313]
133. Passa Ph, Marre M, Leblanc H. Enalapril, captopril, and blood glucose. Lancet . 1986; 1:1447. [PubMed 2872551]
135. Cusi K, Consoli A, DeFronzo RA. Metabolic effects of metformin on glucose and lactate metabolism in NIDDM. (unpublished observations).
138. Anon. Acarbose for diabetes mellitus. Med Lett Drugs Ther . 1996; 38:9-10. [PubMed 8559114]
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.
143. White Jr J, Harman J, Campbell K. Drug interactions in diabetic patients. Postgrad Med . 1993; 93:131-9.
146. Bailey C, Turner R. Metformin. N Engl J Med . 1996; 334:574-9. [PubMed 8569826]
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.
151. Lant A. Diuretics clinical pharmacology and therapeutic use (Part II). Drugs . 1985; 29:162-88. [PubMed 3884320]
152. Houston M. The effects of antihypertensive drugs on glucose intolerance in hypertensive nondiabetics and diabetics. Am Heart J . 1988; 115:640-56. [PubMed 3278578]
153. Joseph J, Schuna A. Management of hypertension in the diabetic patient. Clin Pharm . 1990; 9:864-73. [PubMed 2272152]
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. [PubMed 8532012]
157. Bailey CJ. Hypoglycaemic, antihyperglycaemic and antidiabetic drugs. Diabetic Med . 1992; 9:482-3. [PubMed 1611838]
158. Sirtori CR, Pasik C. Re-evaluation of a biguanide, metformin: mechanism of action and tolerability. Pharmacol Res . 1994; 30:187-228. [PubMed 7862618]
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. [PubMed 8442624]
161. Bailey CJ. Metformin-an update. Gen Pharmacol . 1993; 24:1299-309. [PubMed 8112499]
162. Wilcock C, Bailey CJ. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica . 1994; 24:49-57. [PubMed 8165821]
164. KhanIH, Catto GRD, MacLeod AM. Severe lactic acidosis in patient receiving continuous ambulatory peritoneal dialysis. BMJ . 1993; 307:1056-7. [PubMed 8251784]
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. [PubMed 8743335]
168. Stabler SP. Screening the older population for cobalamin (vitamin B12 deficiency. J Am Geriatrics Soc . 1995; 43:1295-6.
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. [PubMed 8626883]
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. [PubMed 8504825]
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.
179. Williams G. Management of non-insulin-dependent diabetes mellitus. Lancet . 1994; 95-100.
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. [PubMed 8554206]
189. Crofford OB. Metformin. N Engl J Med . 1995; 333:588-9. [PubMed 7623910]
191. The Upjohn Company. Micronase® (glyburide) prescribing information. Kalamazoo, MI; 2002 Mar.
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.
198. Jackson JE, Bressler R. Clinical pharmacology of sulphonylurea hypoglycaemic agents: part 1. Drugs . 1981; 22:211-45. [PubMed 7021124]
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.
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. [PubMed 8742572]
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.
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. [PubMed 9637806]
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.
234. Heritage Pharmaceuticals, Inc. Glyburide and metformin hydrochloride tablet, film-coated, prescribing information. East Brunswick, NJ; 2024 Apr.
237. Takeda Pharmaceuticals America, Inc. Actos® (pioglitazone hydrochloride) tablets prescribing information. Cambridge, MA; 2025 Mar.
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. [PubMed 10333912]
239. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med . 1999; 131:281-303. [PubMed 10454950]
241. Lifsa Drugs LLC. Glimepiride tablets prescribing information. New Brunswick, NJ; 2024 Aug.
242. Pfizer. Glucotrol XL® (glipizide) extended release tablets prescribing information. New York, NY; 2023 Aug.
244. Heritage Pharmaceuticals Inc. Acarbose tablets prescribing information. East Brunswick, NJ; 2024 Apr.
248. Actavis Pharma, Inc. Nateglinide tablets prescribing information. Parsippany, NJ; 2023 Jul.
249. Chartwell RX, LLC. Repaglinide tablets prescribing information. Congers, NY; 2025 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. [PubMed 11192132]
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. [PubMed 11092289]
254. Heritage Pharmaceuticals, Inc. Glipizide and metformin hydrochloride tablets prescribing information. East Brunswick, NJ; 2024 Aug.
257. TruPharma, LLC. Metformin hydrochloride oral solution prescribing information. Tampa, FL; 2024 Nov.
258. Leading Pharma, LLC.. Metformin hydrochloride extended-release tablets prescribing information. Fairfield, NJ; 2024 Oct.
260. Takeda Pharmaceuticals America, Inc. Actoplus Met® (pioglitazone hydrochloride and metformin hydrochloride) tablets for oral use prescribing information. Deerfield, IL; 2025 Mar.
261. Salix Pharmaceuticals. Glumetza® (metformin hydrochloride) extended release tablets prescribing information. Bridgewater, NJ; 2024 Mar.
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. [PubMed 16873813]
265. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2003 clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes . 2003; 27(Suppl 2):S1-152.
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. [PubMed 12436333]
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. [PubMed 15932841]
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.
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. [PubMed 15363722]
293. Ehrmann DA. Polycystic ovary syndrome. New Engl J Med . 2005; 352:1223-36. [PubMed 15788499]
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. [PubMed 17327307]
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. [PubMed 16785142]
297. Lobo RA. Choice of treatment for women with polycystic ovary syndrome. Fertil Steril . 2006; 86(suppl 1):S22-3. [PubMed 16798280]
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. [PubMed 19019358]
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. [PubMed 17055827]
300. Radosh L. Drug treatments for polycystic ovary syndrome. Am Fam Physician . 2009;79:671-6. [PubMed 19405411]
301. Creanga AA, Bradley HM, McCormick C et al. Use of metformin in polycystic ovary syndrome. Obstet Gynecol . 2008; 111:959-68. [PubMed 18378757]
302. Nestler JE. Metformin for the treatment of the polycystic ovary syndrome. N Engl J Med . 2008; 358:47-54. [PubMed 18172174]
303. Liu JH, Bill AH. Expanding applications for metformin in polycystic ovarian syndrome. J Pediatr . 2006; 148:573-4. Editorial. [PubMed 16737862]
304. Urman B, Yahin K. Ovulatory disorders and infertility. J Reprod Med . 2006; 51:267-82. [PubMed 16737024]
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. [PubMed 19007650]
308. Nestler JE. Metformin in the treatment of infertility in polycystic ovarian syndrome: an alternative perspective. Fertil Steril . 2008; 90:14-6. Editorial. [PubMed 18550055]
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. [PubMed 17287476]
310. Guzick DS. Treating the polycystic ovary syndrome the old-fashioned way. N Engl J Med . 2007; 356:622-4. Editorial. [PubMed 17287483]
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. [PubMed 17595241]
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. [PubMed 17823274]
314. Merck Sharp & Dohme LLC. Janumet® (sitagliptin/metformin hydrochloride) tablets prescribing information. Whitehouse Station, NJ; 2022 July.
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. [PubMed 10333912]
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.
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. [PubMed 18782901]
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. [Web]
336. . In brief: New recommendations for use of metformin in renal impairment. Med Lett Drugs Ther . 2016; 58:51.
352. Merck Sharpe & Dohme. Janumet® XR (sitagliptin/extended-release metformin hydrochloride) tablets prescribing information. Whitehouse Station, NJ; 2022 Jul.
355. Merck Sharp & Dohme. Segluromet® (ertugliflozin and metformin hydrochloride) tablets prescribing information. Rahway, NJ; 2024 Dec.
361. Kraut JA, Madias NE. Lactic acidosis. N Engl J Med . 2014; 371:2309-19. [PubMed 25494270]
362. AstraZeneca Pharmaceuticals. Xigduo® XR (dapagliflozin and extended-release metformin hydrochloride) tablets prescribing information. Wilmington, DE; 2024 Dec.
363. AstraZeneca Pharmaceuticals. Xigduo® XR (dapagliflozin and extended-release metformin hydrochloride) medication guide. Wilmington, DE; 2024 Dec.
368. AstraZeneca Pharmaceuticals. Kombiglyze XR® (saxagliptin and metformin HCl extended-release) tablets prescribing information. Wilmington, DE; 2024 Oct.
369. AstraZeneca Pharmaceuticals. Kombiglyze XR® (saxagliptin and metformin HCl extended-release) tablets medication guide. Wilmington, DE; 2024 Oct.
370. Janssen Pharmaceuticals, Inc. Invokamet®/Invokamet® XR (canagliflozin and immediate- or extended-release metformin hydrochloride) tablets prescribing information. Titusville, NJ; 2024 Dec.
371. Janssen Pharmaceuticals, Inc. Invokamet®/Invokamet® XR (canagliflozin and immediate- or extended-release metformin hydrochloride) medication guide. Titusville, NJ; 2024 Dec.
372. Boehringer Ingelheim Pharmaceuticals, Inc. Synjardy® (empagliflozin and metformin hydrochloride) tablets prescribing information. Ridgefield, CT; 2025 Mar.
373. Boehringer Ingelheim Pharmaceuticals, Inc. Synjardy® (empagliflozin and metformin hydrochloride) medication guide. Ridgefield, CT; 2025 Mar.
374. Boehringer Ingelheim Pharmaceuticals, Inc. Synjardy® XR (empagliflozin and metformin hydrochloride extended-release) tablets prescribing information. Ridgefield, CT; 2025 Mar.
375. Boehringer Ingelheim Pharmaceuticals, Inc. Synjardy® XR (empagliflozin and metformin hydrochloride extended-release) medication guide. Ridgefield, CT; 2025 Mar.
376. Boehringer Ingelheim Pharmaceuticals, Inc. Jentadueto® (linagliptin and immediate-release metformin hydrochloride) tablets prescribing information. Ridgefield, CT; 2023 June.
377. Boehringer Ingelheim Pharmaceuticals, Inc. Jentadueto® (linagliptin and immediate-release metformin hydrochloride) tablets medication guide. Ridgefield, CT; 2023 June.
378. Boehringer Ingelheim Pharmaceuticals, Inc. Jentadueto® XR (linagliptin and extended-release metformin hydrochloride) tablets prescribing information. Ridgefield, CT; 2023 June.
379. Boehringer Ingelheim Pharmaceuticals, Inc. Jentadueto® XR (linagliptin and extended-release metformin hydrochloride) tablets medication guide. Ridgefield, CT; 2023 June.
610. Takeda Pharmaceuticals, Inc. Kazano® (alogliptin and metformin hydrochloride) tablets, for oral use, prescribing information. Cambridge, MA; 2025 Feb.
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. [PubMed 19125992]
710. Rising Holdings, Inc. Pioglitazone hydrochloride and metformin hydrochloride tablets prescribing information. East Brunswick, NJ; 2024 Oct.
711. American Diabetes Association Professional Practice Committee. 9. Pharmacologic approaches to glycemic treatment: standards of care in diabetes-2025. Diabetes Care. 2025; 48(Suppl 1): S181-206
712. Samson SL, Vellanki P, Blonde L et al. American Association of Clinical Endocrinology consensus statement: comprehensive type 2 diabetes management algorithm-2023 update. Endocr Pract. 2023; 28: 305-340.
713. Teede HJ, Tay CT, Laven JJE et al. Recommendations from the 2023 international evidence-based guideline for the assessment of polycystic ovary syndrome. J Clin Endocrinol Metab. 2023; 108(10): 2447-69.
714. Institute for Safe Medication Practices (ISMP). ISMP List of Confused Drug Names (2024). http://online.ecri.org/hubfs/ISMP/Resources/ISMP_ConfusedDrugNames.pdf. (accessed 2025 May 12)