ATC Class:A10BA02

VA Class:HS502

AHFS Class:

• Biguanides 68:20.04

Generic Name(s):

• metFORMIN Hydrochloride

Chemical Name:

• 1,1-Dimethylbiguanide monohydrochloride

Molecular Formula:

• C₄H₁₁N₅•HCl

Metformin hydrochloride is a biguanide antidiabetic agent.1,2,3,4,18,20,22,23,27,28,29,30,33,72,146

Type 2 Diabetes Mellitus

Metformin is used as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.1,3,4,6,8,15,16,17,18,19,20,27,29,95,166,234,254,698,704 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 drugs.1,3,6,15,18,20,22,27,29,30,48,59,78,88,95,97,99,112,134,166,191,234,237,238,239,241,242,248,249,250,254,260,352,355,362,368,370,372,374,376,378,610,698,704

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 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 A thiazolidinedione may be added to metformin in fixed combination with glyburide in patients who have inadequate glycemic control with fixed-combination therapy.234

Immediate-release metformin is commercially available in fixed combination with pioglitazone for use as an adjunct to diet and exercise in 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

Metformin is commercially available in fixed combination with a DPP-4 inhibitor (e.g., alogliptin, linagliptin, saxagliptin, sitagliptin) for use when treatment with both drug components is appropriate.314,352,368,377,378,610

Metformin is commercially available in fixed combination with the SGLT2 inhibitors canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin for use when treatment with both drug components is appropriate.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.3,6,88,90,94,95,146,698,704

The American Diabetes Association (ADA) currently classifies diabetes mellitus as type 1 (due to autoimmune β-cell destruction, usually leading to absolute insulin deficiency); type 2 (due to a progressive loss of β-cell insulin secretion, frequently on the background of insulin resistance); gestational diabetes mellitus (diabetes diagnosed in the second or third trimester of pregnancy that was not clearly overt diabetes prior to gestation); or specific types of diabetes due to other causes, such as monogenic diabetes syndromes (e.g., neonatal diabetes or maturity-onset diabetes of the young), diseases of the exocrine pancreas (e.g., cystic fibrosis, pancreatitis), or drug- or chemical-induced diabetes (e.g., diabetes associated with glucocorticoid use, the treatment of HIV/AIDS, or organ transplantation).12 According to ADA and other experts, a diagnosis of diabetes mellitus currently is established by a fasting plasma glucose of 126 mg/dL or greater, a 2-hour plasma glucose of 200 mg/dL or greater during an oral glucose tolerance test, or a glycosylated hemoglobin (hemoglobin A_1c; HbA_1c) concentration of 6.5% or greater; results should be confirmed by repeat testing in the absence of unequivocal hyperglycemia.12,615,616 Alternatively, a random plasma glucose of 200 mg/dL or greater in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis is considered confirmation of the diagnosis of diabetes mellitus.12,615,616

In both type 1 and type 2 diabetes mellitus, various genetic and environmental factors can result in the progressive loss of β-cell mass and/or function that manifests clinically as hyperglycemia.12 Epidemiologic data indicate that the incidence of type 2 diabetes mellitus is increasing in children and adolescents.235 Patients with type 2 diabetes mellitus have insulin resistance and usually have relative (rather than absolute) insulin deficiency.12 Most patients with type 2 diabetes mellitus (about 80-90%) are overweight or obese;12,178,179,180,264 obesity itself also contributes to the insulin resistance and glucose intolerance observed in these patients.8,9,11,12,18,27,30,59,60,73,134,145,178,179,264 Patients with type 2 diabetes mellitus who are not obese may have an increased percentage of abdominal fat, which is an indicator of increased cardiometabolic risk.12,269 While children with immune-mediated type 1 diabetes mellitus generally are not overweight, the incidence of obesity in children with this form of diabetes is increasing with the increasing incidence of obesity in the US population.235 Distinguishing between type 1 and type 2 diabetes mellitus in children may be difficult since obesity may occur with either type of diabetes mellitus, and autoantigens and ketosis may be present in a substantial number of children with features of type 2 diabetes mellitus (e.g., obesity, acanthosis nigricans).235

Patients with type 2 diabetes mellitus are not dependent initially on insulin (although many patients eventually require insulin for glycemic control)12,13,18,27,28,30,78,94,95,99,101,134,146,166,179,181,185,187 nor are they prone to ketosis; however, insulin occasionally may be required for correction of symptomatic or persistent hyperglycemia that is not controlled by dietary regulation or oral antidiabetic agents (e.g., sulfonylureas), and ketosis occasionally may develop during periods of severe stress (e.g., acute infection, trauma, surgery, use of certain drugs [e.g., corticosteroids, atypical antipsychotics, SGLT2 inhibitors]).12,146,179 Type 2 diabetes mellitus is a heterogeneous subclass of the disease; hyperglycemia in these patients often is accompanied by other metabolic abnormalities such as obesity, hypertension, hyperlipidemia, and impaired fibrinolysis.8,9,13,22,27,28,73,94,102,146,178,179,181 Endogenous insulin is present in type 2 diabetic patients, although plasma insulin concentrations may be decreased, increased, or normal.8,9,11,18,27,28,34,71,73,181,189 In patients with type 2 diabetes mellitus, glucose-stimulated secretion of endogenous insulin is frequently, but not always, reduced and decreased peripheral sensitivity to insulin is almost always associated with glucose intolerance.9,11,28,181

Glycemic Control and Microvascular Complications

Current evidence from epidemiologic and clinical studies supports an association between chronic hyperglycemia and the pathogenesis of microvascular complications in patients with diabetes mellitus,8,13,146,163,181,183,185,186,194,195,196,202 and results of randomized, controlled studies in patients with type 1 diabetes mellitus indicate that intensive management of hyperglycemia with near-normalization of blood glucose and glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) concentrations provides substantial benefits in terms of reducing chronic microvascular (e.g., neuropathy, retinopathy, nephropathy) complications associated with the disease.8,163,180,181,182,190 HbA_1c concentration reflects the glycosylation of other proteins throughout the body as a result of recent hyperglycemia and is used as a predictor of risk for the development of diabetic microvascular complications (e.g., neuropathy, retinopathy, nephropathy).134,184,188,194,195,196,202,206 Microvascular complications of diabetes are the principal causes of blindness and renal failure in developed countries and are more closely associated with hyperglycemia than are macrovascular complications.270,271

In the Diabetes Control and Complications Trial (DCCT), a reduction of approximately 50-75% in the risk of development or progression of retinopathy, nephropathy, and neuropathy was demonstrated during an average 6.5 years of follow-up in patients with type 1 diabetes mellitus receiving intensive insulin treatment (3 or more insulin injections daily with dosage adjusted according to results of at least 4 daily blood glucose determinations, dietary intake, and anticipated exercise) compared with that in patients receiving conventional insulin treatment (1 or 2 insulin injections daily, self-monitoring of blood or urine glucose values, education about diet and exercise).182 However, the incidence of severe hypoglycemia, including multiple episodes in some patients, was 3 times higher in the intensive-treatment group than in the conventional-treatment group.182 The reduction in risk of microvascular complications in the DCCT study correlated continuously with the reduction in HbA_1c concentration (hemoglobin A_1c) produced by intensive insulin treatment (e.g., a 40% reduction in risk of microvascular disease for each 10% reduction in hemoglobin A_1c).13,134,182,185,206 These data imply that any decrease in HbA_1c levels is beneficial and that complete normalization of blood glucose concentrations may prevent diabetic microvascular complications.13,134,182,185,206

The DCCT was terminated prematurely because of the pronounced benefits of intensive insulin regimens,182,255 and all treatment groups were encouraged to institute or continue such intensive insulin therapy.255 In the Epidemiology of Diabetes Interventions and Complications (EDIC) study, the long-term, open-label continuation phase of the DCCT, the reduction in the risk of microvascular complications (e.g., retinopathy, nephropathy, neuropathy) associated with intensive insulin therapy has been maintained throughout 7 years of follow-up.255 In addition, the prevalence of hypertension (an important consequence of diabetic nephropathy) in those receiving conventional therapy has exceeded that of those receiving intensive therapy.255 Patients receiving conventional insulin therapy in the DCCT were able to achieve a lower HbA_1c when switched to intensive therapy in the continuation study, although the average HbA_1c values achieved during the continuation study were higher (i.e., worse) than those achieved during the DCCT with intensive insulin therapy.255 Patients who remained on intensive insulin therapy during the EDIC continuation study were not able to maintain the degree of glycemic control achieved during the DCCT; by 5 years of follow-up in the EDIC study, HbA_1c values were similar in both intensive and conventional therapy groups.255 The EDIC study demonstrated that the greater the duration of chronically elevated plasma glucose concentrations (as determined by HbA_1c values), the greater the risk of microvascular complications.255 Conversely, the longer patients can maintain a target HbA_1c of 7% of less, the greater the delay in the onset of these complications.255

In another randomized, controlled study (Stockholm Diabetes Intervention Study) in patients with type 1 diabetes mellitus who were evaluated for up to 7.5 years, blood glucose control (as determined by HbA_1c concentrations) was improved, and the incidence of microvascular complications (e.g., decreased visual acuity, retinopathy, nephropathy, decreased nerve conduction velocity) reduced, with intensive insulin treatment (e.g., at least 3 insulin injections daily accompanied by intensive educational efforts) compared with that in patients receiving standard treatment (e.g., generally 2 insulin injections daily without intensive educational efforts).190

Data from the United Kingdom Prospective Diabetes Study (UKPDS)216,218,219,220 and the Action in Diabetes and VAscular disease: preterax and diamicroN modified release Controlled Evaluation (ADVANCE) study in patients with type 2 diabetes mellitus generally are consistent with the same benefits of oral hypoglycemic agents on microvascular complications as those observed in type 1 diabetics receiving insulin therapy in the DCCT.182,186,216,218,219,220,221,273

The UKPDS evaluated middle-aged, newly diagnosed, overweight (exceeding 120% of ideal body weight) or non-overweight patients with type 2 diabetes mellitus who received conventional or intensive treatment regimens with an oral sulfonylurea agent and/or insulin; overweight patients also could be allocated to metformin therapy in the same proportions as those allocated to sulfonylureas and insulin.218,219,220,222 Initial therapy consisted of an oral antidiabetic agent (sulfonylurea or metformin) or insulin, with stepwise addition of metformin (or glyburide in those initially allocated to metformin) in those poorly controlled on initial therapy or conversion to insulin alone in patients not adequately controlled with 2 oral agents.218,219,220,222 Intensive treatment consisted of antidiabetic therapy targeted to a fasting plasma glucose concentration of less than 108 mg/dL or, in patients receiving insulin, preprandial glucose concentrations of 72-126 mg/dL.218,219,220,222 Conventional treatment consisted of antidiabetic therapy targeted to a fasting plasma glucose concentration of less than 270 mg/dL without symptoms of hyperglycemia.218,219,220,222 Results of UKPDS indicate greater beneficial effects on retinopathy, nephropathy, and possibly neuropathy with intensive glucose-lowering therapy (median achieved HbA_1c concentration: 7%) in type 2 diabetics compared with that in the conventional treatment group (median achieved HbA_1c concentration: 7.9%).219,220 The overall incidence of microvascular complications was reduced by 25% with intensive therapy.219,200 Epidemiologic analysis of UKPDS results indicates a continuous relationship between the risks of microvascular complications and glycemia, with a 35% reduction in risk for each 1% reduction in HbA_1c, and no evidence of a glycemic threshold.219,220,273

The ADVANCE study also evaluated the relatively short-term effects (median follow-up: 5 years) of conventional or intensive therapy on the development of major vascular complications.274,280 The primary end point was the composite of major macrovascular (death from cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke) and major microvascular (new or worsening nephropathy or retinopathy) events.273,274 While the incidence of the primary composite end point was reduced by approximately 10% in the ADVANCE study, the beneficial effect was due principally to a 21% reduction in microvascular events (nephropathy); there was no appreciable reduction in macrovascular outcomes.273,274 Intensive antidiabetic therapy (mean achieved HbA_1c concentration: 6.5%) was associated with a reduction in new or worsening nephropathy compared with conventional treatment (mean achieved HbA_1c concentration of 7.3%), but there was no effect on the development of new or worsening retinopathy.273,274 Results of the Veterans Affairs Diabetes Trial (VADT), another study similar in design to the ADVANCE study, also indicated that intensive therapy in patients with poorly controlled type 2 diabetes mellitus (median baseline HbA_1c concentration of 9.4%) did not lessen the rate of microvascular complications compared with standard antidiabetic therapy.276

In UKPDS, fasting plasma glucose concentrations and HbA_1c values steadily increased over 10 years in the patients receiving conventional therapy, and more than 80% of these patients eventually required antidiabetic therapy in addition to diet to maintain fasting plasma glucose concentrations within the desired goal of less than 270 mg/dL.216,219,220,222 In patients receiving intensive therapy initiated with chlorpropamide, glyburide, or insulin, fasting plasma glucose concentrations and HbA_1c values decreased during the first year of the study.217,219,222 Subsequent increases in these indices of glycemic control after the first year paralleled that in the conventional therapy group for the remainder of the study, indicating slow decline of pancreatic β-cell function and loss of glycemic control regardless of intensity of therapy.217,219,223,224 In contrast to UKPDS, no diminution in the effect on HbA_1c or fasting blood glucose concentrations with either intensive or conventional therapy was observed in ADVANCE or VADT over a median follow-up of 5 or 5.6 years, respectively.273,274,275,276

Data from long-term follow-up (over 10 years) of middle-aged, newly diagnosed UKPDS patients with type 2 diabetes mellitus indicate that strict glycemic control (i.e., maintenance of fasting blood glucose concentrations below 108 mg/dL) was not achieved with initial intensive oral antidiabetic therapy (stepwise introduction of a sulfonylurea [i.e., chlorpropamide, glyburide], then insulin, or an oral sulfonylurea and insulin, or insulin alone to achieve fasting plasma glucose concentrations of 108 mg/dL) in most patients; at 3 and 9 years, 50 and 75%, respectively, of patients required combination therapy with sulfonylureas or initiation of insulin to maintain adequate glycemic control.216,220,223,231 While strict guidelines for insulin dosage adjustments were used in the DCCT study, adjustments of antidiabetic therapy dosage in UKPDS were not as frequent (dosage adjustments allowed every 3 months); in addition, the definition of secondary treatment failure with sulfonylureas and the time of institution of supplementary antidiabetic therapy changed as the study progressed.182,216,219,223,225 Because of the benefits of strict glycemic control, the goal of therapy for type 2 diabetes mellitus is to lower blood glucose to as close to normal as possible, which generally requires aggressive management efforts (e.g., mixing therapy with various antidiabetic agents including sulfonylureas, metformin, insulin, and/or possibly others) over time.220,225,264,272 For additional information on clinical studies demonstrating the benefits of strict glycemic control on microvascular complications in patients with type 1 or type 2 diabetes mellitus, see Glycemic Control and Microvascular Complications under Uses: Diabetes Mellitus, in the Insulins General Statement 68:20.08.

Macrovascular Outcomes and Cardiovascular Risk Reduction

Current evidence indicates that appropriate management of dyslipidemia, blood pressure, and vascular thrombosis provides substantial benefits in terms of reducing macrovascular complications associated with diabetes mellitus; intensive glycemic control generally has not been associated with appreciable reductions in macrovascular outcomes in controlled trials.182,219,220,221,225,258,273,274,275,276,277 Reduction in blood pressure to a mean of 144/82 mm Hg (“tight blood pressure control”) in patients with diabetes mellitus and uncomplicated mild to moderate hypertension in UKPDS substantially reduced the incidence of virtually all macrovascular (e.g., stroke, heart failure) and microvascular (e.g., retinopathy, vitreous hemorrhage, renal failure) outcomes and diabetes-related mortality; blood pressure and glycemic control were additive in their beneficial effects on these end points.217,220,222,225,228,229 While intensive antidiabetic therapy titrated with the goal of reducing HbA_1c to near-normal concentrations (6-6.5% or less) has not been associated with appreciable reductions in cardiovascular events during the randomized portion of controlled trials examining such outcomes,182,219,273,274,275,276 results of long-term follow-up (10-11 years) from DCCT and UKPDS indicate a delayed cardiovascular benefit in patients treated with intensive antidiabetic therapy early in the course of type 1 or type 2 diabetes mellitus.273,275,278,279,280,281 Recent evidence suggests that therapy with certain SGLT2 inhibitors or GLP-1 agonists can reduce the risk of major cardiovascular events (e.g., MI, stroke, cardiovascular death) or the risk of hospitalization for heart failure in patients with type 2 diabetes mellitus and established cardiovascular disease.617,618,619,620,621,622,623,624,704 Patients with type 2 diabetes mellitus who have established (or are at a high risk for) ASCVD, established kidney disease, or heart failure should receive a GLP-1 receptor agonist or SGLT2 inhibitor with demonstrated cardiovascular disease benefit.704,705 (See Reduction in Risk of Major Adverse Cardiovascular Events under Uses: Type 2 Diabetes Mellitus, in Liraglutide 68:20.06 and also see Reduction in Risk of Heart Failure-Related Hospitalization under Uses: Type 2 Diabetes Mellitus, in Dapagliflozin 68:20.18.) Experts state that therapy with a GLP-1 receptor agonist or SGLT2 inhibitor should be considered for patients with the aforementioned comorbidities independently of the patients' baseline or target HbA_1c.704 For additional details regarding the effects of antidiabetic therapy on macrovascular outcomes, see Reduction in Risk of Major Adverse Cardiovascular Events under Uses: Type 2 Diabetes Mellitus, in Canagliflozin 68:20.18, and in Liraglutide 68:20.06.

Treatment Goals

ADA currently recommends target preprandial (fasting) and peak postprandial (1-2 hours after the beginning of a meal) plasma glucose concentrations of 80-130 and less than 180 mg/dL, respectively, and HbA_1c concentrations of less than 7% (based on a nondiabetic range of 4-6%) in general in adults with type 1 or type 2 diabetes mellitus who are not pregnant.702 ADA states that these glycemic targets are appropriate for many patients but must be individualized based on key patient characteristics, such as potential risks of hypoglycemia and other adverse drug effects, disease duration, life expectancy, important comorbidities, established vascular complications, patient preference, and resources and support system.702 Patients with diabetes mellitus who have elevated HbA_1c concentrations despite having adequate preprandial glucose concentrations should monitor glucose concentrations 1-2 hours after the start of a meal and receive treatments aimed at reducing postprandial glucose concentrations.702

More stringent treatment goals (i.e., an HbA_1c less than 6%) can be considered in selected patients (e.g., during the second and third trimester of pregnancy) if achievable without substantial hypoglycemia.263,702,709 An individualized HbA_1c concentration goal that is closer to normal without risking substantial hypoglycemia is reasonable in patients with a short duration of diabetes mellitus, no appreciable cardiovascular disease, and a long life expectancy.273,702 Less stringent treatment goals may be appropriate in patients with long-standing diabetes mellitus in whom the general HbA_1c concentration goal of less than 7% is difficult to obtain despite adequate education on self-management of the disease, appropriate glucose monitoring, and effective dosages of multiple antidiabetic agents, including insulin.273,278,702 For additional details on individualizing treatment in patients with diabetes mellitus, see Treatment Goals under Uses: Diabetes Mellitus, in the Insulins General Statement 68:20.08.

Considerations in Initiating and Maintaining Antidiabetic Therapy

Recognizing that lifestyle interventions often fail to achieve or maintain the target glycemic goal within the first year of initiation of such interventions, ADA currently suggests initiation of metformin concurrently with lifestyle interventions at the time of diagnosis of type 2 diabetes mellitus.264,704 ADA and other clinicians state that lifestyle interventions should remain a principal consideration in the management of diabetes even after pharmacologic therapy is initiated.24,25,95,264,283,705 The importance of regular physical activity also should be emphasized, and cardiovascular risk factors should be identified and corrective measures employed when feasible.10,26,705

Metformin Monotherapy

Current guidelines for the treatment of type 2 diabetes mellitus generally recommend metformin as first-line therapy in addition to lifestyle modifications in patients with recent-onset type 2 diabetes mellitus or mild hyperglycemia because of its well-established safety and efficacy (i.e., beneficial effects on glycosylated hemoglobin [hemoglobin A_1c; HbA_1c], weight, and cardiovascular mortality).264,265,698,704,705 Potential advantages of metformin compared with sulfonylurea antidiabetic agents or insulin include a minimal risk of hypoglycemia, more favorable effects on serum lipids, reduction of hyperinsulinemia, and weight loss or lack of weight gain.2,3,6,16,17,18,19,20,27,30,42,60,68,102,134,146,166,264,698,704 Clinical studies indicate that metformin is as effective (approximately 1.5% decrease in HbA_1c values) as a sulfonylurea antidiabetic agent (e.g., chlorpropamide [no longer commercially available in the US],3,16,17,18,19,27,29,264 glyburide,15,18,19,27,29,45,46,57,78,264 glipizide,18,264 tolbutamide3,48,118,264 ) for the management of type 2 diabetes mellitus. Since metformin may stabilize or decrease body weight,1,3,4,6,8,16,17,18,19,20,21,105,118,166 the drug is particularly useful as initial monotherapy in obese individuals who might gain weight while receiving a sulfonylurea.15,16,17,265 Metformin is equally effective in lean or obese patients with type 2 diabetes mellitus.3,6,15,16,17,18,19,31,46,105,146 In patients receiving initial monotherapy with metformin, the incidence of primary and secondary failures appears to be less than6,27,166 or similar to6,16,17,18,122 that in patients receiving sulfonylurea monotherapy. Metformin may be effective as replacement monotherapy in some patients with primary or secondary failure to sulfonylureas.30,48,78,95,134,179 In patients with metformin contraindications or intolerance (e.g., risk of lactic acidosis, GI intolerance) or in selected other patients, some experts suggest that initial therapy with a drug from another class of antidiabetic agents (e.g., a GLP-1 receptor agonist, SGLT2 inhibitor, DPP-4 inhibitor, sulfonylurea, thiazolidinedione, basal insulin) may be acceptable based on patient factors.698,704 (See Type 2 Diabetes Mellitus: Combination Therapy, in Uses.)

The manufacturer states that metformin is not used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.1,260 (See Cautions: Contraindications.)

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 concentrations15,31,34,35,42,60,78,85,105 and HbA_1c15,35,42,68,78 substantially more than did placebo. 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 HbA_1c 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 drug 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 associated19 with weight gain or an increased incidence of hypoglycemia.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; HbA_1c concentrations generally had increased to baseline levels after 4-5 years of therapy with any of the drug 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

Combination Therapy

Because of the progressive nature of type 2 diabetes mellitus, patients initially receiving an oral antidiabetic agent will eventually require multiple oral and/or injectable noninsulin antidiabetic agents of different therapeutic classes and/or insulin for adequate glycemic control.698,704 Metformin may be used concomitantly with one or more oral antidiabetic agents or insulin to improve glycemic control in patients with type 2 diabetes.1,3,6,15,18,20,22,27,29,30,48,59,78,88,90,94,95,97,99,112,134,146,166,191,237,238,239,240,241,242,244,248,249,250,251,252,254,261,264,352,355,362,368,370,372,374,376,378,698,704 Data suggest that the addition of each noninsulin agent to initial antidiabetic therapy lowers HbA_1c by approximately 0.7-1%.704 Combined therapy with metformin and one or more other oral antidiabetic agents generally is used in patients with longstanding type 2 diabetes mellitus who have poor glycemic control with monotherapy.15,72,95,99,216,238,240,704 While usual practice generally has been to add additional antidiabetic agents in a sequential manner when metformin monotherapy no longer provides adequate glycemic control,264,704 initiating antidiabetic therapy with 2 agents (e.g., metformin plus another drug) may be appropriate in patients with an initial HbA_1c exceeding 7.5% or at least 1.5% above the target level.698,704 In addition, early initiation of combination therapy may help more rapidly attain glycemic goals and extend the time to treatment failure.704 In metformin-intolerant patients with high initial HbA_1c levels, some experts suggest initiation of therapy with 2 agents from other antidiabetic classes with complementary mechanisms of action.698,704 Experts state that the choice of which agent to add to metformin monotherapy is based on drug-specific effects and patient factors.698,704 Inclusion of a GLP-1 receptor agonist or SGLT2 inhibitor with demonstrated cardiovascular disease benefit may be preferred in patients with type 2 diabetes mellitus who have established (or are at a high risk for) ASCVD, established kidney disease, or heart failure.704,705 (See Reduction in Risk of Major Adverse Cardiovascular Events under Uses: Type 2 Diabetes Mellitus, in Liraglutide 68:20.06 and also see Reduction in Risk of Heart Failure-Related Hospitalization under Uses: Type 2 Diabetes Mellitus, in Dapagliflozin 68:20.18.) Experts state that therapy with a GLP-1 receptor agonist or SGLT2 inhibitor should be considered for patients with the aforementioned comorbidities independently of the patients' baseline or target HbA_1c.704 GLP-1 receptor agonists and SGLT2 inhibitors appear to have effects on the kidneys independent of their glycemic effects, and some experts suggest that an agent from one of these classes of drugs be considered in patients with type 2 diabetes mellitus and chronic kidney disease (CKD). 698,704,706 (See Beneficial Effects on Renal Function and Cardiovascular Morbidity and Mortality in Diabetic Nephropathy under Uses: Type 2 Diabetes Mellitus, in Canagliflozin 68:20.18.) In patients without established ASCVD or indicators of high ASCVD risk, heart failure, or CKD, the decision regarding the addition of other antidiabetic agents (e.g., GLP-1 receptor agonist, SGLT2 inhibitor, DPP-4 inhibitor, thiazolidinedione, sulfonylurea, basal insulin) to metformin therapy should be based on avoidance of adverse effects, cost, and individual patient factors.704

Combination Therapy with Oral and/or Injectable Noninsulin Antidiabetic Agents

Combined therapy with metformin and other noninsulin antidiabetic agents in patients not adequately controlled with monotherapy may reduce symptoms and serve as a means to delay or avoid institution of insulin.6,18,20,21,22,23,73,94,95,99,100,101,104,112,122,146,179,193,237,239,698,704 Factors to consider when selecting additional antidiabetic agents for combination therapy in patients with inadequate glycemic control on metformin monotherapy include patient comorbidities (e.g., atherosclerotic cardiovascular disease [ASCVD], established kidney disease, heart failure), hypoglycemia risk, impact on weight, cost, risk of adverse effects, and patient preference.698,699,704,705,706 When glycemic control is closer to the target HbA_1c goal with metformin monotherapy (e.g., HbA_1c less than 7.5%), some clinicians have suggested that an agent with a lesser potential to lower glycemia and/or slower onset of action may be considered (e.g., sulfonylurea, thiazolidinedione) as additional therapy to metformin.264 When the greater glucose-lowering effect of an injectable drug is needed in patients with type 2 diabetes mellitus, some experts currently state that an injectable GLP-1 receptor agonist is preferred over insulin in most patients because of beneficial effects on body weight and a lower risk of hypoglycemia, although adverse GI effects may diminish tolerability.698,704

While addition of a GLP-1 receptor agonist may successfully control hyperglycemia, many patients will eventually require insulin therapy.698 Early introduction of insulin therapy should be considered when hyperglycemia is severe (e.g., blood glucose of at least 300 mg/dL or HbA_1c exceeding 9-10%), especially in the presence of catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis) or symptoms of hyperglycemia.698,704 (See Combination Therapy with Insulin under Type 2 Diabetes Mellitus: Combination Therapy, in Uses.) For additional information regarding the initiation of insulin therapy in patients with diabetes mellitus, see Uses: Diabetes Mellitus, in the Insulins General Statement 68:20.08.

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 HbA_1c 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., HbA_1c 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 HbA_1c 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., HbA_1c 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 HbA_1c 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

Metformin also is used in combination with rosiglitazone in patients with type 2 diabetes mellitus when treatment with both metformin and rosiglitazone is appropriate.166,184,250 (See Combination Therapy under Uses: Type 2 Diabetes Mellitus, in Rosiglitazone 68:20.28.)

In a dose-ranging trial evaluating rosiglitazone 4 or 8 mg as add-on therapy to the maximum daily dosage of metformin hydrochloride, 28.1% of patients receiving the higher dosage of rosiglitazone concurrently with metformin achieved HbA_1c values of 7% or less.240

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 HbA_1c values.234 Strict glycemic control (e.g., HbA_1c 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 HbA_1c values, fasting plasma glucose concentrations) than metformin or repaglinide monotherapy.315 Combined therapy with metformin and repaglinide resulted in a greater reduction in HbA_1c 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 (HbA_1c exceeding 7.1%) with metformin monotherapy, addition of repaglinide to metformin therapy produced reductions in fasting plasma glucose concentrations and HbA_1c 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 HbA_1c.238,249 In a clinical trial in treatment-naive 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 HbA_1c 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 HbA_1c 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 HbA_1c.112,134,244 Fasting plasma glucose concentrations generally are not reduced by 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 HbA_1c 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 (See Combination Therapy under Uses: Type 2 Diabetes Mellitus, in Alogliptin 68:20.05.)

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 (See Combination Therapy under Uses: Type 2 Diabetes Mellitus, in Linagliptin 68:20.05.)

Extended-release metformin is used in fixed combination with saxagliptin in patients with type 2 diabetes mellitus when treatment with both drugs 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 (See Combination Therapy under Uses: Type 2 Diabetes Mellitus, in Saxagliptin 68:20.05.)

Metformin (immediate- or extended-release) is used in fixed combination with sitagliptin in patients with type 2 diabetes mellitus when treatment with both drugs 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 (See Combination Therapy under Uses: Type 2 Diabetes Mellitus, in Sitagliptin 68:20.05.)

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 drugs is appropriate.355,362,370,372,374 Efficacy and safety of these fixed combinations have been established based on concurrent administration of the 2 drugs 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 drugs had substantially greater improvements in HbA_1c than when either drug component was administered alone.355,362,370,372,374 (See Combination Therapy under Uses: Type 2 Diabetes Mellitus, in the individual monographs on Canagliflozin 68:20.18, Dapagliflozin 68:20.18, Empagliflozin 68:20.18, and Ertugliflozin 68:20.18.)

Combination Therapy with Insulin

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.698,704 Some experts state that patients with a HbA_1c exceeding 9-10% who have symptoms secondary to hyperglycemia (polyuria, polydipsia, polyphagia) despite therapy with 2 antidiabetic agents would likely derive the greatest benefit from addition of insulin.698,704 When insulin therapy becomes necessary, some experts recommend that a single daily dose of basal insulin be added to the drug therapy regimen.698 Patients whose basal insulin-containing regimens (which may already include metformin) fail to provide adequate glycemic control may benefit from the addition of a GLP-1 receptor agonist, SGLT2 inhibitor, or DPP-4 inhibitor (if they not already taking one of these drugs).698 When glycemia is still not adequately controlled with the addition of other oral antidiabetic agents or a GLP-1 receptor agonist and basal insulin, therapy with additional short-acting or rapid-acting insulin injections at mealtimes may be required.698 Patients receiving combined therapy with metformin and insulin or insulin secretagogues (e.g., sulfonylureas) may require lower dosages of insulin or insulin secretagogues to minimize the risk of hypoglycemia.1,260,698 (See Cautions: Hypoglycemia.)

Polycystic Ovary Syndrome

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 therapy for polycystic ovary syndrome remain limited, particularly regarding long-term efficacy, and available data are conflicting regarding the benefits of the drug in ameliorating various manifestations of the condition.289,290,295,300,302,306

While metformin has beneficial effects on cardiovascular risk factors such as insulin resistance298,300,303 and obesity,300 evidence from pooled analyses of data suggest that the drug has limited overall benefits on reproductive outcomes (e.g., live birth rates) in women with polycystic ovary syndrome.289,294,300,302,308 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

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 drugs such as metformin reasonable in the treatment of this condition.289,290,292,293,294,295,297,298,299,306,307

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 drug'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

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 drug 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

Administration

Metformin hydrochloride is administered orally.1,3,18,85 In patients receiving metformin hydrochloride immediate-release tablets at a dosage of 2 g or less daily, the drug usually can be given as 2 divided doses daily; however, in patients who require more than 2 g daily, the drug may be better tolerated if administered in 3 divided doses daily.1 Immediate-release metformin hydrochloride in fixed combination with canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, pioglitazone, alogliptin, linagliptin, or sitagliptin is administered in divided doses daily with meals to reduce the GI effects of the metformin hydrochloride component.260,314,355,362,370,372,376,610 Although food decreases the extent and slightly delays absorption of metformin immediate-release tablets, the manufacturer recommends that the drug be taken with meals to decrease adverse GI effects.1,3,18

Metformin hydrochloride extended-release tablets usually are taken with the evening meal.1,258,261 The manufacturer of Fortamet^® (metformin hydrochloride extended-release tablets) states that each dose of the drug should be taken with a full glass of water.258 The matrix core of some extended-release tablet preparations (e.g., Glumetza^®) usually is broken up in the GI tract, but patients should be advised that occasionally the biologically inert components of the tablet may remain intact and be passed in the stool as a soft, hydrated mass.261 Occasionally, Glumetza^® may be eliminated in the feces as a soft, hydrated mass or an insoluble shell.261 The membrane coating surrounding the core of another extended-release tablet (Fortamet^®) remains intact through the GI tract and is excreted in feces as a soft mass that may resemble the original tablet.258 (See Chemistry and Stability: Stability.)

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 drug 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

Dosage

Type 2 Diabetes Mellitus

Dosage of metformin hydrochloride must be individualized carefully based on patient response and tolerance.1,4 The goal of therapy should be to reduce both fasting glucose and glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) values to normal or near normal using the lowest effective dosage of metformin hydrochloride, either when used as monotherapy or combined with another antidiabetic agent.1,8,13,78,85,88,105,134,146,166,235 Patients should be monitored with regular laboratory evaluations, including fasting blood (or plasma) glucose determinations, to assess therapeutic response and the minimum effective dosage of metformin hydrochloride.1,2,85

Following initiation of metformin therapy and dosage titration, determination of HbA_1c concentrations at intervals of approximately 3 months is useful for assessing the patient's continued response to therapy.2,3,134,234

Since adverse GI effects with metformin appear to be dose related, it is recommended that dosage of the drug be increased gradually and that the drug be taken with meals.1,2,18,53,85,261 (See Cautions: GI Effects.)

Initial Dosage

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 Alternatively, an initial metformin hydrochloride dosage of 500 mg once daily has been suggested by some experts.264 Some manufacturers state that in general, clinically important responses are not observed at metformin hydrochloride dosages of less than 1.5 g daily.261

When metformin hydrochloride is administered as an extended-release tablet preparation in adults, some manufacturers recommend an initial dosage of 500 mg once daily with the evening meal.1 The manufacturer of a certain extended-release tablet preparation (Fortamet^®) recommends an initial dosage of 1 g once daily with the evening meal, although the manufacturer states that 500 mg once daily may be used when clinically appropriate.258 The recommended initial dosage of another extended-release preparation of metformin hydrochloride (Glumetza^®) is 1 g once daily with the evening meal.261 Subsequent dosage of metformin hydrochloride should be adjusted according to the patient's therapeutic response, using the lowest possible effective dosage.1,30 (See Dosage: Dosage Titration, under Dosage and Administration.)

Although satisfactory control of blood glucose concentrations may be achieved within a few days after dosage adjustment, the full effects of the drug may not be observed for up to 2 weeks.18,134

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;1,2,3,4,165,254,258,261,314 limited data suggest reducing dosage by approximately 33% in geriatric patients.30,174

For the management of type 2 diabetes mellitus in children or adolescents 10-16 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 Safety and efficacy of Fortamet^®258 and certain other extended-release tablet preparations of metformin hydrochloride have not been established in patients younger than 17 years of a refer to labeling of specific preparations for details.1,258 Safety and efficacy of Glumetza^®, another extended-release tablet preparation, have not been established in patients younger than 18 years of age.261

Transferring from Therapy with Other Antidiabetic Agents

When transferring from most sulfonylurea antidiabetic agents to metformin, a transition period generally is not required, and administration of the sulfonylurea antidiabetic agent may be abruptly discontinued.2,258,261 Because an exaggerated hypoglycemic response may occur in some patients during the transition from a sulfonylurea antidiabetic agent with a prolonged half-life (e.g., chlorpropamide [no longer commercially available in the US]) to metformin, patients being transferred from such agents should be monitored closely for the occurrence of hypoglycemia during the initial 2 weeks of the transition period.2,30,261

Dosage Titration

In adults receiving an initial metformin hydrochloride dosage of 500 mg twice daily as immediate-release tablets or the immediate-release oral solution, daily dosage may be increased by 500 mg at weekly intervals until the desired fasting blood glucose concentration is achieved or a dosage of 2.55 g daily is reached.1,257 In adults receiving an initial dosage of 500 mg of metformin hydrochloride once or twice daily (with breakfast and/or dinner), some experts recommend increasing the dosage to 850 mg or 1 g twice daily after 5-7 days if additional glycemic control is needed and the drug is well tolerated (e.g., no adverse GI effects).264 If adverse GI effects appear during dosage titration of metformin hydrochloride, some experts suggest that dosage be decreased to the previous lower dosage, and further dosage increments attempted at a later time.264 In adults receiving an initial metformin hydrochloride dosage of 850 mg daily as immediate-release tablets or the immediate-release oral solution, daily dosage may be increased by 850 mg every other week (i.e., every 2 weeks) until the desired fasting blood glucose concentration is achieved or a total dosage of 2.55 g daily is reached.1,257 For patients requiring additional glycemic control with metformin hydrochloride, a maximum daily dosage of 2.55 g as immediate-release tablets or the immediate-release oral solution may be used.1,257

In adults (17-18 years of age or older) receiving Glumetza^®261 or certain other extended-release metformin hydrochloride preparations, daily dosage may be increased by 500 mg at weekly intervals until the desired glycemic response is achieved or a maximum dosage of 2 g daily is reached.1,261 If glycemic control is not achieved with extended-release metformin hydrochloride tablets (e.g., Glumetza^®) at a dosage of 2 g once daily, a dosage of 1 g twice daily should be considered.1,261 If a dosage exceeding 2 g daily is needed in patients receiving certain other extended-release metformin hydrochloride preparations, the manufacturers suggest that therapy be switched to immediate-release metformin hydrochloride tablets and dosage titrated up to a maximum dosage of 2.55 g daily in divided doses.1 Conversely, therapy with extended-release tablets may be substituted for immediate-release tablets at the same total daily dosage of immediate-release tablets, up to a dosage of 2 g once daily.1,261

With another extended-release metformin hydrochloride preparation (Fortamet^®), daily dosage may be increased by 500 mg at weekly intervals up to a maximum of 2.5 g once daily with the evening meal.258 In patients transferring from immediate-release tablets to an extended-release preparation, glycemic control should be closely monitored and dosage adjustments made accordingly.258

Dosage in adults generally should not exceed 2.55 g daily when given as metformin hydrochloride immediate-release tablets or immediate-release oral solution, 2.5 g daily when given as certain extended-release tablets (e.g., Fortamet^®),1,257,258 or 2 g daily when given as certain other extended-release tablet preparations.1 Metformin hydrochloride dosages of up to 3 g daily have been associated with modestly greater effectiveness than 1.7 g daily.264 However, adverse GI effects may limit the maximum dosage that can be tolerated.264 (Consult the manufacturer's labeling for product-specific details.) Dosages exceeding 2 g of metformin hydrochloride daily as immediate-release tablets or the immediate-release oral solution may be better tolerated if given in 3 divided doses daily with meals.1,257

Metformin should be used with caution in geriatric patients since aging is associated with reduced renal function, and accumulation of the drug resulting in lactic acidosis may occur in patients with renal impairment.1,3,4,165,258,260,261 In addition, renal function should be monitored periodically in geriatric patients to determine the appropriate dosage of metformin hydrochloride.1,2,3,4,164,165,258,260 Any dosage adjustment in geriatric patients should be based on a careful assessment of renal function.260,261

In children or adolescents 10-16 years of age receiving metformin hydrochloride 500 mg twice daily as immediate-release tablets or the immediate-release oral solution, daily dosage may be increased by 500 mg at weekly intervals until the desired glycemic response is achieved or a maximum dosage of 2 g daily given in 2 divided doses is reached.1,257

Combination Therapy with Metformin and Sulfonylurea Antidiabetic Agents

While additional antidiabetic agents generally are added in a sequential manner to metformin monotherapy when such therapy no longer provides adequate glycemic control,264,704 initial antidiabetic therapy with 2 agents (e.g., metformin plus another drug) also may be appropriate in patients with high initial HbA_1c values.698,704 (See Combination Therapy under Uses: Type 2 Diabetes Mellitus.)

The manufacturers of certain extended-release metformin hydrochloride tablets (Fortamet^®, Glumetza^®) suggest that gradual addition of an oral sulfonylurea agent be considered in patients not responding to 4 weeks of monotherapy with maximum dosages of metformin hydrochloride.258,261 Metformin hydrochloride should be continued at the maximum dosage in such patients even if prior primary or secondary failure to a sulfonylurea has occurred.258,261 Dosage of metformin hydrochloride (Fortamet^®, Glumetza^®) and the sulfonylurea should be adjusted to obtain the desired level of glycemic control with the minimum effective dosage.258,261 Concomitant metformin and sulfonylurea therapy may increase the risk of hypoglycemia; appropriate precautions should be taken.258,261 If the patient has not responded satisfactorily to 1-3 months of concomitant therapy with maximum dosages of metformin hydrochloride (Fortamet^®, Glumetza^®) and an oral sulfonylurea, therapeutic alternatives, including switching to insulin with or without metformin, should be considered.258,261

If the fixed combination of metformin hydrochloride and glipizide is used as initial therapy in 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 2.5 mg of glipizide and 250 mg of metformin hydrochloride or 2.5 mg of glipizide and 500 mg of metformin hydrochloride) at 2-week intervals until the minimum effective dosage required to achieve adequate blood glucose control or 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.254,256

In patients not already receiving therapy with either glyburide (or another sulfonylurea) or metformin hydrochloride, 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 glyburide 2.5 mg and metformin hydrochloride 500 mg or glyburide 5 mg and metformin hydrochloride 500 mg orally twice daily with meals.234 For patients previously treated with the combination of glyburide (or another sulfonylurea) and metformin hydrochloride, the initial dosage of glyburide and metformin hydrochloride 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 20 mg of glyburide and 2 g of metformin hydrochloride.234

Therapy with metformin in fixed combination with glyburide should be used with caution in geriatric patients, since aging is associated with reduced renal function.234 The initial and maintenance dosages of metformin hydrochloride in fixed combination with glyburide should be conservative, 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 drug therapy and higher risk of hypoglycemia and lactic acidosis in the elderly.234

Combination Therapy with Metformin and Pioglitazone

Dosage of the fixed combination of immediate-release metformin hydrochloride and pioglitazone should be based on the patient's current dosages of metformin hydrochloride and/or pioglitazone and on effectiveness and tolerability.260 For patients in whom combination therapy with metformin and pioglitazone is considered appropriate, the usual initial dosage of the fixed combination is metformin hydrochloride 500 mg and pioglitazone 15 mg twice daily or metformin hydrochloride 850 mg and pioglitazone 15 mg once daily.260 For patients inadequately controlled on metformin hydrochloride monotherapy, the usual initial dosage of the fixed combination is metformin hydrochloride 500 mg and pioglitazone 15 mg twice daily or metformin hydrochloride 850 mg and pioglitazone 15 mg once or twice daily (depending on the dosage of metformin hydrochloride already being taken).260 For patients inadequately controlled on pioglitazone monotherapy, the usual initial dosage of the fixed combination is metformin hydrochloride 500 mg and pioglitazone 15 mg twice daily or metformin hydrochloride 850 mg and pioglitazone 15 mg once daily.260 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

For 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 500 mg and pioglitazone 15 mg or metformin hydrochloride 850 mg and pioglitazone 15 mg once daily.260 Initiation of the fixed combination of metformin and pioglitazone is contraindicated in patients with NYHA class III or IV congestive heart failure.260 (See Cautions: Precautions and Contraindications.)

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 Metformin hydrochloride dosages exceeding 2 g daily may be better tolerated if given in 3 divided doses daily.260

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 Dosage should be increased gradually to minimize the adverse GI effects of metformin.610 The maximum recommended dosage of the fixed combination of metformin hydrochloride and alogliptin is 2 g of metformin hydrochloride and 25 mg of alogliptin daily.610

Metformin Hydrochloride/Linagliptin Fixed-combination Therapy

Dosage of the fixed combination of metformin hydrochloride and linagliptin should be individualized based on its effectiveness and patient tolerability.376,378 The dosage may be increased up to a maximum of 2 g of metformin hydrochloride and 5 mg of linagliptin daily.376,378

In 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 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 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 linagliptin and metformin or the fixed combination of linagliptin and immediate-release metformin, 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/Saxagliptin Fixed-combination Therapy

Dosage of extended-release metformin hydrochloride in fixed combination with saxagliptin hydrochloride should be individualized based on the patient's current antidiabetic regimen, clinical response, and tolerability.368 Any change in therapy should be undertaken with care and appropriate monitoring because changes in glycemic control can occur.368

When the fixed-combination preparation containing extended-release metformin hydrochloride and saxagliptin is used in patients inadequately controlled on monotherapy with saxagliptin 5 mg daily, 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

When the fixed-combination preparation containing extended-release metformin hydrochloride and saxagliptin is used in patients inadequately controlled on monotherapy with extended-release metformin hydrochloride, dosage of the fixed combination should provide metformin hydrochloride at the patient's current dosage or at the nearest therapeutically appropriate dosage.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 inadequately controlled on monotherapy with saxagliptin 2.5 mg daily, the recommended initial 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 and who are either metformin naive 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.314,352 When the fixed combination containing immediate-release metformin hydrochloride and sitagliptin is used in 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 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 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 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 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 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 sitagliptin and immediate- or extended-release metformin hydrochloride 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

Concomitant administration of the fixed combination of immediate- or extended-release metformin hydrochloride and sitagliptin with a sulfonylurea or insulin may require reduced dosages of the sulfonylurea or insulin to reduce the risk of hypoglycemia.314,352

Dosage of metformin hydrochloride in fixed combination with sitagliptin should be selected carefully in patients of advanced age, since aging is associated with reduced renal function.314 In geriatric patients, dosage adjustment should be based on careful and regular assessment of renal function.314

Metformin Hydrochloride/Canagliflozin Fixed-combination Therapy

When the commercially available fixed combination of immediate-release metformin hydrochloride and canagliflozin (Invokamet^®) is used in patients with type 2 diabetes mellitus in whom treatment with both drugs is appropriate, the initial dosage should be based on the patient's current regimen with canagliflozin and/or metformin hydrochloride.370 In patients with an estimated glomerular filtration rate (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 of these drugs 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 canagliflozin and metformin hydrochloride 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

Metformin Hydrochloride/Dapagliflozin Fixed-combination Therapy

When the commercially available fixed combination of extended-release metformin hydrochloride and dapagliflozin (Xigduo^® XR) is used in patients 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 dapagliflozin, 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 dapagliflozin and metformin hydrochloride 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 should be individualized based on the patient's current antidiabetic regimen.372,374 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 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 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 an ertugliflozin dosage similar to the patient's existing total daily dosage, 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

Concomitant Therapy with Metformin and Insulin

In patients receiving insulin therapy in whom metformin is to be given concomitantly, the current insulin dosage should initially be continued.258,261 In such patients, some manufacturers recommend an initial metformin hydrochloride dosage of 500 mg once daily as extended-release tablets (Fortamet^®, Glumetza^®).258,261 For patients with inadequate glycemic response, the daily dosage of metformin hydrochloride may be increased by 500 mg at weekly intervals until glycemic control is achieved or a maximum dosage of 2.5 or 2 g daily is reached with the extended-release tablet preparations Fortamet^® or Glumetza^®, respectively.258,261 When fasting plasma glucose concentrations decrease to less than 120 mg/dL in patients receiving combined metformin and insulin therapy, some manufacturers of metformin recommend that insulin dosage be decreased by 10-25%.258,261 Further dosage adjustments should be individualized based on glycemic response.258,261

Polycystic Ovary Syndrome

In women with polycystic ovary syndrome†, metformin hydrochloride dosages of 1.5-2.25 g daily in divided doses generally 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

Dosage in Renal and Hepatic Impairment

Because of the risk of lactic acidosis, which occurs rarely but may be fatal, metformin should not be used in patients with severe renal disease or dysfunction (eGFR less than 30 mL/minute per 1.73 m²) and should be avoided in those with clinical or laboratory evidence of hepatic disease.1,165,260,287,314,330,336 In patients with moderate renal disease, the benefits and risks of continuing metformin therapy should be assessed.330,336 (See Cautions: Lactic Acidosis.)

An FDA review of clinical studies evaluating the safety of metformin in patients with reduced kidney function suggests that metformin can be used safely in patients with mild impairment in kidney function and in some patients with moderate impairment in kidney function.330,331,332,333,334

The manufacturers and FDA state that renal function (eGFR) should be assessed prior to initiation of metformin and at least annually; more frequent monitoring has been recommended in patients with an increased risk of developing renal impairment (e.g., geriatric patients).1,234,254,260,330 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 that the benefits and risks of continuing the drug should be assessed in those already receiving metformin whose eGFR falls below 45 mL/minute per 1.73 m².1,234,254,257,260,330,336 The manufacturers and FDA state that metformin is contraindicated in patients with an eGFR of less than 30 mL/minute per 1.73 m² and that the drug should be discontinued in patients whose eGFR falls below 30 mL/minute per 1.73 m² who are already receiving metformin.1,234,254,257,260,330,336

Adverse effects, principally GI effects, reportedly occur in about 5-50% of patients receiving metformin therapy as immediate-release tablets in clinical trials and generally required discontinuance of the drug in 6% or less of patients.6,18,20,23,27,134

Lactic Acidosis

Accumulation of metformin may occur in patients with renal impairment, and such accumulation rarely can result in lactic acidosis, a serious, potentially fatal metabolic disease.1,6,18,20,27,29,30,62,89,96,158,260,314,352,355,361 The reported overall incidence of lactic acidosis in patients receiving metformin therapy is approximately 0.04 cases per 1000 patient-years of metformin therapy.360 (See Cautions: Precautions and Contraindications and also see Chemistry and Stability: Chemistry.) However, 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 also is recommended.1,23,32,62,117,119,260,314,352,355 (See Acute Toxicity.)

Cases of metformin-associated lactic acidosis reported during postmarketing experience have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias.234,254,260 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), an increased lactate/pyruvate ratio.1,260,314,352 Lactic acidosis also may occur in association with a variety of pathophysiologic conditions, including diabetes mellitus, and generally whenever substantial tissue hypoperfusion and hypoxemia exist.32,53,63,64,93,96,123,146,288,314,361 Approximately 50% of cases of metformin-associated lactic acidosis have been reported to be fatal.2,3,4,33,78,95,146,158,360 However, it has been suggested that in such cases of lactic acidosis not accompanied by conditions predisposing to tissue anoxia (e.g., heart failure, renal or pulmonary disease), techniques for the elimination of metformin from the body may allow recovery rates exceeding 80%.158

The manufacturer states that when metformin has been implicated as the cause of lactic acidosis, plasma metformin concentrations exceeding 5 mcg/mL generally have been observed.1,234,254,314 However, plasma metformin concentrations may not be an accurate indication of tissue accumulation of the drug 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 drug.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).96,134,158,320 Some observational data suggest that neither plasma metformin concentrations nor plasma lactate concentrations are related to mortality in patients with lactic acidosis receiving metformin.320,322

Lactic acidosis often has a subtle onset and may be accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific and unexplained abdominal distress with nausea and vomiting or diarrhea.1,32,62,119,234,260,314 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 Patients and clinicians should be aware of the possible importance of such symptoms, and patients should be instructed to notify their clinician immediately if these symptoms occur;1,2,260 metformin should be discontinued until the patient is hospitalized and a clinician has evaluated the patient's condition.1,30,314 Once a patient is stabilized at any dosage of metformin hydrochloride, GI symptoms, which are common during initiation of therapy, are unlikely to be drug related; later occurrence of GI symptoms could be manifestations of lactic acidosis or other serious disease.314

Lactic acidosis associated with metformin therapy generally has occurred in diabetic patients with severe renal insufficiency; most cases of lactic acidosis have been reported in patients with concomitant medical and/or surgical problems who were receiving multiple drugs.1,2,3,20,50,62,64,76,96,123,158,164,165,234,254,260,287,288,316,317,320,322,361

Some observational studies and meta-analyses suggest that the incidence of lactic acidosis in patients with type 2 diabetes mellitus who are receiving metformin therapy is similar to that in patients not receiving the drug.287,288,318,319,320,321,322 Analyses of pooled data that included all known prospective comparative trials and observational cohort studies of metformin therapy of at least 1 month's duration (up to 70,490 patient-years of metformin treatment) revealed no cases of fatal or nonfatal metformin-induced lactic acidosis; therefore, an incidence rate for metformin-associated lactic acidosis could not be calculated.287,318,321,322 While these analyses allowed for the inclusion of patients with at least one contraindication to metformin (e.g., renal insufficiency), information on the safety of metformin in the presence of such contraindications could not be evaluated because of the lack of information on the number of included patients with such conditions.287,318 In these analyses, all cases of lactic acidosis reportedly occurred in patients with comorbidities predisposing to lactic acidosis, suggesting that association of the condition with metformin use may be coincidental rather than causal.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 drug 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.1,2,62,63,93,234,254,260,314,340 Therapy with the drug alone or in fixed combinations also should be avoided in patients with clinical or laboratory evidence of hepatic impairment since elimination of lactate may be reduced substantially in such patients.1,2,63,65,85,91,93,156,158,234,254,260,314,352,355 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.1,2,63,76,91,93,158,234,254,260,314,352,355

The manufacturers, FDA, and other clinicians state that 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 estimated glomerular filtration rate (eGFR) of 30-60 mL/minute per 1.73 m² and in patients with a history of liver disease, alcoholism, or heart failure.1,257,260,314,330,336,352,355,610 Therapy with metformin-containing preparations also should be withheld temporarily in patients undergoing surgery.1,2,30,62,63,93,158,234,254,260,261,314,330,336,352,355,610 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 (See Cautions: Precautions and Contraindications.)

GI Effects

Adverse GI effects such as diarrhea,1,31,48,49,53,78,109,118,122,135,234,254,258 nausea,1,31,53,78,109,118,122,254,258 vomiting,1,118,122,234,254 flatulence,1,258 indigestion,1 and abdominal discomfort (e.g., bloating, abdominal cramping or pain)1,31,35,42,53,118,122,234 are the most common adverse effects associated with metformin-containing therapy as immediate-release tablets;1,2,18,20,234,254 diarrhea and nausea/vomiting are among the most common drug-related adverse effects reported in clinical trials with the extended-release tablets.1,258 Because substantial diarrhea and/or vomiting may cause dehydration and prerenal azotemia, metformin should be discontinued in patients who develop such potentially serious GI effects; persistent diarrhea resolves promptly upon discontinuance of the drug.18 Unpleasant or metallic taste (taste disorder/disturbance),1,18,118,122 which usually resolves spontaneously, has been reported in approximately 1-5% of patients receiving metformin immediate-release or extended-release tablets.1,2,3,30 Other adverse GI effects reported in 1-5% of patients receiving certain immediate-release or extended-release metformin tablet preparations include abnormal stools,1 abdominal pain,1 distended abdomen,1 constipation,1,49,118 dyspepsia/heartburn,1,49,118 and flatulence.1 Other adverse GI effects reported in 1-5% of patients receiving another metformin extended-release tablet (Fortamet^®) include dyspepsia,258 flatulence,258 and abdominal pain.258 Anorexia also has been reported with metformin therapy.3,6,18

Metformin-induced adverse GI effects appear to be dose related, generally occur at initiation of therapy, and usually subside spontaneously during continued metformin therapy; in some cases, a reduction in metformin hydrochloride dosage may be useful in hastening resolution of these effects.2,3,4,16,21,23,30,69,85,105,134,146 Diarrhea severe enough to require discontinuance of metformin occurred in about 6% of patients receiving the immediate-release tablets and in about 0.6% of those receiving the extended-release tablets in controlled clinical trials.1,30,78,260 Since adverse GI effects occurring during initiation of metformin therapy appear to be dose related, they may be reduced by gradual dosage escalation and administration of the drug with meals.2,16,18,53,85

Diarrhea was reported in up to 7.5% of patients receiving combined therapy with metformin hydrochloride and sitagliptin in clinical trials.314

Hypoglycemia

Hypoglycemia is uncommon in patients receiving metformin as monotherapy; however, it may occur when metformin is used concomitantly with an insulin secretagogue (e.g., sulfonylurea antidiabetic agent), a thiazolidinedione, or insulin; when caloric intake is deficient; or when strenuous exercise is not accompanied by food intake.1,15,30,78,94,99,234,254,698 Symptoms of hypoglycemia (such as dizziness, shakiness, sweating, hunger) have occurred in 21.3, 11.4, or 37.7% of patients receiving glyburide (5.3 mg), glyburide in fixed combination with metformin hydrochloride (2.78 mg of glyburide, 557 mg of metformin hydrochloride), or glyburide in fixed combination with metformin hydrochloride at a final mean titrated dosage of 824 mg of metformin hydrochloride and 4.1 mg of glyburide in controlled clinical trials.234 In a controlled initial therapy trial of metformin hydrochloride in fixed combination with glipizide, symptomatic hypoglycemia and blood glucose concentrations 50 mg/dL or less occurred in 2.9, 0, 7.6, or 9.3% of patients receiving glipizide monotherapy (final mean dosage of 16.7 mg), metformin hydrochloride monotherapy (final mean dosage of 1.749 g of metformin hydrochloride), the fixed combination with glipizide (final mean dosage of 791 mg of metformin hydrochloride and 7.9 mg of glipizide), and the fixed combination with a higher dosage of the metformin hydrochloride component (final mean dosage of 1.477 g of metformin hydrochloride and 7.4 mg of glipizide).254 In a controlled trial in patients inadequately controlled by monotherapy with metformin hydrochloride or a sulfonylurea agent, documented hypoglycemia (as determined by blood glucose concentrations of 50 mg/dL or less) occurred in 0, 1.3, or 12.6% of patients receiving glipizide monotherapy (mean final dosage of 30 mg), metformin hydrochloride monotherapy (mean final dosage of 1.927 g), or metformin hydrochloride in fixed combination with glipizide at a final mean dosage of 1.747 g of metformin hydrochloride and 5 mg of glipizide.254 When rosiglitazone was added to fixed combination therapy of glyburide and metformin hydrochloride, documented hypoglycemia occurred in 22% of such patients compared to 3.3% of patients receiving glyburide in fixed combination with metformin hydrochloride.234 (See Cautions: Precautions and Contraindications.)

Hypoglycemia was reported in 16.4% of patients when sitagliptin was added to combined metformin hydrochloride and glimepiride therapy, compared with 0.9% of those receiving placebo in conjunction with metformin hydrochloride and glimepiride therapy.314

Hematologic Effects

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 29-week controlled clinical trials.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 B₁₂.1,3,6,20,30,70,77,82,134,261,314 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.2,18,114,314 No increased incidence of neuropathy has been observed in patients receiving the drug.18,114,123 Hematologic parameters (e.g., hemoglobin) should be monitored annually and serum vitamin B₁₂ concentrations should be monitored every 2-3 years in patients receiving metformin; any apparent abnormalities should be appropriately investigated and managed (e.g., administration of supplemental vitamin B₁₂ to those who develop neuropathy).1,314,698 Some individuals such as those who have inadequate vitamin B₁₂ or calcium intake or absorption appear to be at an increased risk for developing subnormal vitamin B₁₂ concentrations.1 Some clinicians have suggested that periodic supplementation with parenteral vitamin B₁₂ be considered in such patients and in alcoholics.82,114,122,134,148 (See Cautions: Precautions and Contraindications.)

Dermatologic Reactions

Rash has been reported in 1-5% of patients receiving immediate-release metformin in clinical trials.1

Nervous System Effects

Headache,118 agitation,118 dizziness,118 and tiredness118 were reported in a small comparative study in geriatric diabetic patients receiving metformin.30,85 Headache was reported in 4.7 or 5.1% of patients receiving metformin as an extended-release tablet preparation (Fortamet^®) or as immediate-release tablets, respectively.258 Headache has been reported in 9.3 or 8.9% of patients receiving metformin or metformin in fixed combination with glyburide, respectively.234 Headache has been reported in 5.3 or 12.6% of patients receiving metformin or metformin in fixed combination with glipizide, respectively.254 Headache has been reported in 5.9% of patients receiving combined therapy with metformin and sitagliptin and 6.9% of patients receiving combined therapy with metformin, sitagliptin, and glimepiride in clinical trials.314 Dizziness has been reported in 3.8 or 5.5% of patients receiving metformin or metformin in fixed combination with glyburide, respectively.234 Dizziness has been reported in 3.8 or 5.5% of patients receiving metformin or metformin in fixed combination with glyburide, respectively.234

Respiratory Effects

Pneumonitis with vasculitis has been reported rarely with concomitant metformin and oral sulfonylurea (e.g., glyburide) therapy.18,74 Upper respiratory tract infection was reported in 16.3 or 17.3% of patients receiving metformin or metformin in fixed combination with glyburide, respectively.234 Upper respiratory tract infection was reported in 8.5 or 8.1-9.9% of patients receiving metformin or metformin in fixed combination with glipizide, respectively, as initial therapy for type 2 diabetes mellitus.254 Upper respiratory tract infection was reported in 10.7 or 10.3% of patients receiving metformin or metformin in fixed combination with glipizide, respectively, as second-line therapy for type 2 diabetes mellitus.254 Upper respiratory tract infection was reported in 5.2 or 6.2% of patients receiving metformin or metformin combined with sitagliptin, respectively, in clinical trials.314 Rhinitis was reported in 4.2 or 5.6% of patients receiving metformin as an extended-release tablet preparation (Fortamet^®) or as immediate-release tablets, respectively.258 Infection was reported in 20.5 or 20.9% of patients receiving an extended-release tablet preparation (Fortamet^®) or immediate-release tablets, respectively.258

Macrovascular Outcomes

The manufacturer states that there have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin.1,260

Other Adverse Effects

Urinary tract infection has been reported in 8 or 1.1% of patients receiving metformin alone or in fixed combination with glipizide, respectively.254 Hypertension has been reported in 5.6 or 2.9-3.5% of patients receiving metformin alone or in fixed combination with glipizide, respectively.254 Musculoskeletal pain has been reported in 6.7 or 8% of patients receiving metformin alone or in fixed combination with glipizide, respectively.254 Severe acute hepatitis associated with marked elevations in serum hepatic aminotransferase values and cholestasis has been reported following initiation of metformin therapy in a patient receiving glipizide and enalapril.213 Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported during postmarketing experience with metformin therapy.260 Accidental injury was reported in 7.3 or 5.6% of patients receiving metformin as an extended-release tablet preparation (Fortamet^®) or as immediate-release tablets, respectively.258

Precautions and Contraindications

When metformin hydrochloride is used in fixed combination with other drugs (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

The diagnostic and therapeutic measures for managing diabetes mellitus that are necessary to ensure optimum control of the disease with insulin are generally necessary with metformin.12,13,25,26,134,179,181 Clinicians who prescribe metformin should be familiar with the indications, limitations, and patient-selection criteria for therapy with oral antidiabetic agents to ensure appropriate patient management.10,23,30,134,187 Patients receiving metformin should be monitored with regular laboratory evaluations, including blood glucose determinations, to determine the minimum effective dosage of metformin hydrochloride when used either as monotherapy or in combination with a sulfonylurea or thiazolidinedione antidiabetic agent.1,2,88,179,187,260 Glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) measurements also are useful, particularly for monitoring long-term control of blood glucose concentration.2,134

Patients should be informed of the risks of lactic acidosis and conditions that predispose to its development.1,234,254 (See Cautions: Lactic Acidosis.) Since metformin is excreted substantially by the kidneys, accumulation of the drug resulting in lactic acidosis may occur in patients with renal impairment;1,91,93,164,234,254 the risk of lactic acidosis increases with degree of renal impairment.1,234,254 Hemodialysis has been used in patients with lactic acidosis to accelerate the clearance of metformin.1,23,32,62,117,119,234,254,314,352,355 (See Acute Toxicity.) The manufacturer states that eGFR (renal function) should be evaluated prior to initiation of therapy with metformin preparations and at least annually thereafter.1,2,77,85,234,254,314

Extended-release metformin hydrochloride tablets or fixed-combination preparations containing the extended-release form of the drug should not be chewed, cut, or crushed; these dosage forms must be swallowed whole.1,234,254,258,261,352 Patients should be aware that the biologically inert components of the tablet may occasionally be eliminated in the feces as a soft, hydrated mass.1,234,254,258,261

Some clinicians state that metformin should not be used in patients with heart failure requiring drug therapy (e.g., digoxin, furosemide), such as those with unstable or acute heart failure.209,215 These patients are at risk for hypoperfusion and hypoxemia, which may lead to lactic acidosis.215 It has been suggested that metformin may be reinstituted once acute heart failure has resolved and renal function is normal (as measured by creatinine clearance);215 the decision to continue metformin therapy in such patients should be individualized.320

Iodinated contrast agents are a potential concern for furthering renal damage in patients with acute kidney injury, and in patients with severe chronic kidney disease (stage IV or stage V).335 Since administration of iodinated contrast media may lead to acute alteration of renal function and has been associated with lactic acidosis in patients receiving metformin, the manufacturers state that metformin-containing preparations should be discontinued before or at the time of the procedure in patients with an eGFR between 30-60 mL/minute per 1.73 m²; in patients with a history of liver disease, alcoholism, or heart failure; and in those receiving intra-arterial iodinated contrast agents.1,234,254,257,258,261,330,336,610 Renal function should be evaluated 48 hours after the imaging procedure and metformin therapy may be reinstituted if renal function is stable.1,234,257,258,330,335,610 However, the American College of Radiology states that in patients with no evidence of acute kidney injury and an eGFR of at least 30 mL/minute per 1.73 m², there is no need to discontinue metformin either prior to or following the administration of iodinated contrast media, nor is there a need to reassess the patient's renal function following the test or procedure.335

Patients should be instructed to inform their clinicians that they are taking metformin or metformin-containing therapy prior to any surgical or radiological procedure since temporary discontinuation of the drug may be required.1,234,254,260 The manufacturers state that the drug should be reinitiated only when the patient's oral intake has resumed and renal function has been shown to be normal.1,234,254,314,610 In addition, any diabetic patient previously well controlled with metformin therapy who develops a clinical illness (especially one that is vague and poorly defined) or whose laboratory test results deviate from normal should be evaluated promptly for evidence of ketoacidosis or lactic acidosis.1,88,169,257,258,314 (See Cautions: Lactic Acidosis.) Such evaluation should include determinations of serum electrolytes and ketones, blood glucose, and if indicated, blood pH, lactate, pyruvate, and metformin concentrations.1,88,134,156,169,257,258,314 Since cardiovascular collapse (shock), heart failure, ischemic heart disease (e.g., acute myocardial infarction), peripheral vascular disease (e.g., claudication), obstructive airways disease, or other conditions that are likely to cause central hypoxemia or reduced peripheral perfusion have been associated with lactic acidosis and prerenal azotemia, metformin should be discontinued in patients developing such conditions.1,18,20,30,62,76,91,93,146,156,158,254

Patients should be advised fully and completely about the nature of diabetes mellitus, what they must do to prevent and detect complications, and how to control their condition.88,179,185 Patients should be instructed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular assessment of blood glucose, HbA_1c, renal function, and hematologic parameters.1,24,25,26

Patients and responsible family members should be informed of the risks of hypoglycemia, symptoms and treatment of hypoglycemic reactions, and conditions that predispose to the development of such reactions, since these reactions occasionally may occur during therapy with metformin.1 Hypoglycemia occurs infrequently in patients receiving metformin therapy under usual conditions of use; the incidence of hypoglycemia with metformin is much lower than that in patients receiving sulfonylureas, meglitinides (e.g., repaglinide), or insulin.2,19,62,78,166 However, hypoglycemia may occur when the drug is used concomitantly with a sulfonylurea antidiabetic agent and/or insulin.1,15,78,94,99 In addition, certain other factors (e.g., deficient caloric intake, strenuous exercise not compensated by caloric supplementation, alcohol ingestion, adrenal or pituitary insufficiency) may predispose patients to the development of hypoglycemia.1,2 Debilitated, malnourished, or geriatric patients also may be particularly susceptible to hypoglycemia;2 this condition may be difficult to recognize in geriatric patients or in those receiving β-adrenergic blocking agents or other sympatholytic agents.83,91,128,143,153,159 (See Drug Interactions: β-Adrenergic Blocking Agents.)

To maintain control of diabetes during periods of stress (e.g., fever of any cause, trauma, infection, surgery), temporary discontinuance of metformin and administration of insulin may be required.314 Patients should contact a clinician promptly concerning changes in dosage requirements during periods of stress.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 and any abnormality properly investigated.1,2,3,30,72,85,314 Vitamin B₁₂ concentrations should be monitored every 2-3 years in patients receiving metformin therapy and any abnormalities managed.1 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.30,134,148,168,314

The potential for unplanned pregnancy should be discussed with premenopausal women since metformin-containing therapy may result in ovulation in some anovulatory women.234,260

Metformin-containing therapy is contraindicated in patients with diabetes mellitus complicated by acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma.1,2,234,260,314

Metformin therapy is contraindicated in patients with an eGFR of less than 30 mL/minute per 1.73 m².1,234,254,330 In patients in whom development of impaired renal function is anticipated (e.g., those with blood glucose concentrations exceeding 300 mg/dL, who may develop renal dysfunction as a result of polyuria and volume depletion; geriatric patients),156 renal function should be monitored more frequently.1,2,156,164,314 In addition, drugs that may affect renal function, produce substantial hemodynamic changes, or interfere with metformin elimination (e.g., cimetidine) should be used with caution in patients receiving metformin.1,134,234,254 The National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (KDOQI) recommends temporary discontinuance of potentially nephrotoxic and renally excreted drugs (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, aldosterone inhibitors, direct renin inhibitors, diuretics, nonsteroidal anti-inflammatory agents [NSAIAs], metformin, lithium, digoxin) in patients with a GFR less than 60 mL/minute per 1.73 m².340

Metformin alone or in fixed combination with other drugs is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/minute per 1.73 m²) , which may result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, or septicemia.1,2,18,20,91,234,254,260,314,330 Initiation of therapy with immediate-release metformin in fixed combination with pioglitazone is contraindicated in patients with New York Heart Association (NYHA) class III or IV heart failure.260 (See Heart Failure under Warnings/Precautions: Warnings, in Cautions in Pioglitazone 68:20.28.)

Metformin-containing therapy also is contraindicated in patients with known hypersensitivity to any ingredient in the respective formulations.1,191,192,234,254,260,314

Pediatric Precautions

Safety and efficacy of metformin immediate-release or certain extended-release tablets (e.g., Fortamet^®) in pediatric patients younger than 10 or younger than 17 years of age, respectively, have not been established.1,3,4,30,134,234,254,258 Safety and efficacy of another extended-release preparation (Glumetza^®) have not been established in pediatric patients younger than 18 years of age.261 Safety and efficacy of immediate-release metformin oral solution in children younger than 10 years of age have not been established.257 Data from a placebo-controlled clinical trial indicated a similar glycemic response and adverse effect profile for metformin in pediatric patients (10-16 years of age) as in adults.1,257 (See Type 2 Diabetes Mellitus: Metformin Monotherapy, in Uses.)

The safety and efficacy of metformin in fixed combination with glipizide, glyburide, pioglitazone, or sitagliptin in pediatric patients have not been established.234,254,260,314 Data from a comparative trial evaluating the safety and efficacy of metformin in fixed combination with glyburide compared with monotherapy with each agent in pediatric patients (9-16 years of age) with type 2 diabetes mellitus indicate no unexpected safety concerns with such combination therapy.234

The American Diabetes Association (ADA) states that most pediatric diabetologists use oral antidiabetic agents in children with type 2 diabetes mellitus because of greater patient compliance and convenience for the patient's family and a lack of evidence demonstrating better efficacy of insulin as initial therapy for type 2 diabetes mellitus.235

Geriatric Precautions

Controlled clinical trials evaluating metformin hydrochloride immediate-release and extended-release tablets (Glumetza^®) 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.1,261,314 Data from controlled clinical trials evaluating another metformin hydrochloride extended-release preparation (Fortamet^®) indicate no overall differences in safety or efficacy in geriatric patients compared with younger adults.258 Data from controlled clinical trials with metformin in fixed combination with glyburide or glipizide have not revealed age-related differences in safety and efficacy of the combination, but greater sensitivity of geriatric patients to these fixed combinations cannot be ruled out.234,254 Since metformin is excreted principally by the kidneys and renal function declines with age, accumulation of the drug may occur in patients with renal impairment; the drug should be used with caution in geriatric patients.1,3,4,30,85,165,174,234,254,314 As geriatric patients are at risk for the development of lactic acidosis, metformin therapy should not be initiated in geriatric patients 80 years of age and older without confirmation of adequate renal function as measured by creatinine clearance.1,209,234,254,261 In addition, renal function should be monitored periodically and care should be taken in dosage selection for geriatric patients;1 such patients generally should not receive the maximum recommended dosage of metformin hydrochloride.2,3,4,30,85,174,234,254,261,314 (See Dosage: Dosage Titration in Dosage and Administration.)

Mutagenicity and Carcinogenicity

No evidence of mutagenicity or chromosomal damage was observed in vivo in a micronucleus test in mice or in in vitro test systems, including microbial (Ames test) and mammalian (mouse lymphoma and human lymphocytes) assays.1

No evidence of carcinogenic potential was seen in a 104-week study in male and female rats receiving metformin hydrochloride dosages up to and including 900 mg/kg daily or in a 91-week study in male and female mice receiving metformin hydrochloride at dosages up to and including 1500 mg/kg daily; these dosages are about 3 times the maximum recommended human daily dosage based on body surface area.1 However, an increased incidence of benign stromal uterine polyps was observed in female rats treated with 900 mg/kg of metformin hydrochloride daily.1

Pregnancy, Fertility, and Lactation

Pregnancy

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 drug exists.1,3,314 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.1,3,4,18,72,88,92

The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes mellitus who have an HbA_1c exceeding 7 and has been reported to be as high as 20-25% in women with a HbA_1c exceeding 10.234,254 The estimated background risk of miscarriage for the indicated population is unknown.234,254 In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.234,254

Available studies on the use of metformin in pregnant women have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes.1 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 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.234,254,260 Metformin should be used during pregnancy only when clearly needed.3,4

Lactation

Metformin is distributed into milk in lactating rats.1 Limited data indicate that small amounts of metformin also are distributed into breast milk in humans.260,284,285,286 In a study in 7 nursing women 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 drug and potential adverse effects on the breastfed child (e.g., hypoglycemia).234,254 Breastfed infants should be monitored for signs of hypoglycemia (e.g., jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, seizures).234,254

Antidiabetic Agents

Although hypoglycemia occurs infrequently in patients receiving metformin therapy alone,1,19,62,78,166 hypoglycemia may occur when the drug is used concomitantly with an insulin secretagogue such as a sulfonylurea antidiabetic agent (e.g., glyburide), a meglitinide (e.g., repaglinide), and/or insulin.1,15,78,94,99,260 (See Cautions: Precautions and Contraindications.)

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

Diuretics

Thiazide diuretics can exacerbate diabetes mellitus, resulting in increased requirements of oral antidiabetic agents, temporary loss of diabetic control, or secondary failure to 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, or increasing the dosage of the oral antidiabetic agent.73,134,152,153,154,159,160

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 drugs 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

Nifedipine

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

Cationic Agents

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 drug should be considered.30,254,260,314 Patients receiving metformin concomitantly with a cationic drug that is excreted by the proximal renal tubules should be monitored carefully and the need for possible dosage adjustment of either agent considered.314

Beta-Adrenergic Blocking Agents

In single-dose studies in healthy individuals, concomitant administration of metformin and propranolol did not alter the pharmacokinetics of either drug.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.128,143,153,159 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.36,83,91,127,128,153 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 When an oral antidiabetic agent and a β-adrenergic blocking agent are used concomitantly, the patient should be advised about and monitored closely for altered antidiabetic response.134

Alcohol

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.1,2,18,33,63,72,76,91,93,107,143,314 (See Cautions: Lactic Acidosis.) 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.130,131,132,134,152,155,160

Clomiphene

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

Carbonic Anhydrase Inhibitors

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.1,234,254,260 Concomitant use of these drugs with metformin hydrochloride tablets may increase the risk for lactic acidosis; consider more frequent monitoring in patients receiving these drugs in combination.1,234,254,260

Drugs That May Antagonize Hypoglycemic Effects

Drugs 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.1,80,85,91,120,121,134,139,143,151,152,153,154,159,160,234,254 When such drugs are added to or withdrawn from therapy in patients receiving oral antidiabetic agents, patients should be observed closely for evidence of altered glycemic control.1,30,134,234,254

Acute Toxicity

Limited information is available on the acute toxicity of metformin.2,119 Hypoglycemia has been reported in approximately 10% of cases after acute oral ingestion of amounts exceeding 50 g of metformin hydrochloride; lactic acidosis has been reported in approximately 32% of metformin overdose cases.2,62,119,314 (See Cautions: Lactic Acidosis.) Since metformin is eliminated by dialysis (with a clearance of up to 170 mL per minute under good hemodynamic conditions), prompt hemodialysis is recommended to correct acidosis and remove accumulated drug; such management often results in rapid reversal of symptoms and recovery.1,23,32,62,117,119,314

Pharmacology

Antidiabetic Effects

Metformin hydrochloride, a biguanide antidiabetic agent, is chemically and pharmacologically unrelated to sulfonylurea antidiabetic agents.2,18,20,27,28,29 Unlike sulfonylureas, biguanides such as metformin lower blood glucose concentrations in patients with type 2 diabetes mellitus without increasing insulin secretion from pancreatic β cells;2,3,4,18,20,27,31,40,60,134,234 however, metformin is ineffective in the absence of some endogenous or exogenous insulin.18,27,40,71,122 Biguanides usually do not produce hypoglycemia in diabetic patients 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.2,18,20,27,28,29,72,102,103,111 (See Acute Toxicity.) Therefore, while biguanides as well as sulfonylureas historically have been referred to as oral hypoglycemic agents,27,28,29 biguanides such as metformin are more appropriately referred to as antihyperglycemic agents.6,18,20,157

Type 2 diabetes mellitus is characterized by insulin resistance (impaired uptake and disposal of glucose by peripheral tissues and excessive glucose production by the liver), and abnormal insulin secretion, which may result in insulin deficiency (impaired secretion of insulin from pancreatic β cells) during the late stage of the disease.8,18,20,24,25,27,28,31,40,41,42,44,71,81,134,145,146,161 (See Uses.) Although the underlying pathophysiology of type 2 diabetes mellitus may be similar in obese and nonobese patients with the disease, severe peripheral and hepatic insulin resistance appears to predominate in obese patients, while nonobese patients tend to have milder degrees of insulin resistance but more marked insulin deficiency; however, both abnormalities eventually occur in the course of the disease.8,9,18,60,134,145,178 Obesity itself often is associated with insulin resistance and an elevated rate of fatty acid oxidation, which may contribute to the glucose intolerance observed in obese patients with type 2 diabetes mellitus.9,11,27,59,73,134,146,178,179

Metformin lowers both basal (fasting) and postprandial glucose concentrations in patients with type 2 diabetes mellitus.1,2,18,22 Although the precise mechanism(s) by which metformin exerts its antihyperglycemic effect has not been fully established, current evidence suggests that the drug 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.18,42,44,71,72,135,146,161 Increases of 18-29% in the rate of insulin-stimulated glucose uptake (principally by skeletal muscle) have been reported in patients with type 2 diabetes mellitus with metformin hydrochloride and in normoglycemic insulin-resistant individuals in whom glucose utilization during therapy (0.5-3 g daily) generally was evaluated using a euglycemic, hyperinsulinemic clamp technique (a high-dose, continuous IV infusion of insulin administered concurrently with a glucose infusion titrated to maintain euglycemia).18,20,39,41,60,68,69,146,161 However, some studies in which insulin and/or glucose concentrations were not regulated during metformin therapy have reported no increases and/or even decreases in glucose uptake,44,81 possibly because of the nonphysiologic conditions inherent in the euglycemic, hyperinsulinemic clamp technique.60,102,122

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).3,4,6,18,27,31,39,68,71,79,134,146,149 Studies in animals and humans indicate that metformin, unlike phenformin, enhances glucose oxidation and does not affect fasting lactate production in peripheral tissues.20,53,60,61,72,78,79,81,135,146,149 While increases in postprandial plasma lactate concentrations have been demonstrated in type 2 diabetic patients receiving metformin alone or in combination with a sulfonylurea (e.g., glyburide), plasma lactate concentrations generally remain within the normal range during metformin therapy.31,60,61,72,84,97,146 Postprandial increases in serum lactate concentration observed with metformin therapy may occur as a result of increased conversion of glucose to lactate and glycogen in the splanchnic bed by metformin.6,44,72,145,146,158 While most of the lactate from the portal circulation serves as a substrate for gluconeogenesis and is thus cleared, some may escape into the systemic circulation as increased amounts are presented to the liver after a meal.6,44,72,146 Metformin does not increase lactate production or alter lactate uptake or release from skeletal muscle;23,81,149 however, the drug reportedly decreases liver uptake of lactate, which may increase the risk of lactic acidosis especially in patients at risk for this condition.260 (See Cautions: Lactic Acidosis.)

Metformin reduces basal hepatic glucose production by decreasing gluconeogenesis and possibly glycogenolysis, thereby lowering fasting plasma glucose concentrations.6,20,23,31,37,39,61,72,81,134,135 Although some investigators have suggested that reduction of hepatic glucose production may be the drug's principal antihyperglycemic mechanism,18,27,44,61,81,134 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.1,2,3,18,20,42,60,68,102,166 The magnitude of the decrease in fasting blood glucose concentrations generally is proportional to the level of fasting baseline hyperglycemia.134,146 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.18,42,68,72,134,146

Receptor binding of insulin is decreased in patients with type 2 diabetes mellitus, and some studies using radiolabeled insulin in rat and human cell cultures have demonstrated improved insulin binding with metformin.18,54,67,84,98,145 However, conflicting data also have been reported,40,41,42,79,84 and a direct correlation between increases in insulin binding and decreases in blood glucose concentration has not been observed.18,20,22,37,40,41,42,71,134 In in vitro studies in animal and human skeletal muscle cells or adipocytes, metformin has increased glucose uptake through enhancement of insulin-stimulated recruitment of specific glucose transporters (e.g., GLUT-1, GLUT-4) to the plasma membrane of insulin target cells (e.g., adipose tissue, skeletal muscle) and through increases in the activity of these glucose transporters.4,33,40,47,52 In in vitro studies using metformin concentrations within the therapeutic range, metformin has not consistently enhanced basal glucose uptake, which is noninsulin-mediated; however, in vitro data may not accurately reflect in vivo actions of the drug, and further study is needed to determine whether metformin acts through insulin-dependent or -independent pathways, or both, to affect basal glucose uptake.37,40,47,52,134,149,150

Metformin accumulates in the walls of the intestine but does not appear to have clinically important effects on glucose absorption.6,18,28,37,44,134,146

Antilipemic Effects

Metformin has demonstrated modest favorable effects on serum lipids, which are often abnormal in patients with type 2 diabetes mellitus.3,6,15,18,20,34,146 In clinical studies, particularly in patients with elevated baseline serum lipid concentrations (e.g., patients with type II, type III, or type IV hyperlipoproteinemia), metformin alone or combined with a sulfonylurea antidiabetic agent lowered fasting serum triglyceride concentrations and total and LDL-cholesterol concentrations without adversely affecting other serum lipids.3,4,6,15,18,20,31,34,42,46,53,58,78,81,102,135,146 Modest reductions (e.g., 10-20%) in serum triglyceride concentrations noted with metformin therapy generally have been attributed to decreased hepatic synthesis of VLDL-cholesterol, particularly in patients with elevated baseline triglyceride concentrations.3,4,6,18,20,22,31,35,42,102,146 Characteristics of patients who are likely to exhibit a decrease in serum triglycerides with metformin therapy have not been determined, and correlation of potential antilipemic effect with the degree of glycemic control has been inconsistent.46,49,72,78 Small reductions (e.g., 5-10%) in serum total cholesterol also have been reported in some studies;15,20,31,42,46,58,78,102 these effects may be attributed to decreased LDL- or VLDL-cholesterol concentrations.6,15,18,31,42,46,58,78,102 Increases in HDL-cholesterol also have been reported with metformin therapy in nondiabetic patients18,20 and in those with type 2 diabetes mellitus.18,31,42,102 Consistent changes in plasma glycerol and free fatty acid concentrations have not been reported during metformin therapy in patients with type 2 diabetes mellitus or in nondiabetic individuals.20,31,35,42,44,58,61,68,81,102,135 A reduction in free fatty oxidation has been suggested as a possible mechanism for the decrease in plasma free fatty acids observed in some studies with metformin therapy.31,35,42,68,102

Hematologic Effects

Metformin may exert potentially beneficial effects on the fibrinolytic system by increasing the activity of tissue-type plasminogen activator (t-PA) and/or reducing concentrations of plasminogen activator inhibitor-1 (PAI-1) in nondiabetic, hypertensive patients and in patients with type 2 diabetes mellitus; serum fibrinogen concentrations do not appear to be affected by metformin therapy.18,34,55,56,58,108,109,136 Patients with type 2 diabetes mellitus, hypertension, and obesity often have hyperinsulinemia and a high incidence of vascular disease.55,108 PAI-1 concentrations, which are regulated by insulin, may be substantially increased in patients with type 2 diabetes mellitus and in obese individuals,34,55,108,136 and it has been suggested that the reduced fibrinolytic activity associated with elevated PAI-1 concentrations may be important in the pathogenesis of vascular disease in these individuals.34,55,108,134,136 Metformin has been shown to increase fibrinolytic activity (as measured by blood clot lysis time, euglobulin fibrinolytic activity, and by increases in t-PA activity) in patients with coronary artery disease, obese individuals, and in patients with mild hypertension; increases in fibrinolytic activity with metformin therapy generally occur in patients who have low fibrinolytic activity at baseline.56,58,108 Reduced platelet density, activation, and/or aggregation;18,73,109 decreased blood pressure; and decreased peripheral arterial resistance18,57,58 also have been reported in some normotensive patients with type 2 diabetes mellitus and in nondiabetic, mildly hypertensive patients receiving metformin; however, whether these effects are associated with the drug or are secondary to improvement in glycemic control or a reduction in body weight has not been determined.18,57,58,73,109,146

Other Effects

Therapy with metformin may be associated with weight stabilization19,35,41,42,46,69 or loss.15,31,17,45,49,57,78,81,84,118 Although the exact mechanism associated with such alterations in weight has not been established,6,16,17,20,30,31,81,85 suggested mechanisms include the absence of a hyperinsulinemic effect (which if present may increase appetite and/or lipogenesis)15,17,18,72 and decreased dietary intake associated with adverse GI effects of metformin.17,29,85,189 The antihyperglycemic effect of the drug does not appear to be related to weight loss in patients with type 2 diabetes mellitus receiving metformin, nor does weight loss appear to be dose related.6,17,20,34 Limited data from studies comparing metformin therapy with oral sulfonylurea (e.g., glyburide, chlorpropamide, tolbutamide) therapy indicate that patients with type 2 diabetes mellitus receiving oral sulfonylureas gained weight or lost less weight than patients receiving metformin.15,16,17,20,46,57,118,134

Metformin has little or no effect on fasting plasma glucagon, somatostatin, serum growth hormone, or serum cortisol concentration in patients with normal renal function; glucagon, growth hormone, and cortisol concentrations are elevated in patients with lactic acidosis and renal failure who have been receiving metformin.6,61,62,81,135

Pharmacokinetics

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.2,18,89,260,314 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 area under the concentration-time curve (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

Bioequivalence has been demonstrated between the fixed combination of sitagliptin and metformin and each agent given concurrently.314 Bioequivalence also has been demonstrated between the fixed combination of pioglitazone and immediate-release metformin (ActoPlus Met^®) and each agent (pioglitazone [Actos^®] and immediate-release metformin [Glucophage^®]) given concurrently.260 Results of a bioequivalence study indicate that the fixed-combination tablets of canagliflozin and immediate-release metformin hydrochloride are bioequivalent to the corresponding doses of canagliflozin and metformin hydrochloride given as individual tablets under fed conditions.370 Bioequivalence between the fixed combination of dapagliflozin and extended-release metformin hydrochloride (Xigduo^® XR) and each agent (dapagliflozin and extended-release metformin hydrochloride) given concurrently as separate tablets has been demonstrated; however, the relative bioavailability of the fixed combination of dapagliflozin and extended-release metformin hydrochloride (Xigduo^® XR) and concomitantly administered dapagliflozin and immediate-release metformin hydrochloride has not been established.362 Bioequivalence between the fixed-combination tablets of empagliflozin and immediate-release metformin hydrochloride and the corresponding doses of empagliflozin and metformin hydrochloride 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

Absorption

Metformin is slowly and incompletely absorbed from the GI tract, mainly from the small intestine; absorption is complete within 6 hours.6,18,43,50,51,65,72,89 The absolute oral bioavailability of the drug under fasting conditions is reported to be approximately 50-60% with metformin hydrochloride doses of 0.5-1.5 g;1,2,3,4,18,33,43,50,65,72,85,89,314 binding of the drug to the intestinal wall may explain the difference between the amount of drug absorbed (as determined by the urinary and fecal excretion of unchanged drug) and the amount bioavailable in some studies.6,18,51,72,89,129 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.1,18,65,72,89,111,126 Similarly, in single-dose studies with an extended-release tablet preparation (Glumetza^®) at doses of 0.5-2.5 g, plasma metformin concentrations did not increase in proportion to increasing doses.261 At steady state after administration of a metformin hydrochloride extended-release tablet preparation, the AUC and peak plasma concentrations were not dose proportional within the range of 0.5-2 g.1 However, limited data from studies in animals and in human intestinal cell cultures suggest that transepithelial transfer of metformin in the intestine may occur through a passive, nonsaturable mechanism, possibly involving a paracellular route.129,134 In several studies with another metformin hydrochloride extended-release tablet preparation (Fortamet^®) using doses of 1-2.5 g, metformin exposure was dose-related.258

Food decreases and slightly delays the absorption of metformin immediate-release tablets; the clinical importance of these effects is unknown.1,2,3,4,18,208,314 (See Dosage and Administration: Administration.) Administration of metformin hydrochloride immediate-release tablets with food reportedly has decreased peak plasma concentrations of the drug by 35-40%, reduced area under the plasma concentration-time curve (AUC) by 20-25%, and delayed time to peak plasma drug 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 drug 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.1 Following administration of another metformin hydrochloride extended-release tablet formulation (Fortamet^®) with food, the extent of absorption (as measured by AUC) increased by approximately 60%, peak plasma concentrations were increased by approximately 30%, and time to achieve peak plasma concentrations was prolonged (6.1 hours versus 4 hours) compared with those in the fasting state.258 The pharmacokinetics of a certain metformin extended-release tablet preparation were not affected by the fat content of meals.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 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 of approximately 0.4-3 mcg/mL usually are attained within 2-4 hours.2,6,18,33,38,43,44,50,85,125 At usual clinical doses and dosing schedules of metformin hydrochloride, steady-state plasma concentrations of metformin are reached within 24 to 48 hours and are generally less than 1 mcg/mL.234 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 of 0.47-1.6 mcg/mL usually are attained within 7-8 hours.261 Peak plasma drug 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 and generally average about 1 mcg/mL or less.1,30,38,51

A precise correlation between plasma metformin concentrations and the drug's antihyperglycemic effect has not been established.5,51,53,72 In addition, plasma metformin concentrations generally have shown no correlation with plasma lactate concentrations during metformin therapy in patients with type 2 diabetes mellitus.5,30,53,64,96,134 Although metformin-associated lactic acidosis generally has been associated with plasma metformin concentrations exceeding 5 mcg/mL1,2,62,96,119 (see Cautions: Lactic Acidosis), such high concentrations reportedly were not observed during controlled clinical trials with the drug, even at maximum dosage (2.5-2.55 g daily).134

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.18,53,72,98,134 Following discontinuance of metformin therapy, blood glucose concentration increases within 2 weeks.53,134

Distribution

Metformin is distributed rapidly in animals and humans into peripheral body tissues and fluids, particularly the GI tract; the drug also appears to distribute slowly into erythrocytes and into a deep tissue compartment (probably GI tissues).30,50,65,72,89,134,162,167 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.6,18,44,50,51,65,72,162 The drug distributes into salivary glands with a half-life of about 9 hours.50,65 Metformin concentrations in saliva are tenfold lower than those in plasma and may be responsible for the metallic taste reported in some patients receiving the drug.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 drug compared with those in other tissues.6,18,43 It is not known whether metformin crosses the blood-brain barrier or the placenta in humans or if the drug is distributed into human milk; however, in lactating rats, metformin is distributed into breast milk at levels comparable to those in plasma.1,2,85

Following oral administration of single 850-mg doses of metformin hydrochloride as immediate-release tablets, the apparent volume of distribution has been reported to average 654 L.1,260 Volume of distribution reported after IV administration of the drug generally has been smaller (e.g., 63-276 L) than that with oral administration, perhaps because of less drug binding in the GI tract and/or different methods of determining volume of distribution in various studies.30,50,51,89,134 Unlike oral sulfonylurea antidiabetic agents, which are more than 90% bound to plasma proteins, metformin is negligibly bound to plasma proteins.1,18,50,51,65,85,89,260 Metformin equilibrates freely between erythrocytes and plasma, most likely as a function of time; drug bound to erythrocytes is approximately 5% of total blood concentration.1,2,3,18,89,260

Elimination

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 Following multiple-dose administration of metformin hydrochloride (500 mg twice daily for 7-14 days) as immediate-release tablets in a limited number of patients with type 2 diabetes mellitus, peak plasma concentrations remained unchanged, but trough drug concentrations were higher than with single-dose administration, suggesting some drug accumulation in a peripheral tissue compartment.89 (See Pharmacokinetics: Distribution.) No accumulation of metformin appears to occur following repeated oral doses of the drug as extended-release tablets.1 The principal plasma elimination half-life of metformin averages approximately 6.2 hours; 90% of the drug is cleared within 24 hours in patients with normal renal function.1,2,6,18,33,38,50,51,65,85,89,125,134,258,314 The decline in plasma metformin concentrations is slower after oral than after IV administration of the drug, 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.1,3,18,50,65,72,89,134,174,314

Metformin is not metabolized in the liver or GI tract and is not excreted in bile; no metabolites of the drug 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.2,6,33,50,63,65,75,85,89,314 Following single-dose oral administration of metformin hydrochloride (0.5-1.5 g) as immediate-release tablets, urinary recovery ranges from 35-52% of the total dose.50,51,89 Following administration of a single dose of metformin hydrochloride as an extended-release tablet (Fortamet^®) in healthy individuals, urinary recovery was 40.9% over 24 hours.258 Approximately 20-33% of the total oral dose as immediate-release tablets is excreted in feces within 4-7 days.6,33,43,50,72,89 Total plasma clearance of metformin hydrochloride following single-dose oral administration (0.5-1.5 g) has ranged from 718-1552 mL/minute.33,89 Metformin is removed by hemodialysis with a clearance of up to 170 mL/minute under good hemodynamic conditions.1,23,32,33,62,117

Renal clearance is approximately 3.5 times greater than creatinine clearance, indicating that tubular secretion is the principal route of metformin elimination.1,314 Following a single 850-mg oral dose of metformin hydrochloride, renal clearance averaged 552, 491, or 412 mL/minute in nondiabetic adults, diabetic adults, or healthy geriatric individuals, respectively.174 Renal impairment results in increased peak plasma concentrations of metformin, a prolonged time to peak plasma concentration, and a decreased volume of distribution.1,3,51,174 Renal clearance is decreased in patients with renal impairment (as measured by decreases in creatinine clearance) and, apparently 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 also results in increased plasma concentrations of the drug; volume of distribution remains unaffected.1,174,314 (See Cautions: Precautions and Contraindications.)

Chemistry and Stability

Chemistry

Metformin hydrochloride, a dimethylbiguanide, is an orally active antidiabetic agent derived from guanidine.1,2,3,4,18,20,22,23,27,28,29,30,33,72,146 Guanidine occurs naturally in Galega officinalis , a medieval European remedy for diabetes mellitus.6,18,20,44,72,146

Metformin is structurally and pharmacologically related to phenformin, a phenethylbiguanide (no longer commercially available in the US).18,27,28,29 However, the guanidinium group of metformin has 2 methyl substituents rather than a single hydrophobic phenethyl substituent as in phenformin, giving metformin improved water solubility and decreased binding affinity for biologic membranes (e.g., mitochondrial, plasma membranes) compared with phenformin.2,6,20,23,38,47 Consequently, metformin causes less disturbance to mitochondrial-mediated glucose oxidative pathways, resulting in a decrease in the formation of lactate from glucose via anaerobic metabolism and a reduced potential for the development of lactic acidosis compared with phenformin.3,6,20,23

Metformin hydrochloride is commercially available as immediate- or extended-release tablets alone or in fixed combination with dipeptidyl peptidase-4 [DPP-4] inhibitors, sodium-glucose cotransporter 2 [SGLT2] inhibitors, sulfonylureas, or thiazolidinediones.1,234,254,260,314,352,355,362,368,370,372,374,376,378

Certain extended-release tablet formulations (e.g., Glumetza^®) contain hydrophilic polymer(s) that form a swellable gel matrix when in contact with gastric or intestinal fluids and release the drug by diffusion slowly over time.262 Another commercially available metformin hydrochloride extended-release tablet formulation (Fortamet^®) contains the drug in an oral osmotic delivery system.258 This delivery system consists of an osmotically active core (comprised of a layer containing the drug and a coating that delays release of the drug from the core) surrounded by a semipermeable membrane with laser-drilled delivery orifices; the semipermeable membrane allows the passage of water but not higher molecular weight components of biological fluids.258 When exposed to water in the GI tract, the drug dissolves and is pushed out of the delivery orifices of the membrane into the GI tract at a constant rate.258 The rate of metformin hydrochloride delivery in the GI tract depends on the maintenance of a constant osmotic gradient across the membrane.258 The inert components of the drug delivery system (membrane coating) remain intact and are eliminated in feces.258

Metformin is a weak base; the pH of a 1% aqueous solution of metformin hydrochloride is 6.68.1,47,261 The pK_a of metformin base is 12.4.1,2,30,261 Metformin hydrochloride is freely soluble in water and practically insoluble in acetone, ether, and chloroform.1,2,261

Stability

Commercially available metformin hydrochloride immediate-release (including fixed-combination preparations with glipizide) and extended-release tablets should be stored at a controlled room temperature of 20-25°C and protected from light but may be exposed to temperatures ranging from 15-30°C .1,234,254,258,261 Metformin hydrochloride immediate-release oral solution should be stored at 15-30°C.257 Fixed-combination preparations containing metformin hydrochloride and glyburide should be stored at a controlled room temperature up to 25°C and be protected from light.234 Immediate-release metformin hydrochloride in fixed combination with pioglitazone should be stored at 20-25°C and protected from moisture and humidity.260 Preparations containing metformin hydrochloride and canagliflozin, dapagliflozin, ertugliflozin, saxagliptin, or sitagliptin in fixed combination should be stored at 20-25°C but may be exposed to temperatures ranging from 15-30°C.314,352,355,362,368,369,370 The fixed combination of metformin hydrochloride and ertugliflozin should be protected from moisture and stored in a dry place.355 Preparations containing metformin hydrochloride and empagliflozin, alogliptin, or linagliptin in fixed combination should be stored at 25°C but may be exposed to temperatures ranging from 15-30°C.372,374,376,378,610 The fixed combination of metformin hydrochloride and linagliptin should be protected from exposure to high humidity.376,378

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