68:20 Antidiabetic Agents

68:20.04 Biguanides

Metformin Hydrochloride

Introduction

C4H11N5•HCl

• Metformin hydrochloride is a biguanide antidiabetic agent.1, 2, 3, 4, 18, 20, 22, 23, 27,28, 29, 30, 33, 72, 146, 243, 245, 246

Uses

• Diabetes MellitusMetformin is used as monotherapy as an adjunct to diet and exercise for the management of type 2 (noninsulin-dependent) diabetes mellitus (NIDDM) in patients whose hyperglycemia cannot be controlled by diet alone.1, 3, 4, 6, 8, 15, 16, 17, 18, 19,20, 27, 29, 95, 166, 243, 245, 246 Metformin may also be used in combination with asulfonylurea or a thiazolidinedione antidiabetic agent as an adjunct to diet and exercise in patients with type 2 diabetes who do not achieve adequate glycemic control withmetformin, sulfonylurea, or thiazolidinedione monotherapy.1, 3, 6, 15, 18, 20, 22, 27, 29,30, 48, 59, 78, 88, 95, 97, 99, 112, 134, 166, 191, 234, 237, 239, 241, 242, 243, 245, 246, 250

Metformin may be used with repaglinide in patients with type 2 diabetes mellitus who have inadequate glycemic control with diet, exercise, and monotherapy with metformin,a sulfonylurea, repaglinide, or a thiazolidinedione antidiabetic agent.238, 249 Metforminalso may be used concomitantly with nateglinide in patients who no longer respond adequately to metformin despite appropriate diet, exercise, and metforminmonotherapy. Metformin is commercially available in fixed combination with glyburide or glipizide for use as initial therapy in the management of patients with type 2 diabetesmellitus whose hyperglycemia cannot be controlled by diet and exercise alone, or as second-line therapy in patients who do not achieve adequate control of hyperglycemiadespite therapy with diet, exercise, and initial treatment with a sulfonylurea antidiabeticagent or metformin. A thiazolidinedione may be added to metformin in fixed combination with glyburide in patients who have inadequate glycemic control with fixed-combinationtherapy. Metformin is commercially available in fixed combination with rosiglitazone forthe management of type 2 diabetes mellitus in patients who who have inadequate glycemic control with metformin monotherapy or are already receiving therapy withmetformin and rosiglitazone as separate components. Metformin also may be used asadjunctive therapy in patients with type 2 diabetes mellitus receiving insulin therapy to improve glycemic control and/or decrease the dosage of insulin needed to obtainoptimal glycemic control.

The National Diabetes Data Group and the American Diabetes Association (ADA)

currently classify diabetes mellitus as type 1 (insulin dependent, IDDM), type 2 (noninsulin dependent, NIDDM), or that associated with certain conditions or syndromes (e.g., drug- or chemical-induced, hormonal, that associated with pancreatic disease).7,12 Type 2 diabetes mellitus previously was described as maturity-onset (MOD) oradult-onset (AODM) diabetes mellitus, since it usually occurs in patients older than 40years of age.7 However, type 1 or 2 diabetes mellitus can occur at any age, and the current classification is based on clinical presentation rather than on age of onset.7, 12

Epidemiologic data indicate that the incidence of type 2 diabetes mellitus is increasing inchildren and adolescents such that 8-45% of children with newly diagnosed diabetes have nonimmune-mediated diabetes mellitus; most of these individuals have type 2diabetes mellitus, although other types, including idiopathic or nonimmune-mediatedtype 1 diabetes mellitus, also have been reported.235 Most individuals with type 2 diabetes mellitus (about 50-90%) are obese;7, 12, 178, 179, 180, 236 obesity itself alsocontributes to the insulin resistance and glucose intolerance observed in these patients.8, 9, 11, 18, 27, 30, 59, 60, 73, 134, 145, 178, 179, 236 While children withimmune-mediated type 1 diabetes generally are not overweight, the incidence of obesityin children with this form of diabetes is increasing with the increasing incidence ofobesity in the US population.235

Metformin is not effective as sole therapy in patients with type 1 diabetes mellitus;insulin is necessary in these patients.6, 30, 134, 146

Patients with type 2 diabetes mellitus are not dependent initially on insulin (although many patients eventually require insulin for glycemic control)13, 18, 27, 28, 30, 78, 94, 95,99, 101, 134, 146, 166, 179, 181, 185, 187 nor are they prone to ketosis;7, 12 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 severestress (e.g., acute infection, trauma, surgery).7, 12, 14, 146, 179 Type 2 diabetes mellitusis 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.7, 8, 9, 13, 14, 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 type 2 diabetic patients, glucose-stimulated secretion of endogenousinsulin 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 ComplicationsCurrent 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 mellitusindicate that intensive management of hyperglycemia with near-normalization of blood glucose and glycosylated hemoglobin (hemoglobin A1c [HbA1c]) concentrations

provides substantial benefits in terms of reducing chronic microvascular (e.g., neuropathy, retinopathy, nephropathy) complications associated with the disease.8, 14,163, 180, 181, 182, 190 Glycosylated hemoglobin reflects the glycosylation of otherproteins 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

In the Diabetes Control and Complications Trial (DCCT), a reduction of approximately50-75% 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 withtype 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 glucosedeterminations, dietary intake, and anticipated exercise) compared with that in patientsreceiving conventional insulin treatment (1 or 2 insulin injections daily, self-monitoring ofblood or urine glucose values, education about diet and exercise).14, 182 However, theincidence of severe hypoglycemia, including multiple episodes in some patients, was 3times 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 glycosylated hemoglobin concentration (hemoglobin A1c) produced by intensive insulin treatment (e.g., a 40% reduction in risk

of microvascular disease for each 10% reduction in hemoglobin A1c).13, 14, 134, 182,185, 206 These data imply that any decrease in glycosylated hemoglobin levels is beneficial and that complete normalization of blood glucose concentrations may prevent diabetic microvascular complications.13, 14, 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 DiabetesInterventions 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 glycosylated hemoglobin when switched to intensive therapy in the continuation study, although the average glycosylated hemoglobin 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, glycosylated hemoglobin 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 glycosylated hemoglobin values), the greater the risk of microvascular complications.255 Conversely, the longer patients can

maintain a target glycosylated hemoglobin 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 glycosylated hemoglobin 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 standardtreatment (e.g., generally 2 insulin injections daily without intensive educational efforts).190

Evidence from the United Kingdom Prospective Diabetes (UKPD) study216, 218, 219, 220

and other smaller studies51 in patients with type 2 diabetes mellitus generally is 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 The UKPD study evaluated more than 5000middle-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; overweightpatients also could be allocated to metformin therapy in the same proportions as thoseallocated to sulfonylureas and insulin.218, 219, 220, 222 Initial therapy consisted of anoral antidiabetic agent (sulfonylurea or metformin) or insulin, with stepwise addition of metformin (or glyburide in those initially allocated to metformin) in those poorlycontrolled on initial therapy or conversion to insulin alone in patients not adequatelycontrolled with 2 oral agents.218, 219, 220, 222 Intensive treatment consisted ofantidiabetic therapy targeted to a fasting plasma glucose concentration of less than 108 mg/dL or, in patients receiving insulin, preprandial glucose concentrations of 72-126mg/dL.218, 219, 220, 222 Conventional treatment consisted of antidiabetic therapytargeted to a fasting plasma glucose concentration of less than 270 mg/dL withoutsymptoms of hyperglycemia.218, 219, 220, 222 Results of the UKPD study indicatebeneficial effects on retinopathy, nephropathy, and possibly neuropathy with intensive glucose-lowering therapy in type 2 diabetics, in whom a median glycosylatedhemoglobin of 7% was achieved compared with a value of 7.9% in the conventionaltreatment group.219, 220 The overall incidence of microvascular complications was reduced by 25% with intensive therapy.219, 200 Epidemiologic analysis of the UKPDstudy results indicates a continuous relationship between the risks of microvascularcomplications and glycemia, with a 35% reduction in risk for each 1% reduction in glycosylated hemoglobin.219, 220 While an association between the risk ofmacrovascular (e.g., cardiovascular) complications was also demonstrated by the UKPD study, there was no statistically significant effect of lowering blood glucose on cardiovascular complications.219, 220

In the UKPD study, fasting plasma glucose concentrations and percent glycosylated hemoglobin 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 percent glycosylated hemoglobin values decreased during the first year of the study.217, 219, 222 Subsequent increases in these indices ofglycemic control after the first year paralleled that in the conventional therapy group for the remainder of the study, indicating slow decline of pancreatic ß-cell function and loss of glycemic control regardless of intensity of therapy.217, 219, 223, 224

The ADA currently recommends the same blood glucose and glycosylated hemoglobin goals for all patients with type 1 or type 2 diabetes mellitus but states that less stringent treatment goals may be appropriate for certain individuals.14 Based on target values for blood glucose and glycosylated hemoglobin used in clinical trials (e.g., DCCT) for type 1 diabetic patients,182 modified somewhat to reduce the risk of severe hypoglycemia,ADA currently recommends target preprandial (fasting) and peak postprandial plasma glucose concentrations of 90-130 and less than 180 mg/dL, respectively, and glycosylated hemoglobin concentrations of less than 7% (based on a nondiabetic range of less than 6%) in patients with type 1 or 2 diabetes mellitus who are not pregnant.14

Patients with diabetes mellitus who have elevated glycosylated hemoglobin concentrations despite having adequate preprandial glucose concentrations should monitor glucose concentrations 1-2 hours after the start of a meal.14 Treatment with agents (e.g., a-glucosidase inhibitors) that principally lower postprandial glucose concentrations to within target ranges also should reduce glycosylated hemoglobin.14,244 The effect of adequate control of postprandial glucose concentrations on the microvascular and macrovascular complications of diabetes mellitus is not known.14

Treatment goals should be individualized, and specific target values for blood glucoseand glycosylated hemoglobin appropriately adjusted, based on the patient's capacity to understand and adhere to the treatment regimen, the risk of severe hypoglycemia, and other patient factors that may increase risk or decrease benefit (e.g., very young or oldage, comorbid conditions, other diseases that materially shorten life expectancy).14

Strict glycemic control (e.g., maintenance of fasting blood glucose concentrations below140 mg/dL) usually is not achieved in patients with type 2 diabetes mellitus who have moderately severe to severe hyperglycemia prior to therapy; most patients with a baseline fasting blood glucose concentration exceeding 200 mg/dL are unlikely toexperience a return to euglycemia with oral antidiabetic agent monotherapy.18, 78, 105,134, 146

Data from the long-term UKPD study in middle-aged, newly diagnosed 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 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 the UKPD study 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

• Considerations in Initiating and Maintaining Antidiabetic TherapyWhen initiating therapy for patients with type 2 diabetes mellitus who do not have severe symptoms, diet should be emphasized as the primary form of treatment;10, 14,18, 24, 25, 95, 123 caloric restriction and weight reduction are essential in obese patients.14, 24, 25, 26, 88, 95, 123 Although appropriate dietary management and weightreduction alone may be effective in controlling blood glucose concentration andsymptoms of hyperglycemia, many patients receiving dietary advice fail to achieve andmaintain adequate glycemic control with dietary modification alone.13, 23, 24, 25, 26, 95,134, 146, 184

The importance of regular physical activity also should be emphasized, and cardiovascular risk factors should be identified and corrective measures employed when feasible.10, 14, 26 Efforts also should be aimed at blood pressure control, as 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 the UKPD study 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.14, 217, 220, 222, 225, 228, 229

If this treatment program (dietary management, weight reduction, exercise, reduction of cardiovascular risk factors) fails to reduce symptoms and/or blood glucose concentrations within 2-3 months of diagnosis, initiation of monotherapy with an oral antidiabetic agent (e.g., sulfonylurea, metformin, acarbose) or insulin should be considered.10, 14, 15, 18, 19, 26, 72, 88, 95, 105, 113, 179 The patient and physician should recognize that dietary management is the principal consideration in the management of diabetes mellitus, and that oral antidiabetic therapy is used only as an adjunct to, andnot as a substitute for or a convenient means to avoid, proper dietary management.30,95, 189, 191, 192 In addition, loss of blood glucose control on diet alone can be temporary in some patients, requiring only short-term management with drug therapy.1, 134, 243,245, 246

• Metformin MonotherapyClinical studies indicate that metformin is as effective as a sulfonylurea antidiabetic agent (e.g., chlorpropamide,3, 16, 17, 18, 19, 27, 29 glyburide,15, 18, 19, 27, 29, 45, 46, 57,78 glipizide,18 tolbutamide3, 48, 118) for the management of type 2 diabetes mellitus.Although metformin often has been used in patients who did not achieve adequate glycemic control with sulfonylurea monotherapy and who did not have symptoms ofsevere insulin deficiency (e.g., ketosis, uncontrolled weight loss),6, 15, 18, 22, 48, 59, 78,95, 112, 123, 146, 166 either a sulfonylurea or metformin may be used as initialmonotherapy in patients with type 2 diabetes whose hyperglycemia is not controlled

despite dietary modification and exercise.1, 15, 18, 19, 72, 88, 95, 105, 146, 243, 245, 246

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.1, 2, 3, 6, 16, 17, 18,19, 20, 27, 30, 42, 60, 68, 102, 134, 146, 166 Type 2 diabetic patients who are very obese orwho have baseline fasting blood glucose concentrations exceeding 200 mg/dL may be less likely to respond to therapy with sulfonylurea antidiabetic agents.197, 198 Therefore,since metformin may stabilize or even decrease body weight,1, 3, 4, 6, 8, 16, 17, 18, 19,20, 21, 105, 118, 166, 243, 245, 246 the drug may be particularly useful as initial monotherapy in obese individuals who might gain weight while receiving asulfonylurea.15, 16, 17 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 Metformin may be effective asreplacement monotherapy in some patients with primary or secondary failure tosulfonylureas.1, 30, 48, 78, 95, 134, 179 (See Diabetes Mellitus: Combination Therapy, inUses.)

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 glycosylated hemoglobin15,35, 42, 68, 78 substantially more than did placebo. The antihyperglycemic effect ofmetformin 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 aplacebo-controlled study in pediatric (10-16 years of age), treatment-naive (i.e., those receiving diet therapy only), obese patients with type 2 diabetes mellitus, the net difference in fasting plasma glucose concentrations in patients receiving metformin hydrochloride (up to 2 g daily) or placebo for up to 16 weeks was 64.3 mg/dL, reflecting an increase in fasting plasma glucose concentrations in the placebo group and an improvement in glycemic control with metformin therapy.1 The improvement in glycemic control with metformin in these pediatric patients was similar to that observed in clinical studies with the drug in adults.1 A small, similar weight loss occurred in patients receiving either metformin or placebo in this study.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 glycosylated hemoglobin 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 associated with weight gain or an increased incidence of hypoglycemia.19, 166, 184 In this long-term study, gradual deterioration in glycemic control occurred with all therapies over the study period despite increases in drug dosage or combined drug therapy; glycosylated hemoglobin concentrationsgenerally 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 progressivedecline in pancreatic ß-cell function94, 95, 146, 166, 184 rather than a reduction in insulin

sensitivity.166

• Combination TherapyMetformin may be used concomitantly with one or more oral antidiabetic agents (e.g., a sulfonylurea, a thiazolidinedione, a meglitinide, and/or an a-glucosidase inhibitor) 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, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 254

While metformin may be effective as replacement monotherapy in some patients who develop primary or secondary failure to sulfonylurea antidiabetic agents, optimumbenefit generally is obtained by addition of metformin to existing sulfonylurea therapy assoon as monotherapy no longer provides adequate glycemic control (i.e., before primaryor secondary failure with symptomatic hyperglycemia occurs).1, 30, 48, 78, 95, 134, 179,239, 243, 245, 246 Primary or secondary failure may occur with metformin as well as with sulfonylurea therapy.6, 16, 17, 18, 27, 78, 95, 99, 146, 166 In patients receiving initialmonotherapy with metformin, the incidence of primary and secondary failures appearsto be less than6, 27, 166 or similar to6, 16, 17, 18, 122 that in patients receivingsulfonylurea monotherapy. Secondary failure to sulfonylurea antidiabetic agents or metformin is characterized by progressively decreasing diabetic control following 1month to several years of good control.30, 134, 166, 184, 199 Combined therapy withmetformin and another oral antidiabetic agent generally is used in patients with longstanding type 2 diabetes mellitus who have poor glycemic control withmonotherapy;15, 72, 95, 99, 216, 238, 240 the sequence in which metformin or asulfonylurea is used at initiation of therapy does not appear to alter the effectiveness ofcombined therapy with the drugs.15, 95, 146

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 determinedby glycosylated hemoglobin values, fasting plasma glucose concentrations) than monotherapy with either component. 234, 254 A greater percentage of patients receivingmetformin in fixed combination with glipizide or glipizide achieved strict glycemic control (e.g., glycosylated hemoglobin values less than 7%)14 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 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 glycosylated hemoglobin 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., glycosylated hemoglobin values less

than 7%)14 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

Metformin also is used in combination with rosiglitazone (either as a fixed-combination preparation or as individual drugs given concurrently) in patients with type 2 diabetes who have inadequate glycemic control with metformin monotherapy or in those who arealready receiving metformin and rosiglitazone concurrently as separate components.166, 184, 247, 250 In a controlled clinical trial, concurrent therapy with metforminhydrochloride (2.5 g once daily) and rosiglitazone (4 or 8 mg once daily) in patients inadequately controlled with metformin monotherapy reduced mean fasting plasma glucose concentrations and glycosylated hemoglobin values compared with metforminmonotherapy.240 247 No clinical trials have evaluated the fixed combination of metforminand rosiglitazone; efficacy and safety of the fixed combination has been establishedbased on concurrent administration of the 2 agents separately.247 Bioequivalence hasbeen demonstrated between the fixed combination of rosiglitazone and metformin andeach agent given concurrently.247 No clinical trials have evaluated metformin as add-ontherapy in patients inadequately controlled with rosiglitazone monotherapy or the combination of the agents given separately as initial therapy in patients with type 2diabetes mellitus.247 In a dose-ranging trial evaluating rosiglitazone 4 or 8 mg asadd-on therapy to the maximum daily dosage of metformin hydrochloride, 28.1% of patients receiving the higher dosage of rosiglitazone concurrently with metforminachieved glycosylated hemoglobin values of 7% or less.240

Metformin may be used concomitantly with glyburide and a thiazolidinedione antidiabetic agent to improve glycemic control in patients with type 2 diabetes who are inadequately controlled with the fixed combination of metformin and glyburide. 234 In such patients, the addition of rosiglitazone to combined therapy with metformin and glyburide has reduced fasting glucose concentrations and glycosylated hemoglobin values.234 Strict glycemic control (e.g., glycosylated hemoglobin values less than 7%)14

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

Metformin also is used in combination with other insulin secretagogues (e.g., meglitinides such as repaglinide or nateglinide), other thiazolidinediones (e.g., pioglitazone), or acarbose to improve glycemic control in patients with type 2 diabetes

mellitus.112, 237, 238, 244, 248, 249

In a clinical trial in patients who had inadequate glycemic control (glycosylated hemoglobin exceeding 7.1%) with metformin monotherapy, addition of repaglinide to metformin therapy produced reductions in fasting plasma glucose concentrations and glycosylated hemoglobin 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 glycosylated hemoglobin. 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 glycosylated hemoglobin 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 glycosylated hemoglobin 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 improvementin glycosylated hemoglobin.112, 134, 244 Fasting plasma glucose concentrationsgenerally are not reduced by addition of acarbose to therapy with metformin sinceacarbose 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 glycosylatedhemoglobin concentrations than combined therapy with acarbose and a sulfonylurea; however, acarbose may provide better control of postprandial blood glucose concentrations.205

Combined therapy with metformin and other oral antidiabetic agents (e.g., sulfonylureas, acarbose) in patients not adequately controlled with monotherapy may reducesymptoms and delay or avoid institution of insulin or allow reduced insulin dosages.1, 6,18, 20, 21, 22, 23, 73, 94, 95, 99, 100, 101, 104, 112, 122, 146, 179, 193, 237, 239 In patientspoorly controlled by diet and oral sulfonylurea therapy, the addition of metformin has reduced fasting glucose concentrations by 25-40%; it has been suggested that up to50% of patients who are not controlled by high-dose sulfonylurea therapy will improvesubstantially with concomitant metformin therapy.15, 21, 22, 44, 78, 97, 179 However,strict glycemic control (e.g., fasting blood glucose less than 140 mg/dL) has not beenachieved in most of these patients, and insulin therapy eventually is required for

control.15, 21, 22, 44, 78, 97, 134

Conflicting data regarding the long-term benefit of metformin as part of an intensive antidiabetic regimen have been reported in the United Kingdom Prospective Diabetes (UKPD) study, which consisted of middle-aged, newly diagnosed, overweight (exceeding 120% of ideal body weight) or non-overweight patients with type 2 diabetes mellitus who received long-term therapy (over 10 years) with intensive or conventional treatment.218, 219, 220, 222 (See Glycemic Control and Microvascular Complications, under Uses: Diabetes Mellitus.) In one UKPD study substudy, overweight patients receiving metformin as initial therapy in a stepwise intensive regimen had a 32% lower

risk of developing any diabetes-related endpoint (including macrovascular and microvascular complications) compared with those managed by dietary modification alone; the reduction in any diabetes-related end point was greater in those receivingmetformin than in those receiving initial intensive therapy with a sulfonylurea or insulin.216 The risk for diabetes-related death or myocardial infarction (39% lower) was also lower with intensive therapy with metformin or sulfonylureas or insulin compared with conventional therapy; no differences between the effects of intensive therapies were noted.216, 218, 220, 221 In contrast, a second UKPD substudy in which metforminwas added to sulfonylurea therapy to improve glycemic control resulted in an increase in the risk of diabetes-related death or death from any cause compared with continuing therapy with a sulfonylurea alone.216, 217, 218, 220, 221, 225 A pooled analysis of both trials and epidemiologic analysis of other data from the UKPD study in patients who received stepwise therapy with metformin and sulfonylurea therapy because of progressive hyperglycemia showed a small reduction in diabetes-related death,all-cause mortality, myocardial infarction, and stroke.216 Reasons for disparate resultsof these trials are unclear but may be related to trial design, the relatively smaller number of patients receiving metformin, analytical methods, or differences in responsebetween overweight and non-overweight patients.217, 218, 220 Pending the results ofadditional studies, the American Diabetes Association (ADA) and other clinicians do not recommend changing current guidelines regarding the use of metformin asmonotherapy or in combination with sulfonylureas.220, 221, 224

When glycemic control cannot be improved after 1-3 months of combined therapy with oral antidiabetic agents at maximal doses or if the effectiveness of such combined therapy declines, most clinicians recommend discontinuance of oral antidiabetic agents and initiation of insulin therapy.1, 3, 88, 94, 95, 134, 179

Metformin may be used in combination with insulin to improve glycemic control and reduce insulin requirements in patients with type 2 diabetes mellitus who no longer respond to combinations of oral antidiabetic agents.1, 3, 6, 88, 90, 94, 95, 146 Combined therapy with insulin and one or more oral antidiabetic agents appears to increase glycemic control with lower doses of insulin than would be required with insulin alone and with a decreased potential for body weight gain associated with insulin therapy.1,94, 95, 104, 122, 179 Data from a small, placebo-controlled, 24-week trial indicate thataddition of metformin improved glycemic control (as measured by a reduction in glycosylated hemoglobin) in patients who failed to achieve adequate glycemic controlwith insulin therapy; insulin dosage in patients receiving adjunctive metformin therapywas decreased by 16%.1 In another small, placebo-controlled study in patientsadequately controlled with insulin therapy, insulin dosage requirements were reduced by19% after addition of metformin.1 Limited data in patients who no longer respond tomonotherapy with a sulfonylurea or metformin suggest that combined therapy with metformin and a sulfonylurea, with or without a single daily dose of intermediate-actinginsulin, is at least as effective in providing glycemic control as combined therapy with asulfonylurea and intermediate-acting insulin,104, 193 combined therapy with a sulfonylurea and an a-glucosidase inhibitor (e.g., acarbose),193 or combined therapywith intermediate- and short-acting insulins.94

Metformin has been used as an adjunct to insulin to reduce insulin requirements in a limited number of patients with type 1 diabetes mellitus, but the potential benefits and risks require further evaluation before such combined therapy can be recommended.6,86, 87, 116, 122, 134

Oral antidiabetic agents, including metformin, are not effective as sole therapy in patients with diabetes mellitus complicated by acidosis, ketosis, or coma; management of these conditions requires the use of insulin.1, 6, 30, 146, 191, 192, 243, 245, 246

• Misuse and Abuse• Dietary SupplementsSome herbal dietary supplements promoted for the treatment of diabetes mellitus and purported to contain only natural Chinese herbal ingredients have been found to contain phenformin (a biguanide similar to metformin but no longer commercially available in the US) and glyburide.233 Adulteration of these dietary supplements was discovered after use of one of the glyburide- and phenformin-containing dietary supplements by a patient with diabetes mellitus resulted in several episodes of hypoglycemia, from which the patient fully recovered.233 Restrictions on the importation and sale of these dietary supplements have been initiated by FDA.233

Dosage and Administration

• AdministrationMetformin is administered orally.1, 3, 18, 85, 243, 245, 246 In patients receiving a metformin hydrochloride conventional 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 usually should be administered as 3 divided doses daily.1, 243,245, 246 Although food decreases the extent and slightly delays absorption of metforminconventional tablets, the manufacturer states that the clinical importance of these effects is not known and recommends that the drug be taken with meals to decreaseadverse GI effects.1, 3, 18, 243, 245, 246

Metformin hydrochloride extended-release tablets should be taken with the evening meal.1 The matrix core of the tablets 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.1

• DosageDosage of metformin hydrochloride must be individualized carefully based on patient

response and tolerance.1, 4, 243, 245, 246 The goal of therapy should be to reduce both fasting glucose and glycosylated hemoglobin (hemoglobin A1c [HbA1c]) values to normal or near normal using the lowest effective dosage of metformin hydrochloride, either when used as monotherapy or combined with another oral antidiabetic agent (e.g., sulfonylurea, acarbose).1, 8, 13, 14, 78, 85, 88, 105, 134, 146, 166, 234, 235, 243, 245,

246 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, 243, 245, 246 (Glucose concentrations in plasma generally are 10-15% higher than those in whole blood; glucose concentrations also may vary according to the method and laboratory used for these determinations.)204 Glucose determinations also should be monitored to detect primary failure (inadequate lowering of glucose concentration at the maximum recommended dosage) or secondary failure (loss of glycemic control following an initial period of effectiveness) to the drug.1, 3, 243, 245, 246 If inadequate glycemic control and/or secondary failure occurs during maintenance therapy with metformin or an oral sulfonylurea alone, combined therapy may result in an adequate response.1, 134, 243,245, 246 If secondary failure occurs with combined metformin and oral sulfonylureatherapy, most clinicians currently recommend discontinuance of oral antidiabetic agentsand initiation of insulin therapy.1, 3, 13, 30, 88, 90, 94, 95, 134, 146, 179, 243, 245, 246

Following initiation of metformin therapy and dosage titration, determination of glycosylated hemoglobin concentrations at intervals of approximately 3 months is useful for assessing the patient's continued response to therapy.1, 2, 3, 14, 134, 234, 243, 245,246 Glycosylated hemoglobin is a better indicator of long-term glycemic control than fasting plasma glucose concentrations alone.14, 234 In patients usually well controlledby dietary management alone, short-term therapy with metformin may be sufficientduring periods of transient loss of diabetic control.1, 134, 243, 245, 246

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, 243, 245, 246 (See Cautions: GI Effects.)

Initial Dosage in Previously Untreated PatientsAdult DosageFor the management of type 2 (noninsulin-dependent) diabetes mellitus (NIDDM) in adults not previously receiving insulin or a sulfonylurea antidiabetic agent, the usualinitial dosage of metformin hydrochloride as conventional tablets is 500 mg twice dailygiven in the morning and evening with meals.1, 4, 134, 243, 245, 246 Alternatively, ametformin hydrochloride dosage of 500-850 mg daily (given in the morning) asconventional tablets has been suggested.1, 2, 3, 4, 23, 30, 146, 243, 245, 246 When theextended-release preparation of metformin hydrochloride is used, the usual initial dosage in adults is 500 mg once daily with the evening meal.1 Subsequent dosageshould be adjusted according to the patient's therapeutic response, using the lowest possible effective dosage.1, 30, 243, 245, 246 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

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, 243, 245, 246 In addition, renal

function should be monitored regularly in geriatric patients to determine the appropriate dosage of metformin hydrochloride.1, 2, 3, 4, 164, 165, 243, 245, 246 Metformin should not be initiated in geriatric patients 80 years of age or older unless determinations of creatinine clearance indicate normal renal function.1, 209 Initial dosages of metformin hydrochloride should be conservative and should be titrated carefully; dosage generally should not be titrated to the maximum level recommended for younger adults.1, 2, 3, 4,165, 243, 245, 246 It has been suggested, based on limited data, that initial dosages ofmetformin hydrochloride in geriatric patients be reduced by approximately 33%compared with such dosages in other patients with type 2 diabetes mellitus.30, 174

Pediatric DosageFor the management of type 2 (noninsulin-dependent) diabetes mellitus (NIDDM) in children 10 years of age or older, the usual initial dosage of metformin hydrochloride asconventional tablets is 500 mg twice daily given in the morning and evening with meals.1, 246 Use of the extended-release tablets of metformin hydrochloride is not recommended in children younger than 17 years of age.1

Transferring from Therapy with Other Antidiabetic AgentsWhen transferring from most sulfonylurea antidiabetic agents to metformin, a transition period generally is not required, and administration of the sulfonylurea antidiabetic agentmay be abruptly discontinued.1, 2, 243, 245, 246 Because an exaggerated hypoglycemicresponse may occur in some patients during the transition from a sulfonylurea antidiabetic agent with a prolonged half-life (e.g., chlorpropamide) to metformin, patients being transferred from such agents should be monitored closely for the occurrence ofhypoglycemia during the initial 2 weeks of the transition period.1, 2, 30, 243, 245, 246

Maintenance DosageAdult DosageThe usual adult maintenance dosage of metformin hydrochloride as conventional tablets is 850 mg twice daily with the morning and evening meals; when additional glycemiccontrol is necessary, patients may be given 850 mg 3 times daily with meals.1, 243, 245,246 In adults receiving an initial metformin hydrochloride dosage of 500 mg twice dailyas conventional tablets, dosage may be increased by 500 mg daily at weekly intervals until the desired fasting blood glucose concentration (e.g., less than 140 mg/dL) isachieved or up to 2 g daily.1, 2, 14, 18, 21, 30, 85, 134, 243, 245, 246 In adults receiving500 mg of metformin hydrochloride twice daily as conventional tablets, dosage may be increased to 850 mg twice daily (i.e., using the 850-mg tablets) after 2 weeks.1, 243, 245,246 Alternatively, in adults receiving an initial metformin hydrochloride dosage of 850 mgdaily as conventional tablets, dosage may be increased by 850 mg daily every otherweek until the desired fasting blood glucose concentration (e.g., less than 140 mg/dL) isachieved or up to a maximum dosage of 2.55 g daily.1, 2, 3, 4, 14, 18, 22, 85, 243, 245,246

In adults receiving metformin hydrochloride extended-release tablets, dosage may be increased by 500 mg daily at weekly intervals until the desired glycemic response is

achieved or a maximum dosage is 2 g daily is reached.1 If glycemic control is not achieved with metformin hydrochloride extended-release tablets at a dosage of 2 g once daily, a dosage of 1g twice daily should be considered.1 If a dosage exceeding 2 g daily is needed in patients receiving metformin hydrochloride extended-release tablets, patients should be switched to conventional metformin hydrochloride tablets and may receive up to a maximum of 2.55 g of the drug daily in divided doses.1 Conversely, therapy with extended-release tablets can be substituted for conventional tablets at the same total daily dosage of conventional tablets; dosage subsequently should beadjusted according to glycemic response.1

Dosage in adults generally should not exceed 2.55 g daily as conventional tablets1, 243,245, 246 or 2 g daily as extended-release tablets.1 Dosages exceeding 2 g of metforminhydrochloride daily as conventional tablets may be better tolerated if given in 3 divideddoses daily with meals.1, 243, 245, 246 Maintenance dosage of metformin hydrochlorideshould be conservative in debilitated, malnourished, or geriatric patients because of an increased risk of hypoglycemia in these patients.1, 243, 245, 246 (See Cautions:Precautions and Contraindications.)

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, 243, 245, 246 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, 243, 245, 246

Maintenance dosage of metformin hydrochloride in geriatric patients generally shouldnot be titrated to the maximum level recommended for younger adults.1, 2, 3, 4, 165,243, 245, 246 It has been suggested, based on limited data, that maximum dosages ingeriatric patients be reduced by approximately 33% compared with such dosages in other patients with type 2 diabetes mellitus.30, 174

Pediatric DosageIn children 10 years of age or older receiving metformin hydrochloride 500 mg twice daily as conventional tablets, dosage may be increased by 500 mg daily at weekly intervals until the desired glycemic response is achieved or up to a maximum dosage of2 g daily.1, 14, 246

Concomitant Therapy with Metformin and Sulfonylurea Antidiabetic AgentsIn patients who do not respond to a 4-week trial of metformin hydrochloride therapy at the maximum recommended dosage, the manufacturer suggests that gradual addition of a sulfonylurea antidiabetic agent be considered even if prior primary or secondaryfailure to a sulfonylurea antidiabetic agent has occurred.1, 2, 4, 191, 243, 245, 246 Themanufacturer of glipizide states that other oral antidiabetic agents may be added toglipizide therapy if glycemic control is inadequate with glipizide. 242 The manufacturersof glimepiride or glyburide state that combination therapy with metformin may be used in patients who no longer respond adequately to either antidiabetic agent alone, despiteappropriate antidiabetic monotherapy, diet, and exercise.191, 241, 246 With concomitant

metformin hydrochloride and sulfonylurea therapy, dosage of each drug should be adjusted to obtain adequate glycemic control with the minimum effective dosage of each drug.1, 2, 191, 243, 245, 246 In patients who do not respond to 1-3 months of concomitant therapy at the maximum dosage of each oral antidiabetic agent, therapeutic alternatives include use of insulin1, 243, 245, 246 with or without concomitant metforminhydrochloride therapy.1

The commercially available preparation containing metformin hydrochloride in fixed combination with glyburide may be used as initial therapy in patients with type 2 diabetes mellitus whose blood glucose is not adequately controlled with diet and exercise alone, or as second-line therapy in those in whom glycemic control with glyburide or metformin monotherapy is not adequate.234, 254 If the fixed combination of metformin and glyburide is used as initial therapy, the recommended initial dosage is250 mg of metformin hydrochloride and 1.25 mg of glyburide daily with a meal.234

Patients with more severe hyperglycemia (as determined by glycosylated hemoglobin exceeding 9% or fasting plasma glucose concentrations exceeding 200 mg/dL) mayreceive an initial dosage of 250 mg of metformin hydrochloride and 1.25 mg of glyburidetwice daily with the morning and evening meals.234 Dosage may be increased inincrements of 1.25 mg of glyburide and 250 mg of metformin hydrochloride daily at2-week intervals until the minimum effective dosage required to achieve adequate bloodglucose control is reached.234 A total daily dosage exceeding 10 mg of glyburide and 2g of metformin hydrochloride has not been evaluated in clinical trials in patientsreceiving the fixed-combination preparation as initial therapy.234 The manufacturerstates that the fixed-combination preparation containing 5 mg of glyburide and 500 mg of metformin hydrochloride should not be used as initial therapy in treatment-naivepatients because of the increased risk for hypoglycemia.234

If the fixed combination of metformin and glipizide is used as initial therapy, the recommended initial dosage is 250 mg of metformin hydrochloride and 2.5 mg of glipizide once daily with a meal. 254 Patients with more severe hyperglycemia (as determined by fasting plasma glucose concentrations of 280-320 mg/dL) may receive an initial dosage of 500 mg of metformin hydrochloride and 2.5 mg of glipizide twice daily. 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. 254Dosage 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 in hydrochloride) daily at 2-week intervals until the minimum effective dosage required to achieve adequate blood glucose control is reached or the maximal dosage of 2 g ofmetformin hydrochloride and 10 mg of glipizide is reached. 254, 256 A total daily dosageexceeding 2 g of metformin hydrochloride and 10 mg of glipizide has not been evaluatedin clinical trials in patients receiving the fixed-combination preparation as initial therapy.254

The commercially available preparation containing metformin hydrochloride in fixed combination with glyburide or glipizide also may be used as second-line therapy in

patients with type 2 diabetes mellitus whose blood glucose is not adequately controlled with either glyburide or glipizide (or another sulfonylurea antidiabetic agent) ormetformin alone.234, 254 The recommended initial dosage of the commercially availablefixed-combination tablets in previously treated patients is 500 mg of metformin hydrochloride and 2.5 or 5 mg of glyburide or glipizide twice daily with the morning andevening meals.234, 254 In order to minimize the risk of hypoglycemia, the initial dosageof glyburide and metformin hydrochloride in fixed combination should not exceed the daily dosage of metformin hydrochloride, glyburide, or glipizide (or the equivalentdosage of another sulfonylurea) previously received.234, 254 The dosage of the fixedcombination of metformin hydrochloride and glyburide or glipizide should be titrated upward in increments not exceeding 500 mg of metformin hydrochloride and 5 mg of glyburide or glipizide until adequate control of blood glucose is achieved or a maximumdaily dosage of 2 g of metformin hydrochloride and 20 mg of glyburide or glipizide isreached.234, 254

For patients being switched from combined therapy with separate preparations, the initial dosage of the fixed-combination preparation of glyburide or glipizide and metformin hydrochloride should not exceed the daily dosage of glyburide, glipizide (or equivalent dosage of another sulfonylurea antidiabetic agent), and metforminhydrochloride currently being taken.234, 254 Such patients should be monitored for signs and symptoms of hypoglycemia following the switch.234, 254 In the transfer fromprevious antidiabetic therapy to fixed combination of metformin hydrochloride, thedecision to switch to the nearest equivalent dosage or to titrate dosage should be basedon clinical judgment.254 Hypoglycemia and hyperglycemia are possible in such patients,and any change in the therapy of type 2 diabetic patients should be undertaken withcaution and appropriate monitoring.234 If blood glucose concentrations are notadequately controlled following initial administration of the fixed-combination preparation, the dose may be titrated in increments of no more than 5 mg of glyburideand 500 mg of metformin hydrochloride until adequate control of blood glucose is achieved or a maximum dosage of 20 mg of glyburide or glipizide and 2 g of metforminhydrochloride is reached.234, 254 The safety and efficacy of switching from anothercombined therapy with separate preparations of glyburide (or another sulfonylurea antidiabetic agent) and metformin in the fixed-combination preparation have not beenestablished in clinical studies.234

For patients whose hyperglycemia is not adequately controlled on therapy with metformin in fixed combination with glyburide, a thiazolidinedione (e.g., pioglitazone, rosiglitazone) may be added at its recommended initial dosage and the dosage of the fixed combination may be continued unchanged. 234 In patients requiring further glycemic control, the dosage of the thiazolidinedione may be titrated upward, based on the dosage regimen recommended by the manufacturer.234 Triple therapy with glyburide, metformin, and a thiazolidinedione may increase the potential for hypoglycemia at any time of day.234 If hypoglycemia develops during such triple therapy, consideration should be given to reducing the dosage of the glyburide component; adjustment of the dosage of the other components of the antidiabetic regimen also should be considered as clinically indicated.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 and should be titrated carefully in such patients.234

Renal function should be assessed with initial dosage selection and with each dosage adjustment, particularly in geriatric patients, to aid in prevention of lactic acidosis.234 To minimize the risk of hypoglycemia, maintenance dosage of the fixed combination of metformin hydrochloride and glyburide in geriatric, debilitated, or malnourished patients should not be titrated to the maximum dosage recommended for other patients.234

Combination Therapy with Metformin and a ThiazolidinedioneThe manufacturers of pioglitazone or rosiglitazone state that combination therapy with metformin hydrochloride may be used in patients who do not respond adequately to either antidiabetic agent alone despite appropriate antidiabetic monotherapy, diet, andexercise.237, 250 In patients with inadequate glycemic control receiving metforminhydrochloride, the current dosage of metformin hydrochloride may be continued upon initiation of thiazolidinedione therapy, as dosage adjustments of metforminhydrochloride because of hypoglycemia are not likely to be needed.237, 250

The commercially available fixed-combination preparation containing metformin hydrochloride and rosiglitazone is used as second-line therapy in patients who have inadeqate glycemic control with metformin monotherapy.247 Metformin in fixed combination with rosiglitazone also is used in patients with type 2 diabetes mellitus who are already receiving each drug component separately. 247 Any change in the therapyof type 2 diabetic patients should be undertaken with caution and appropriate monitoring. 247

When the commercially available preparation containing metformin hydrochloride in fixed combination with rosiglitazone is used as second-line therapy in patients inadequately controlled on metformin or rosiglitazone monotherapy or to replace concurrent therapy with the drugs given as separate tablets, dosage of the fixed combination is based on the patient's current dosages of metformin hydrochloride and/or rosiglitazone.247 In patients inadequately controlled on rosiglitazone monotherapy, the usual initial dosage of metformin hydrochloride (in fixed combinationwith rosiglitazone) is 1 g daily plus the patient's existing dosage of rosiglitazone, given in2 divided doses. 247 In patients inadequately controlled with metformin hydrochloridemonotherapy, the usual initial dosage of rosiglitazone (in fixed combination with metformin hydrochloride) is 4 mg daily plus the patient's existing dosage of metforminhydrochloride, given in 2 divided doses. 247 The tablet strength of the fixed combinationthat is selected should be the one that most closely provides the patient's existingdosage of metformin hydrochloride or rosiglitazone, respectively. 247 (See Table.)

Initial Dosage of the Fixed Combination of Rosiglitazone and Metformin Hydrochloride (Avandamet®) Prior Therapy Usual Initial Dosage of Avandamet®

Total Daily Dosage Tablet strength Number of tabletsMetformin Hydrochloride1 g 2 mg/500 mg 1 tablet twice daily2 g 1 mg/500 mg 2 tablets twice dailyRosiglitazone4 mg 2 mg/500 mg 1 tablet twice daily8 mg 4 mg/500 mg 1 tablet twice daily

Therapy should be individualized in patients already receiving metformin hydrochloride at dosages not available in the fixed combination (i.e., dosages other than 1 or 2 g). 247

The safety and efficacy of transferring from therapy with other oral antidiabetic agents to the fixed-combination of metformin hydrochloride and rosiglitazone have not been established in clinical studies.247

For patients switching from combined therapy with separate preparations of metformin hydrochloride and rosiglitazone, the initial dosage of the fixed-combination preparation of metformin hydrochloride and rosiglitazone should be the same as the daily dosage of metformin hydrochloride and rosiglitazone currently being taken. 247

If additional glycemic control is needed following initial therapy or transfer from other antidiabetic therapy, the dosage of the fixed combination of metformin hydrochloride and rosiglitazone may be titrated upward in increments not exceeding 500 mg of metformin hydrochloride and/or 4 mg of rosiglitazone until adequate glycemic control is achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 8 mg of rosiglitazone is reached. 247

Therapy with metformin in fixed combination with rosiglitazone should be used with caution in geriatric patients, since aging is associated with reduced renal function.247

The initial and maintenance dosages of metformin hydrochloride in fixed combination with rosiglitazone should be conservative and should be titrated carefully in such patients.247 Renal function should be assessed with initial dosage selection and with each dosage adjustment, particularly in geriatric patients, to aid in prevention of lactic acidosis.247 To minimize the risk of hypoglycemia, maintenance dosage of the fixed combination of metformin hydrochloride and glyburide in geriatric, debilitated, or malnourished patients should not be titrated to the maximum dosage recommended for other patients. 247

Concomitant Therapy with Metformin and InsulinCombination therapy with metformin and insulin may be used in patients who no longer respond adequately to therapy with oral antidiabetic agents.1 In such patients, themanufacturer recommends an initial metformin hydrochloride dosage of 500 mg once daily; the daily dosage may be increased by 500 mg at weekly intervals up to a maximum of 2.5 g daily or until the desired fasting blood glucose concentration is achieved.1 Dosages up to 2 g may be given in 2 divided doses daily (e.g., 2 g daily divided as 1 g with the morning and evening meal) and dosages exceeding 2 g of metformin hydrochloride daily may be better tolerated if given in 3 divided doses daily

with meals.1 Concurrent insulin dosage should initially remain unchanged.1 Patients should be monitored closely (e.g., with determination of fasting glucose concentrations) during the dosage titration.1 When fasting plasma glucose concentrations decrease to less than 120 mg/dL in patients receiving combined metformin and insulin therapy, the insulin dosage may be decreased by 10-25%.1 Further dosage adjustments should be individualized based on glycemic response.1 Periodic adjustments in dosage may be necessary during continued combination therapy, as guided by monitoring of fasting glucose and/or glycosylated hemoglobin concentrations.1

• Dosage in Renal and Hepatic ImpairmentBecause of the risk of lactic acidosis, which often is fatal, metformin should not be used in patients with renal disease or dysfunction and should be avoided in those with clinical or laboratory evidence of hepatic disease.1, 165, 243, 245, 246 (See Cautions: Lactic Acidosis.)

Cautions

Adverse effects, principally GI effects, reportedly occur in about 5-50% of patients receiving metformin therapy as conventional tablets in clinical trials and generally required discontinuance of the drug in 6% or less of patients.1, 6, 18, 20, 23, 27, 134, 243,245, 246 When metformin in used in fixed combination with glyburide, glipizide, orrosiglitazone, the cautions, precautions, and contraindications associated with theseconcomitant agents must be considered in addition to those associated with metformin.234, 247, 254

• GI Effects

Adverse GI effects such as diarrhea1, 31, 48, 49, 53, 78, 109, 118, 122, 135, 234, 243, 245,246, 254, nausea1, 31, 53, 78, 109, 118, 122, 254, vomiting,1, 118, 122, 234, 243, 245, 246,254 flatulence,1, 243, 245, 246 indigestion,1, 243, 245, 246 and abdominal discomfort (e.g., bloating, abdominal cramping or pain),1, 31, 35, 42, 53, 118, 122, 234, 243, 245, 246 are themost common adverse effects associated with metformin-containing therapy asconventional tablets;1, 2, 18, 20, 234, 243, 245, 246, 247, 254 diarrhea or nausea/vomitingare the most common adverse effects reported in clinical trials with theextended-release tablets.1 Because substantial diarrhea and/or vomiting may causedehydration and prerenal azotemia, metformin should be discontinued in patients who develop such potentially serious GI effects; persistent diarrhea resolves promptly upondiscontinuance of the drug.1, 18 Unpleasant or metallic taste (taste disorder/disturbance),1, 18, 118, 122, 243, 245, 246 which usually resolves spontaneously,has been reported in approximately 1-5% of patients receiving metformin conventionalor extended-release tablets.1, 2, 3, 30 Other adverse GI effects reported in 1-5% ofpatients receiving conventional or extended-release metformin tablets include abnormalstools,1, 243, 245, 246 distended abdomen,1 constipation,49, 118 or dyspepsia/heartburn.1, 49, 118 Anorexia also has been reported with metformintherapy.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.1, 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 conventional tablets and in about 0.6% of those receiving the extended-release tablets in controlled clinical trials.1, 30, 78, 243, 245, 246 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.1, 2, 16, 18, 53, 85, 243, 245, 246

• HypoglycemiaHypoglycemia is uncommon in patients receiving metformin as monotherapy; however,it may occur when metformin is used concomitantly with an oral sulfonylurea antidiabetic agent, a thiazolidinedione, or insulin, when caloric intake is deficient, or when strenuousexercise is not accompanied by food intake.1, 15, 30, 78, 94, 99, 234, 243, 245, 246, 247,254 Symptoms of hypoglycemia (such as dizziness, shakiness, sweating, hunger) haveoccurred 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 ofmetformin hydrochloride), or glyburide in fixed combination with metformin hydrochlorideat a final mean titrated dosage of 824 mg of metformin hydrochloride and 4.1 mg ofglyburide in controlled clinical trials. 234 In a controlled initial therapy trial of metforminhydrochloride 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), metforminhydrochloride 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 dosageof the metformin hydrochloride component (final mean dosage of 1.477 g of metforminhydrochloride and 7.4 mg of glipizide). 254 In a controlled trial in patients inadequatelycontrolled by monotherapy with metformin hydrochloride or a sulfonylurea agent, documented hypoglycemia (as determined by blood glucose concentrations of 50 mg/dLor 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 of1.927 g), or metformin hydrochloride in fixed combination with glipizide at a final meandosage of 1.747 g of metformin hydrochloride and 5 mg of glipizide. 254 Whenrosiglitazone was added to fixed combination therapy of glyburide and metformin hydrochloride, documented hypoglycemia occurred in 22% of such patients comparedto 3.3% of patients receiving glyburide in fixed combination with metforminhydrochloride. 234 (See Cautions: Precautions and Contraindications.)

• Hematologic EffectsAsymptomatic decreases in serum vitamin B12 concentration were reported in about

7-9% of patients receiving metformin alone,1, 18, 243, 245, 246 and in about 6% of those receiving metformin concomitantly with a sulfonylurea antidiabetic agent, during

29-week controlled clinical trials.1, 18 Such decreases may be related to interference

with absorption of vitamin B12 from B12-intrinsic factor complex;1, 70, 243, 245, 246

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, 243, 245, 246 Serum folic acid concentrations do not appear to decrease

substantially in patients receiving metformin therapy.1, 70, 82 Megaloblastic anemia has been reported rarely (e.g., approximately 5 case reports outside the US to date) in

patients receiving metformin,1, 2, 18, 114, 243, 245, 246 and no increased incidence of

neuropathy has been observed in patients receiving the drug.1, 18, 114, 123 Hematologic parameters (e.g., hemoglobin, serum vitamin B12 concentrations) should be monitored annually in patients receiving metformin, and any apparent abnormalities appropriately

investigated and managed.1, 243, 245, 246 Some clinicians have suggested that periodic supplementation with parenteral vitamin B12 be considered in patients receiving metformin who are at high risk for developing subnormal vitamin B12 levels (e.g.,

alcoholics, patients with low calcium or vitamin B12 intake or absorption).82, 114, 122,134, 148 (See Cautions: Precautions and Contraindications.)

• Dermatologic ReactionsThe manufacturer states that incidence of rash or dermatitis in patients receiving metformin monotherapy is similar to that with placebo, and that the incidence of these dermatologic effects in patients receiving metformin concomitantly with a sulfonylurea antidiabetic agent is similar to that in individuals receiving a sulfonylurea antidiabetic agent alone.1, 30

• Lactic AcidosisAccumulation 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 However, the risk of developing lactic acidosis is less with metformin than with phenformin (no longer commercially available in the US).3, 6, 20, 23(See Chemistry and Stability: Chemistry.) Lactic acidosis also may occur in association with a variety of pathophysiologic conditions, including diabetes mellitus, and may occur whenever substantial tissue hypoperfusion and hypoxemia exist.1, 32, 53, 63, 64, 93, 96, 123, 146 Lactic acidosis is characterized by elevated blood lactate concentrations (exceeding 45 mg/dL), decreased blood pH (less than 7.35),electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio.1, 30

When metformin has been implicated as the cause of lactic acidosis, plasma drug

concentrations exceeding 5 mcg/mL generally have been observed.1 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 plasmaconcentrations of lactic acid or lactic acidosis have been demonstrated during metformin

therapy despite normal plasma concentrations of the drug.51, 64, 96, 146, 158 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

Fasting venous plasma lactate concentrations that exceed the upper limit of normal but are less than 45 mg/dL do not necessarily indicate impending lactic acidosis in patients receiving metformin.1 Such concentrations may be related to poorly controlled diabetes, obesity, vigorous physical activity, or technical problems in handling samples for plasma lactate determinations.1

The reported overall incidence of lactic acidosis in patients receiving metformin therapy is low (approximately 0.03 cases per 1000 patient-years of metformin therapy); approximately 50% of such cases have been fatal.1, 2, 3, 4, 33, 78, 95, 146, 158 It has been suggested that in metformin-associated 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 a recovery rate exceeding 80%.158 Lactic acidosis associated with metformin therapy generally has occurred in diabetic patients with severe renal insufficiency, including those with both intrinsic renal impairment and renal hypoperfusion; such patients frequently had concomitant medical and/or surgical problems and were receiving multiple drugs.1, 2, 3,20, 50, 62, 64, 76, 96, 123, 158, 164, 165

The risk of lactic acidosis increases with the degree of renal impairment and the patient's age; therefore, the risk of this condition can be minimized by periodic monitoring of renal function and use of the minimum effective dosage of metforminhydrochloride.1, 32, 62, 63, 65, 76, 85, 91, 93, 96, 123, 124, 158, 164, 165, 234, 247 Metformintherapy should be withheld promptly in patients with any condition associated withhypoxemia, sepsis, or dehydration.1, 2, 62, 63, 93, 234, 247 Therapy with the drug aloneor in fixed combinations also should be avoided in patients with clinical or laboratory evidence of hepatic impairment since elimination of lactate may be reducedsubstantially in such patients.1, 2, 63, 65, 85, 91, 93, 156, 158, 234, 247 Patients should beadvised not to consume excessive amounts of alcohol, either acutely or chronically, since alcohol may potentiate the effects of metformin on lactate metabolism bydecreasing hepatic gluconeogenesis.1, 2, 63, 76, 91, 93, 158, 234, 247 In addition, therapywith metformin preparations should be withheld temporarily in patients undergoingsurgery or receiving parenteral iodinated radiographic contrast media.1, 2, 30, 62, 63, 93,158, 234, 247, 254 (See Cautions: Precautions and Contraindications.)

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 abdominal distress.1, 32, 62, 119 Associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis also may occur.1, 62, 117

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 metformin should be discontinued until the clinician has evaluated the patient's condition.1, 30 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.1 In diabetic patients, lactic acidosis may be manifested as metabolic acidosis without ketoacidosis (ketonuria and ketonemia).1

Lactic acidosis constitutes a medical emergency requiring immediate hospitalization and

treatment;1 in such cases, metformin should be discontinued and general supportive therapy (e.g., volume expansion, diuresis) should be initiated immediately.1, 32, 62, 119

(See Acute Toxicity.)

• Other Adverse EffectsHeadache,118 agitation,118 dizziness,118 and tiredness118 were reported in a small

comparative study in geriatric diabetic patients receiving metformin.30, 85 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 or12.6% of patients receiving metformin or metformin in fixed combination with glipizide,

respectively. 254 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

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 fixedcombination 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 receivingmetformin or metformin in fixed combination with glipizide, respectively, as second-line therapy for type 2 diabetes mellitus. 254 Urinary tract infection has been reported in 8 or1.1% 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

• Precautions and ContraindicationsWhen metformin in used in fixed combination with glyburide, the cautions, precautions, and contraindications associated with glyburide must be considered in addition to those associated with metformin.234

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, 14, 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 antidiabetic agent.1, 2, 14, 88, 179, 187 Glycosylated hemoglobin (hemoglobin A1c [HbA1c]) measurements also are useful, particularly for monitoring

long-term control of blood glucose concentration.1, 2, 134 Blood glucose determinations are important to detect primary failure (inadequate lowering of blood glucose concentration at the maximum recommended dosage) or secondary failure (loss of control of blood glucose concentration following an initial period of effectiveness) to the drug.1

Patients should be informed of the risks of lactic acidosis and conditions that predispose

to its development.1 (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 the risk of lactic acidosis increases with degree of renal impairment.1 Therefore, the manufacturer states that renal function should be evaluated prior to initiation of therapy with metformin preparations and atleast annually thereafter.1, 2, 77, 85, 234 The manufacturer also states that patientswhose serum creatinine concentrations exceed the upper limit of normal for their ageshould not receive metformin.1 In patients in whom development of impaired renalfunction is anticipated (e.g., those with blood glucose concentrations exceeding 300 mg/dL, who may develop renal dysfunction as a result of polyuria and volumedepletion),156 renal function should be monitored more frequently; the drug should be discontinued if evidence of renal impairment is present.1, 2, 156, 164 In addition, drugsthat may affect renal function, produce substantial hemodynamic changes, or interferewith metformin elimination (e.g., cimetidine) should be used with caution in patients receiving metformin.1, 134 Hemodialysis has been used in patients with lactic acidosis toaccelerate the clearance of metformin. (See Acute Toxicity.)

Metformin should not be used in patients with congestive heart failure requiring drug therapy (e.g., digoxin, furosemide), such as those with unstable or acute congestive heart failure.1, 209, 214, 215 These patients are at risk for hypoperfusion and hypoxemia, which may lead to lactic acidosis.1, 215 Some clinicians suggest that metformin may be reinstituted once acute heart failure has resolved and renal function is normal (as measured by creatinine clearance).215

Since administration of parenteral iodinated contrast media may lead to acute alteration of renal function and has been associated with lactic acidosis in patients receiving metformin, the manufacturer states that metformin should be discontinued at the time of or prior to the procedure, and should not be reinstituted until 48 hours after such procedures;1, 234, 243, 245, 246, 247, 254 metformin should not be reinstituted until renal

function has been evaluated and found to be normal.1, 234, 247 Metformin also should be discontinued temporarily in patients undergoing surgery, except minor surgery that is not associated with restricted food or fluid intake; the drug should be reinitiated only when patient's oral intake has resumed and renal function has been shown to be normal.1, 254 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 (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 Since cardiovascular collapse (shock), congestive 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 patientsdeveloping such conditions.1, 18, 20, 30, 62, 76, 91, 93, 146, 156, 158, 254

The cardiovascular risks associated with use of oral antidiabetic agents have not been fully determined.1, 2, 34, 136, 216 In 1970, the University Group Diabetes Program (UGDP) reported that administration of oral antidiabetic agents (i.e., tolbutamide or phenformin) was associated with increased cardiovascular mortality compared with treatment with dietary regulation alone or with dietary regulation and insulin.1, 191, 192,200, 234 The UGDP reported that type 2 diabetic patients who were treated for 5-8 yearswith dietary regulation and a fixed dose (1.5 g daily) of tolbutamide or dietary regulation and a fixed dose (100 mg daily) of phenformin (currently not commercially available inthe US) had a cardiovascular mortality rate approximately 2.5 times that of patientstreated with dietary regulation alone.1, 191, 192, 200, 234 Although a substantial increasein total mortality was observed only with phenformin, both tolbutamide and phenforminwere discontinued because of the increases in cardiovascular mortality.1, 191, 192, 200,234 The results of the UGDP study have been analyzed exhaustively, and there hasbeen general disagreement in the scientific and medical communities regarding thestudy's validity and clinical importance.1, 10, 23, 180, 198, 200 The management ofpatients with type 2 diabetes mellitus has changed substantially since the UGDP was initiated in 1961.10, 180, 184, 198 Dietary management, weight reduction, better controlof blood glucose concentration, and regular physical activity have received greater emphasis in the management of diabetes in these patients.8, 10, 14, 24, 25, 26, 88, 179,181 In addition, reduction of existing cardiovascular risk factors (e.g., management of hypertension, discontinuance of smoking) has been emphasized.10, 14, 26, 88, 179, 181,185, 187 The American Diabetes Association (ADA) currently recommends that clinicianjudgment in the management of type 2 diabetes mellitus be based on assessment of all available therapeutic information, including data on cardiovascular risk factors, the positive effect of metabolic control of diabetes on cardiovascular disease, theimportance of dietary management and weight reduction in obese diabetic patients, theimportance of regular physical activity, and objective reports in the scientific literaturethat pertain to the UGDP study and to the long-term use of sulfonylureas.10, 14, 26, 136

Results of several recent, long-term studies by the United Kingdom Prospective Diabetes Study (UKPD study) group indicate that effects of metformin on mortality and macrovascular outcomes vary considerably depending on the patient population evaluated.216, 218 In one study, intensive therapy (target fasting plasma glucose of less than 108 mg/dL) initiated with metformin or other antidiabetic agents (chlorpropamide, glyburide, or insulin) was compared with conventional therapy (target fasting plasma glucose of less than 270 mg/dL) consisting of diet and supplemental therapy with the same antidiabetic agents for marked hyperglycemia in overweight (exceeding 120% of ideal body weight) patients.216 In this study, cardiovascular disease accounted for 62% of the total mortality observed in patients receiving conventional therapy.216 Intensive therapy initiated with metformin in these overweight patients was associated with a 36% reduction in all-cause mortality and a 30% lower risk of developing macrovascular disease (myocardial infarction, sudden death, angina, stroke, peripheral vascular disease) compared with conventional therapy; the reduction in macrovascular disease was similar among intensive therapies employing other antidiabetic agents.216

In another study, metformin was given as supplemental therapy in overweight andnon-overweight patients who were poorly controlled on existing sulfonylurea therapy, orsulfonylurea therapy alone was continued.216 In this study, intensive metformin andsulfonylurea therapy was associated with an increase in the risk of diabetes-related death or death from any cause compared with that in patients continuing to receivesulfonylurea therapy alone.216 Similarly, another study by the UKPD Study Group foundno decrease in mortality when metformin was added to sulfonylurea therapy (i.e., chlorpropamide or glyburide) or insulin alone in an intensive regimen (target fastingplasma glucose concentration of 108 mg/dL) in obese and non-obese patients.216, 220

A pooled analysis of both UKPD trials and epidemiologic analysis of othernon-overweight and overweight patients from UKPD studies who received metformin and sulfonylurea therapy because of progressive hyperglycemia showed a small reduction in diabetes-related death, all-cause mortality, myocardial infarction, andstroke.216 As reasons for the inconsistent effects of metformin are unclear, furthercomparative studies of metformin alone or in combination with a sulfonylurea are needed to determine the long-term safety and efficacy of metformin in the treatment oftype 2 diabetes mellitus.217, 220, 221, 222, 225, 226 Pending the results of such studies,the American Diabetes Association (ADA) and other clinicians do not recommend changing current guidelines regarding the use of metformin as monotherapy or incombination with sulfonylureas.220, 221, 224 ADA currently recommends that clinicianscontinue to emphasize dietary management and weight reduction as the principal therapy for the management of type 2 diabetes mellitus and that oral antidiabetic agentsor insulin be used only after these measures have failed; the decision to use an oralantidiabetic agent or insulin should be made by the clinician in consultation with thepatient.1, 10, 14, 26

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.14, 88, 179, 185 Patients should be informed of the potential risks and

advantages of metformin therapy and of alternative forms of treatment.1 Patients should be instructed that dietary regulation is the principal consideration in the management of diabetes,1, 24, 25, 26 and that metformin therapy is used only as an adjunct to,1 and not a substitute for, proper dietary regulation.134, 187 Patients also should be advised that they should not neglect dietary restrictions, develop a careless attitude about their condition, or disregard instructions about body-weight control, exercise, hygiene, and avoidance of infection.1, 30, 134 The possibility of primary and secondary failure to metformin therapy also should be explained to patients.1

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 occasionallymay occur during therapy with metformin.1 Hypoglycemia occurs infrequently in patientsreceiving metformin therapy under usual conditions of use; the incidence of hypoglycemia with metformin is much lower than that in patients receiving sulfonylureasor insulin.1, 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 Inaddition, certain other factors (e.g., deficient caloric intake, strenuous exercise notcompensated by caloric supplementation, alcohol ingestion, adrenal or pituitaryinsufficiency) may predispose patients to the development of hypoglycemia.1, 2

Debilitated, malnourished, or geriatric patients also may be particularly susceptible to hypoglycemia;1, 2 this condition may be difficult to recognize in geriatric patients or inthose receiving ß-adrenergic blocking agents or other sympatholytic agents.1, 83, 91,128, 143, 153, 159 (See Drug Interactions: ß-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.1 Metformin therapy may be reinstituted after the acute episodeis resolved.1

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, 243, 245, 246 Some patients (i.e., those with an inadequate absorption or intake ofvitamin B12 or calcium) appear to be predisposed to developing decreased vitamin B12concentrations; vitamin B12 concentrations should be monitored every 2-3 years while

these patients are receiving metformin therapy.1, 30, 134, 148, 168, 243, 245, 246

Metformin alone or in fixed combination with glyburide, glipizide, or rosiglitazone is contraindicated in patients with renal impairment (e.g., men or women with serum creatinine concentrations equal to or exceeding 1.5 or 1.4 mg/dL, respectively) or abnormal creatinine clearance, which may result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, or septicemia.1, 2, 18, 20, 91, 234, 247, 254

Metformin alone or in fixed combination with glyburide, glipizide, or rosiglitazone is

contraindicated in patients with congestive heart failure requiring drug therapy.1, 234,247, 254 Metformin-containing therapy also is contraindicated as sole therapy in patientswith type 1 diabetes and in patients with diabetes complicated by acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma.1, 2, 234, 247

Metformin alone or in fixed combination with glyburide, glipizide, or rosiglitazone also is contraindicated in patients with known hypersensitivity any ingredient in the respective formulations.

• Pediatric PrecautionsSafety and efficacy of metformin conventional or extended-release tablets in children younger than 10 or younger than 17 years of age, respectively, have not been established.1, 3, 4, 30, 134, 243, 245, 246 Data from a placebo-controlled clinical trial indicated a similar glycemic response and adverse effect profile in pediatric patients(10-16 years of age) as in adults.1, 246 (See Diabetes Mellitus: Metformin Monotherapy,in Uses.) The safety and efficacy of metformin in fixed combination with glyburide,glipizide, or rosiglitazone in pediatric patients have not been established. 234, 247, 254

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

• Geriatric PrecautionsIt is not known whether geriatric patients respond differently to metformin than younger

patients.1 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, the drug should be used with caution in geriatric patients.1, 3, 4, 30, 85, 174 234, 247, 254 Metformin therapy should be used only in patients with normal renal function. 1, 234, 254 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.209, 214, 234, 247, 254 In addition, renal function should be monitored periodically and care should be taken in dosage selection for geriatric patients; such patients generally should not receive the maximum recommended dosage of metformin hydrochloride.1, 2, 3, 4, 30, 85, 174, 234, 247, 254

• Mutagenicity and CarcinogenicityNo 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 orin 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, Fertitlity and LactationReproduction 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 2 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)1 have not revealed evidence of harm to the fetus.1

Determination of fetal concentrations of metformin suggest that a partial placental barrier to the drug exists.1, 3 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

There are no adequate and controlled studies to date using metformin in pregnant women.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

Metformin should be used during pregnancy only when clearly needed.1, 3, 4

No evidence of impaired fertility was observed in rats following administration of metformin hydrochloride dosages of 600 mg/kg daily (about twice the maximum recommended human dosage based on body surface area).1

Metformin is distributed into milk of lactating rats and achieves concentrations comparable to those attained in plasma.1, 85 Since it is not known if metformin is distributed into milk in humans, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1, 3, 4

If metformin is discontinued in a nursing mother and dietary therapy is inadequate for glycemic control, insulin therapy should be considered.1

Drug Interactions

• Antidiabetic AgentsAlthough hypoglycemia occurs infrequently in patients receiving metformin therapy

alone,1, 19, 62, 78, 166 hypoglycemia may occur when the drug is used concomitantly with a sulfonylurea antidiabetic agent (e.g., glyburide) and/or insulin.1, 15, 78, 94, 99 (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 Although variable decreases in the area under the blood concentration-time curve (AUC) and peak blood concentration of glyburide were

observed, the single-dose nature of this study and the lack of a relationship between glyburide blood concentrations and pharmacodynamic effects preclude evaluation of the clinical importance of these effects.1

In a single-dose study, administration of metformin concomitantly with an a-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 astandard meal in healthy individuals reduced and delayed the absorption of metforminfrom the GI tract.18, 85, 99, 106

• DiureticsThiazide 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%.1 Administration of metformin concomitantly with furosemide increased peak plasma furosemide concentrations by approximately 31% and AUC by approximately 12%.1 The renal clearance of both drugs remained unchanged during such concomitant use, but thehalf-life of furosemide was decreased by 32%.1 The manufacturer states that noinformation is available on potential interactions between metformin and furosemideduring long-term administration.1

• NifedipineConcomitant administration of single doses of metformin and nifedipine in healthy individuals resulted in enhanced absorption of metformin, as indicated by increases of20 and 9% in the peak plasma concentration and AUC, respectively, of metformin.1

Nifedipine also increased the urinary excretion of metformin; half-life and time to peak plasma concentration of metformin remained unchanged.1 Metformin appears to haveminimal effects on the pharmacokinetics of nifedipine.1

• CimetidineCimetidine may reduce the urinary excretion of metformin by competing for renal tubular

organic cationic transport systems.1, 75 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%.1, 75 Metformin has negligible effects on cimetidine pharmacokinetics, possibly because cimetidine has a higher affinity for renal tubular

transport sites.1, 75 The manufacturer states that the possibility of other cationic drugs that undergo substantial tubular secretion (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, vancomycin) decreasing the urinary excretion of metformin should be considered.1, 30 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.1

• ß-Adrenergic Blocking AgentsIn 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 ß-adrenergic blocking agents and oral antidiabetic agents (e.g., sulfonylureas, metformin) exist.91, 127, 143, 153, 159, 160, 198 ß-Adrenergicblocking 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 ß- adrenergic blocking agents (e.g., propranolol, nadolol) without intrinsicsympathomimetic activity are more likely to affect glucose metabolism than more selective ß-adrenergic blocking agents (e.g., metoprolol, atenolol) or those with intrinsicsympathomimetic 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 orselective ß-adrenergic blocking agents.128, 143, 153, 159 These drugs should be usedwith caution in patients with type 2 diabetes mellitus who are receiving antidiabeticagents, especially in those with labile disease or in those prone to hypoglycemia.36, 83,91, 127, 128, 153 Use of low-dose, selective ß1-adrenergic blockers (e.g., metoprolol) or ß-adrenergic blocking agents with intrinsic sympathomimetic activity in patientsreceiving oral antidiabetic agents may theoretically decrease the risk of affectingglycemic control.36, 143, 152, 160, 173 When an oral antidiabetic agent and aß-adrenergic blocking agent are used concomitantly, the patient should be advisedabout and monitored closely for altered antidiabetic response.134

• AlcoholCombined 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 (See Cautions: Lactic Acidosis.) Excessive alcohol intake, on an acute or chronic basis, should be avoided in patients receiving metformin therapy.1

• Protein-Bound DrugsBinding of metformin to plasma proteins is negligible; therefore, metformin is less likely to interact with drugs that are highly protein bound compared with sulfonylurea

antidiabetic agents, which are extensively bound to plasma proteins.1

• Angiotensin-Converting Enzyme InhibitorsAngiotensin-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 beconsidered 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

• ClomipheneIn 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 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

• Other DrugsDrugs that cause hyperglycemia and may exacerbate glycemic control in patients with diabetes mellitus include corticosteroids, oral contraceptives, thiazide diuretics, sympathomimetics, phenothiazines, niacin, calcium-channel blocking agents, and

isoniazid.1, 80, 85, 91, 120, 121, 134, 139, 143, 151, 152, 153, 154, 159, 160 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

Acute Toxcicity

Limited information is available on the acute toxicity of metformin.1, 2, 119

Hypoglycemia has not been observed even with acute oral ingestion of up to 85 g ofmetformin hydrochloride; however, lactic acidosis has occurred in such circumstances.1,2, 62, 119 (See Cautions: Lactic Acidosis.) Since metformin is eliminated by dialysis (witha clearance of up to 170 mL per minute under good hemodynamic conditions), prompt hemodialysis is recommended to correct acidosis and remove accumulated drug; suchmanagement often results in rapid reversal of symptoms and recovery.1, 23, 32, 62, 117,119

Pharmacology

• Antidiabetic EffectsMetformin hydrochloride, a biguanide antidiabetic agent, is chemically and pharmacologically unrelated to sulfonylurea antidiabetic agents.1, 2, 18, 20, 27, 28, 29

Unlike sulfonylureas, biguanides such as metformin lower blood glucose concentrations in patients with type 2 (noninsulin-dependent) diabetes mellitus (NIDDM) without increasing insulin secretion from pancreatic ß cells;1, 2, 3, 4, 18, 20, 27, 31, 40, 60, 134

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.1, 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.1, 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 (impairedsecretion of insulin from pancreatic ß 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 theunderlying pathophysiology of type 2 diabetes mellitus may be similar in obese and nonobese patients with the disease, severe peripheral and hepatic insulin resistanceappears to predominate in obese patients, while nonobese patients tend to have milderdegrees of insulin resistance but more marked insulin deficiency; however, bothabnormalities 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 obesepatients 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 enhancedinsulin-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 thesemechanisms 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 ofinsulin-stimulated glucose uptake (principally by skeletal muscle) have been reported inpatients 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 notregulated during metformin therapy have reported no increases and/or even decreasesin 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, unlikephenformin, enhances glucose oxidation and does not affect fasting lactate productionin peripheral tissues.20, 53, 60, 61, 72, 78, 79, 81, 135, 146, 149 While increases inpostprandial 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 rangeduring metformin therapy.31, 60, 61, 72, 84, 97, 146 Postprandial increases in serumlactate concentration observed with metformin therapy may occur as a result of increased conversion of glucose to lactate and glycogen in the splanchnic bed bymetformin.6, 44, 72, 145, 146, 158 While most of the lactate from the portal circulationserves as a substrate for gluconeogenesis and is thus cleared, some may escape intothe 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

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 thatreduction 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 concentrationssimilar to or higher than those observed with therapeutic dosages, enhancesinsulin-induced suppression of gluconeogenesis and decreases glucagon-stimulatedgluconeogenesis.6, 146, 175, 176, 177 Insulin secretion usually remains unchangedduring 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 Themagnitude of the decrease in fasting blood glucose concentrations generally is proportional to the level of fasting baseline hyperglycemia.1, 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 EffectsMetformin has demonstrated modest favorable effects on serum lipids, which are often

abnormal in patients with type 2 diabetes mellitus.1, 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.1, 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 ofVLDL-cholesterol, particularly in patients with elevated baseline triglyceride concentrations.1, 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%) inserum 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 havebeen 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 freefatty acid concentrations have not been reported during metformin therapy in patientswith NIDDM or in nondiabetic individuals.20, 31, 35, 42, 44, 58, 61, 68, 81, 102, 135 Areduction 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 toimprovement in glycemic control or a reduction in body weight has not been determined.18, 57, 58, 73, 109, 146

• Other EffectsTherapy 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 gender, race, or the presence of diabetes mellitus.1, 2, 18, 89

• AbsorptionMetformin 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 approximately50-60% with metformin hydrochloride doses of 0.5-1.5 g;1, 2, 3, 4, 18, 33, 43, 50, 65, 72,85, 89 binding of the drug to the intestinal wall may explain the difference between theamount of drug absorbed (as determined by the urinary and fecal excretion ofunchanged drug) and the amount bioavailable in some studies.6, 18, 51, 72, 89, 129 In single-dose studies with metformin hydrochloride doses of 0.5-1.5 g1, 89 or 0.85-2.55g,1, 111 plasma metformin concentrations did not increase in proportion to increasingdoses, suggesting an active saturable absorption process.1, 18, 65, 72, 89, 111, 126

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 apassive, nonsaturable mechanism, possibly involving a paracellular route.129, 134

Food decreases and slightly delays the absorption of metformin conventional tablets;

the clinical importance of these effects is unknown.1, 2, 3, 4, 18, 208 (See Dosage and Administration: Administration.) Administration of metformin hydrochloride conventional tablets with food reportedly has decreased peak plasma concentrations of the drug by35-40%, 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

However, in one study, concomitant administration of the drug as conventional tablets with food had a less pronounced effect (average reduction in bioavailability of 10%) on absorption.208 Following oral administration of metformin hydrochloride as anextended-release tablet 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 The pharmacokinetics of metformin extended-release tablets were not affected by the fat content of meals.1

Following oral administration of 0.5-1.5 g of metformin hydrochloride as conventional 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.1, 2, 6, 18, 33, 38, 43, 44, 50, 85, 125 Following oral administration of a single dose (0.5-2 g) of metformin hydrochloride as extended-release tablets, peak plasma drug concentrations of 0.6-1.8 mcg/mL usually are attained within a median of 7 hours (range: 4-8 hours).1 Peak plasma drug concentrations following administration of metformin extended-release tablets are approximately 20% lower than those following administration of the same dose as conventional 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 conventional tablets.1

Steady-state plasma concentrations with usual dosages of metformin hydrochloride as conventional 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).1, 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 diabetesmellitus, 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

• DistributionMetformin 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 theplasma concentration) occur in the GI tract (e.g., esophagus, stomach, duodenum, jejunum, ileum), with lower concentrations (twice the plasma concentration) occurring inkidney, 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 insaliva are tenfold lower than those in plasma and may be responsible for the metallictaste reported in some patients receiving the drug.50, 65 Any local effect of metformin onglucose absorption in the GI tract may be associated with the relatively high GIconcentrations of the drug compared with those in other tissues.6, 18, 43 It is not knownwhether 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 distributedinto breast milk at levels comparable to those in plasma.1, 2, 85

Following oral administration of single 850-mg doses of metformin hydrochloride as conventional tablets, the apparent volume of distribution has been reported to average654 L.1 Volume of distribution reported after IV administration of the drug generally hasbeen 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 ofdistribution in various studies.30, 50, 51, 89, 134 Unlike oral sulfonylurea antidiabeticagents, which are more than 90% bound to plasma proteins, metformin is negligiblybound to plasma proteins.1, 18, 50, 51, 65, 85, 89 Metformin equilibrates freely betweenerythrocytes and plasma, most likely as a function of time; drug bound to erythrocytes isapproximately 5% of total blood concentration.1, 2, 3, 18, 89

• Elimination

Following oral administration of metformin hydrochloride (0.5-1.5 g) as conventional 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 conventional 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 ranges from 3-6 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 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 anddata from whole blood indicate a slower terminal-elimination phase of 8-20 hours occurring 12 hours after the oral dose, but this phase represents only 0.4-5% of totaldrug clearance and may represent elimination from a small, deep tissue compartment.3,18, 50, 65, 72, 89, 134, 174

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 Renal elimination of metformin involves glomerular filtration and secretion by the proximal convolutedtubules as unchanged drug.1, 2, 6, 33, 50, 63, 65, 75, 85, 89 Following single-dose oraladministration of metformin hydrochloride (0.5-1.5 g), urinary recovery ranges from35-52% of the total dose.50, 51, 89 Approximately 20-33% of the total oral dose is excreted in feces within 4-7 days.6, 33, 43, 50, 72, 89 Total plasma clearance ofmetformin hydrochloride following single-dose oral administration (0.5-1.5 g) has rangedfrom 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 decreased (as measured by decreases in creatinine clearance) in patients with renal impairment and, apparently because of reduced renal function with age, in geriatric individuals.1, 33, 51, 174 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.1, 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 In geriatric individuals, decreased renal clearance of metformin also results in increased plasma concentrations of the drug; volume of distribution remainsunaffected.1, 174 (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 Guanidineoccurs 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 conventional tablets, extended-release tablets, and as conventional tablets in fixed combination with glyburide.234, 1

The extended-release tablets contain dual hydrophilic polymers that form a swellable gel matrix when in contact with gastric or intestinal fluids and release the drug slowly over time.1

Metformin is a weak base; the pH of a 1% aqueous solution of metformin hydrochloride

is 6.68.1, 47 The pKa of metformin base is 12.4.1, 2, 30 Metformin hydrochloride is freely

soluble in water and practically insoluble in acetone, ether, and chloroform.1, 2

• StabilityCommercially available metformin hydrochloride conventional (includingfixed-combination preparations with glipizide or rosiglitazone) and extended-release tablets should be stored at a controlled room temperature of 20-25°C and protectedfrom light but may be exposed to temperatures ranging from 15-30°C .1, 247, 254

Fixed-combination preparations containing metformin hydrochloride and glyburide should be stored at a controlled room temperature up to 25°C and be protected fromlight.234

Preparations

Metformin Hydrochloride

Oral

Tablets, film- 500 mg Glucophage®, (with povidone)

coated Bristol-Myers Squibb

850 mg Glucophage ®, (with povidone) Bristol-Myers Squibb

1 g Glucophage ®, (with povidone) Bristol-Myers Squibb

Tablets, extended- 500 mg Glucophage® XR®, Bristol- release Myers Squibb

750 mg Glucophage ® XR®, Bristol- Myers Squibb

Metformin Hydrochloride Combinations

Oral

Tablets, film- 250 mg with Glyburide 1.25 Glucovance®, Bristol-Myers coated mg Squibb

500 mg with Glyburide 2.5 mg Glucovance®, Bristol-MyersSquibb

500 mg with Glyburide 5 mg Glucovance®, Bristol-MyersSquibb

500 mg with Rosiglitazone 1 Avandamet ®, mg GlaxoSmithKline

500 mg with Rosiglitazone 2 Avandamet ®, mg GlaxoSmithKline

500 mg with Rosiglitazone 4 Avandamet ®, mg GlaxoSmithKline

References

1. Bristol-Myers Squibb Company. Glucophage® (metformin hydrochloride) tablets andGlucophage® XR (metformin hydrochloride) extended-release tablets prescribing