VA Class:HS502

ATC Class:A10BB

AHFS Class:

• Sulfonylureas 68:20.20

Generic Name(s):

• glyBURIDE

Chemical Name:

• 1-[[ p -[2-(5-Chloro- o -anisamido)ethyl]phenyl]sulfonyl]3-cyclohexylurea

Molecular Formula:

• C₂₃H₂₈ClN₃O₅S

Glyburide is a sulfonylurea antidiabetic agent.1,2,3,4

Type 2 Diabetes Mellitus

Glyburide alone or in fixed combination with metformin hydrochloride is used as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.1,2,3,4,49,50,51,52,53,54,55,56,57,58,59,60,158 Sulfonylureas, including glyburide, also may be used in combination with one or more other oral antidiabetic agents or insulin as an adjunct to diet and exercise for the management of type 2 diabetes mellitus in patients who do not achieve adequate glycemic control with diet, exercise, and oral antidiabetic agent monotherapy.1,124,158,162,165,166,168,169,170,195,196,197,198,199,200,201,202,203

Current guidelines for the treatment of type 2 diabetes mellitus generally recommend metformin as first-line therapy in addition to lifestyle modifications in patients with recent-onset type 2 diabetes mellitus or mild hyperglycemia because of its well-established safety and efficacy (i.e., beneficial effects on glycosylated hemoglobin [hemoglobin A_1c; HbA_1c], weight, and cardiovascular mortality).698,704,705 (See Uses: Type 2 Diabetes Mellitus, in Metformin 68:20.04.) In patients with contraindications or intolerance to metformin (e.g., risk of lactic acidosis, GI intolerance) or in selected other patients, some experts suggest that initial therapy with a drug from another class of antidiabetic agents (e.g., a glucagon-like peptide-1 [GLP-1] receptor agonist, sodium-glucose cotransporter 2 [SGLT2] inhibitor, dipeptidyl peptidase-4 [DPP-4] inhibitor, sulfonylurea, thiazolidinedione, basal insulin) may be acceptable based on patient factors.698,704 Initiating antidiabetic therapy with 2 agents (e.g., metformin plus another drug) may be appropriate in patients with an initial HbA_1c exceeding 7.5% or at least 1.5% above the target level.698,704 In metformin-intolerant patients with high initial HbA_1c levels, some experts suggest initiation of therapy with 2 agents from other antidiabetic drug classes with complementary mechanisms of action.698

Because of the progressive nature of type 2 diabetes mellitus, patients initially receiving an oral antidiabetic agent will eventually require multiple oral and/or injectable noninsulin antidiabetic agents of different therapeutic classes and/or insulin for adequate glycemic control.698,704 Patients who have inadequate glycemic control with initial (e.g., metformin) monotherapy should receive treatment with additional antidiabetic agents; data suggest that the addition of each noninsulin agent to initial therapy lowers HbA_1c by approximately 0.7-1%.704 In addition, early initiation of combination therapy may help to more rapidly attain glycemic goals and extend the time to treatment failure.704

Factors to consider when selecting additional antidiabetic agents for combination therapy in patients with inadequate glycemic control on metformin monotherapy include patient comorbidities (e.g., atherosclerotic cardiovascular disease [ASCVD], established kidney disease, heart failure), hypoglycemia risk, impact on weight, cost, risk of adverse effects, and patient preference.698,699,704,705,706 When the greater glucose-lowering effect of an injectable drug is needed in patients with type 2 diabetes mellitus, some experts currently state that an injectable GLP-1 receptor agonist is preferred over insulin in most patients because of beneficial effects on body weight and a lower risk of hypoglycemia, although adverse GI effects may diminish tolerability.704 While addition of a GLP-1 receptor agonist may successfully control hyperglycemia, many patients will eventually require insulin therapy.698 Early introduction of insulin therapy should be considered when hyperglycemia is severe (e.g., blood glucose of at least 300 mg/dL or HbA_1c exceeding 9-10%), especially in the presence of catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis) or symptoms of hyperglycemia.698,704 For additional information regarding the initiation of insulin therapy in patients with diabetes mellitus, see Uses: Diabetes Mellitus, in the Insulins General Statement 68:20.08.

Glyburide Monotherapy

Glyburide may be useful in some patients with type 2 diabetes mellitus who have primary3 or secondary1,2,3,4 failure to other sulfonylurea antidiabetic agents; however, primary or secondary failure to glyburide may also occur.1,2,3,4,129

Primary failure to sulfonylurea drugs is characterized by lack of efficacy when the drug is first administered to a patient.2 Secondary failure to sulfonylurea drugs is characterized by progressively decreasing diabetic control1,2,60 following 1 month to several years of good control.60,103,129 Interim data from a substudy (UKPDS 26) of UKPDS in newly diagnosed type 2 diabetic patients receiving intensive antidiabetic therapy (maintenance of fasting plasma glucose below 108 mg/dL by increasing doses of glyburide or chlorpropamide [no longer commercially available in the US] to maximum recommended dosage) showed that secondary failure (defined as fasting plasma glucose exceeding 270 mg/dL or symptoms of hyperglycemia despite maximum recommended daily dosage of 20 mg of glyburide or 500 mg of chlorpropamide) occurred overall at about 7% per year.128,129 The failure rate at 6 years was 48% among patients receiving glyburide and about 40% among patients receiving chlorpropamide.129 In the UKPD studies, stepwise addition of insulin or metformin to therapy with maximal dosage of a sulfonylurea was required periodically over time to improve glycemic control.127,128,129,130,136,143,146,147 In another substudy (UKPDS 49), progressive deterioration in diabetes control was such that monotherapy was effective in only about 50% of patients after 3 years and in only about 25% of patients after 9 years; thus, most patients require multiple-drug antidiabetic therapy over time to maintain such target levels of disease control.147 At diagnosis, risk factors predisposing toward sulfonylurea failure included higher fasting plasma glucose concentrations, younger age, and lower pancreatic β-cell reserve.129,147

Combination Therapy with Metformin or Other Oral Antidiabetic Agents

Sulfonylureas, including glyburide, may be used in combination with one or more other oral antidiabetic agents (e.g., metformin, GLP-1 receptor agonists, SGLT2 inhibitors, DPP-4 inhibitors, thiazolidinedione derivatives) as an adjunct to diet and exercise for the management of type 2 diabetes mellitus in patients who do not achieve adequate glycemic control with diet, exercise, and oral antidiabetic agent monotherapy.158,195,196,197,198,200,201,202,208,209,698,704 For information on the stepwise approach to drug therapy in patients with type 2 diabetes mellitus, see Uses: Type 2 Diabetes Mellitus, in Metformin 68:20.04.

Glyburide may be used concomitantly with metformin as initial therapy in the management of patients with type 2 diabetes mellitus whose hyperglycemia cannot be controlled by diet and exercise alone.1,124,158 In a 20-week, double-blind, randomized trial in drug-naive patients with type 2 diabetes mellitus whose hyperglycemia was inadequately controlled (baseline HbA_1c values between 7 and 11%) by diet and exercise, treatment was initiated with either placebo, glyburide 2.5 mg, metformin hydrochloride 500 mg, or the fixed combination of glyburide 1.25 mg/metformin hydrochloride 250 mg or glyburide 2.5 mg/metformin hydrochloride 500 mg daily.158 The dosage of each therapy was progressively increased during weeks 4-8 to achieve a target fasting plasma glucose concentration of 126 mg/dL or to a maximum of 4 tablets daily.158 Patients receiving the fixed combination of glyburide and metformin had greater reductions in HbA_1c and fasting plasma glucose concentrations than those receiving glyburide, metformin, or placebo; at the end of the study, strict glycemic control (e.g., HbA_1c values less than 7%) was achieved in 59.9, 50.4, 66.4, or 71.7% of patients receiving mean dosages of glyburide 5.3 mg, metformin hydrochloride 1.32 g, glyburide 2.78 mg/metformin hydrochloride 557 mg, or glyburide 4.1 mg/metformin hydrochloride 824 mg, respectively.158

Glyburide also may be used concomitantly with metformin in patients who do not achieve adequate control of hyperglycemia despite diet, exercise, and monotherapy with either glyburide (or another sulfonylurea antidiabetic agent) or metformin.1,124,158,188,189,194,158 In a double-blind, randomized study, patients with type 2 diabetes mellitus whose hyperglycemia was inadequately controlled (mean baseline HbA_1c values: 9.5%, mean baseline fasting plasma glucose: 213 mg/dL) with oral sulfonylurea therapy at a dosage at least 50% of the maximum recommended daily dosage (e.g., glyburide 10 mg daily, glipizide 20 mg daily) received therapy with glyburide 20 mg (fixed dosage), metformin hydrochloride 500 mg, or the fixed combination of glyburide 2.5 mg/metformin hydrochloride 500 mg or glyburide 5 mg/metformin hydrochloride 500 mg daily.158 The dosages of metformin and the fixed-combination preparations were titrated to achieve a target fasting plasma glucose concentration of less than 140 mg/dL or to a maximum of 4 tablets daily.158 At 16 weeks, patients receiving the fixed combination of glyburide and metformin hydrochloride in daily dosages of up to 20 mg of glyburide and 2 g of metformin hydrochloride had lower HbA_1c, fasting plasma glucose, and postprandial plasma glucose concentrations than patients receiving monotherapy with glyburide or metformin, who had no appreciable change in HbA_1c values.158

Combination Therapy with Insulin

Combined therapy with insulin and oral antidiabetic agents may be useful in some patients with type 2 diabetes mellitus whose blood glucose concentrations are not adequately controlled with maximal dosages of the oral agent and/or as a means of providing increased flexibility with respect to timing of meals and amount of food ingested.116,117,118,119,120,162,165,166,168,169,170 Concomitant therapy with insulin (e.g., given as intermediate- or long-acting insulin at bedtime or rapid-acting insulin at meal times)165,166,167,171,172,173 and one or more oral antidiabetic agents appears to improve glycemic control with lower dosages of insulin than would be required with insulin alone and may decrease the potential for body weight gain associated with insulin therapy.162,165,166,167,174,171,172,175,173,176,177 Oral antidiabetic therapy combined with insulin therapy may delay progression to either intensive insulin monotherapy or to a second daytime injection of insulin combined with oral antidiabetic therapy.171 However, such combined therapy may increase the risk of hypoglycemic reactions.166,168,178,171,172

Misuse and Abuse

Dietary Supplements

Some herbal dietary supplements promoted for the treatment of diabetes mellitus and purported to contain only natural Chinese herbal ingredients have been found to contain glyburide and phenformin (a biguanide similar to metformin but no longer commercially available in the US).148 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.148

Administration

Glyburide is administered orally.1,2,124 The drug (as conventional or micronized formulations; see Dosage: Type 2 Diabetes Mellitus, under Dosage and Administration) is usually administered as a single daily dose given each morning with breakfast, or with the first main meal.1,2,3,124 Once-daily dosing of glyburide provides adequate control of blood glucose concentration throughout the day in most patients with usual meal patterns;1,2,91,92,93 however, some patients, particularly those who require more than 10 mg of the drug daily (as conventional formulations) or more than 6 mg daily (as micronized glyburide),124 may have a more satisfactory response when glyburide is administered in 2 divided doses daily.1,2,124 When a twice-daily dosing regimen is employed in patients receiving more than 10 mg of glyburide daily, the doses and schedule of administration should be individualized according to the patient's meal pattern and response.101 There is some evidence that, when a divided-dosing regimen is used, blood glucose concentration following breakfast may be better controlled when the morning dose is administered 30 minutes before rather than with the meal;28 a similar tendency has been observed following the midday meal, but not the evening meal, when the remaining portions of the equally divided daily dose were administered 30 minutes before rather than with these meals.28

When given concomitantly with colesevelam, glyburide should be administered at least 4 hours prior to colesevelam.1,2,124 (See Drug Interactions: Colesevelam.)

Dosage

Type 2 Diabetes Mellitus

Dosage of glyburide must be based on periodic fasting blood glucose and glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) determinations and must be carefully individualized.1,2 Periodic HbA_1c determinations are the principal means of assessing long-term glycemic control.1,2,158 Following initiation of glyburide-containing therapy, determination of HbA_1c concentrations at intervals of approximately 3 months is useful for assessing the patient's continued response to therapy.702 Patients must be closely monitored to determine the minimum effective glyburide dosage and to detect primary or secondary failure to the drug.1,2 If appropriate glyburide dosage regimens are not followed, hypoglycemia may be precipitated .1,2

Formulations of micronized glyburide (Glynase^® PresTab^® and other micronized tablets available by nonproprietary name) contain smaller particles of the drug than those contained in nonmicronized (conventional) formulations (e.g., DiaBeta^®).124As a result, micronized formulations of glyburide are not bioequivalent with conventional formulations, and dosage should be retitrated when transferring patients from micronized to conventional formulations or vice versa.124In general, initial dosages of micronized glyburide range from 1.5-3 mg daily, although it may be necessary to initiate micronized therapy with 0.75 mg daily in patients who are sensitive to the hypoglycemic effects of sulfonylureas (e.g., geriatric, debilitated, or malnourished patients); the manufacturer recommends that the initial dosage not exceed 3 mg daily regardless of the dosage of other sulfonylurea employed at transfer.124Maintenance dosage of the micronized formulation should be individualized according to glycemic control but usually ranges from 0.75-12 mg daily.124The manufacturers' labeling should be consulted for additional information on the use of micronized glyburide, including associated precautions and detailed information on dosage titration.124

Patients who do not adhere to their prescribed dietary and drug regimens are more likely to have an unsatisfactory response to therapy.1,2 In patients usually well controlled by dietary management alone, short-term therapy with glyburide may be sufficient during periods of transient loss of diabetic control.1,2

Initial Dosage in Previously Untreated Patients

For the management of type 2 diabetes mellitus in patients not previously receiving insulin or sulfonylurea antidiabetic agents, the usual initial adult dosage of glyburide is 2.5-5 mg daily;1,2 in debilitated, malnourished, or geriatric patients, or other patients at increased risk of hypoglycemia (See Cautions: Precautions and Contraindications), the initial dosage of glyburide should be 1.25 mg daily.1,2 The manufacturers also recommend an initial dosage of 1.25 mg daily in patients with impaired renal or hepatic function.1,2 (See Cautions: Precautions and Contraindications.) Subsequent dosage should be adjusted according to the patient's tolerance and therapeutic response;1,2 increases in dosage should be made in increments of no more than 2.5 mg daily at weekly intervals.1,2

Initial Dosage in Patients Transferred from Other Oral Antidiabetic Agents

A transition period generally is not required when transferring from most other sulfonylurea antidiabetic agents to glyburide, and administration of the other agent may be abruptly discontinued.1,2,3,96 Because of the prolonged elimination half-life of chlorpropamide (no longer commercially available in the US), an exaggerated hypoglycemic response may occur in some patients during the transition from chlorpropamide to glyburide, and patients being transferred from chlorpropamide should be closely monitored for the occurrence of hypoglycemia during the initial 2 weeks of the transition period.1,2 A drug-free interval of 2-3 days may be advisable before glyburide therapy is initiated in patients being transferred from chlorpropamide, particularly if blood glucose concentration was adequately controlled with chlorpropamide.106 An initial or loading dose of glyburide is not necessary when transferring from other sulfonylurea antidiabetic agents to glyburide.1,2 The transfer should be performed conservatively.1,2

For the management of type 2 diabetes mellitus in patients previously receiving other sulfonylurea antidiabetic agents, the initial dosage of glyburide should be 2.5-5 mg daily.1,2 Although patients may be transferred from the maximum dosage of other sulfonylurea antidiabetic agents, the initial dosage of glyburide should not exceed 5 mg daily.1,2 Subsequent dosage is adjusted according to the patient's tolerance and therapeutic response.1,2 Although an exact dosage relationship between glyburide and other sulfonylurea antidiabetic agents does not exist, approximate dosage equivalencies have been estimated.1,2 (See Pharmacology: Antidiabetic Effect.)

Initial Dosage in Patients Transferred from Insulin

In general, patients who were previously maintained on insulin dosages not exceeding 40 units daily may be transferred directly to glyburide, and administration of insulin may be abruptly discontinued;1,2,96 the initial glyburide dosage is 2.5-5 mg daily in patients whose insulin dosage was less than 20 units daily and 5 mg daily in patients whose insulin dosage was 20-40 units daily.1,2 In patients requiring insulin dosages exceeding 40 units daily, an initial glyburide dosage of 5 mg daily should be started and insulin dosage reduced by 50%.1,2 Subsequently, insulin is withdrawn gradually and dosage of glyburide is increased in increments of 1.25-2.5 mg daily every 2-10 days, according to the patient's tolerance and therapeutic response.1,2 During the period of insulin withdrawal, patients should test their blood for glucose2,60,106 and their urine for glucose and/or ketones at least 3 times daily,1,2,124 and should be instructed to report the results to their physician so that appropriate adjustments in therapy may be made, if necessary.1,2,3,124 The presence of persistent ketonuria with glycosuria,1,2 ketosis,86 and/or inadequate lowering or persistent elevation of blood glucose concentration86 indicates that the patient requires insulin therapy.1,2,86 During the period of insulin withdrawal, hypoglycemia may rarely occur.1,2 In some patients, hospitalization may be necessary during the transition from insulin to glyburide.96

Maintenance Dosage

The adult maintenance dosage of glyburide for the management of type 2 diabetes mellitus ranges from 1.25-20 mg daily.1,2,96 Most patients require 2.5-10 mg daily and some may require up to 15 mg daily;96 only a few patients will benefit from dosages exceeding 15 mg daily.3,96 Maintenance dosage of glyburide should be conservative in debilitated, malnourished, or geriatric patients or patients with impaired renal or hepatic function because of an increased risk of hypoglycemia in these patients.1,2 (See Cautions: Precautions and Contraindications.)The maximum recommended dosage is 20 mg daily.1,2,96

Concomitant Glyburide and Metformin Therapy

Glyburide should be added gradually to the existing dosage regimen of patients not responding adequately to 4 weeks of metformin monotherapy at maximum dosage.1,124 When glyburide and metformin are administered concomitantly, dosage of each drug should be adjusted upward until adequate glycemic control is achieved, and patients should be monitored periodically (e.g., determination of blood glucose concentrations) to determine the optimal effective dosage of each drug.1,124 In patients receiving glyburide concomitantly with metformin, the risk of hypoglycemia may be increased, and appropriate precautions should be taken.1,124 (See Cautions: Precautions and Contraindications.)

If the commercially available fixed-combination preparation of glyburide and metformin hydrochloride is used in patients not currently receiving either glyburide (or another sulfonylurea antidiabetic agent) or metformin hydrochloride, the recommended initial dosage is 1.25 mg of glyburide and 250 mg of metformin hydrochloride once or twice daily with meals.158

In patients with inadequate glycemic control on either glyburide (or another sulfonylurea antidiabetic agent) or metformin hydrochloride alone, the recommended initial dosage of the commercially available fixed-combination preparation is 2.5 or 5 mg of glyburide with 500 mg of metformin hydrochloride twice daily with meals.158 In patients previously treated with a combination of glyburide (or another sulfonylurea antidiabetic agent) and metformin hydrochloride, the initial dosage of glyburide and metformin hydrochloride in fixed combination should not exceed the daily dosages of glyburide (or another sulfonylurea antidiabetic agent) and metformin given separately.158 The dosage of the fixed combination of glyburide and metformin should be titrated upward based on glycemic control and tolerability until a maximum daily dosage of 20 mg of glyburide and 2 g of metformin hydrochloride is reached.158

Glyburide alone or in fixed combination with metformin should be used with caution in geriatric patients, since aging is associated with reduced renal function.1 The initial and maintenance dosages of glyburide alone or in fixed combination with metformin should be conservative in geriatric, debilitated, or malnourished patients and those with impaired renal or hepatic function and should be titrated carefully in such patients.1,2,124 Renal function should be assessed with initial dosage selection and with each dosage adjustment in geriatric patients.1,124

Cardiovascular Effects

Several large, long-term studies have evaluated the cardiovascular risks associated with the use of oral sulfonylurea antidiabetic agents.60,61,62,63,127,128,131,144 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 as compared to treatment with dietary regulation alone or with dietary regulation and insulin.1,2,63 The UGDP reported that type 2 diabetic patients who were treated for 5-8 years with dietary regulation and a fixed dose of tolbutamide (1.5 g daily) had a cardiovascular mortality rate approximately 2.5 times that of patients treated with dietary regulation alone;1,2,63 although a substantial increase in total mortality was not observed, the use of tolbutamide was discontinued because of the increase in cardiovascular mortality, thereby limiting the ability of the study to show an increase in total mortality.1,2,63 The results of the UGDP study have been exhaustively analyzed, and there has been general disagreement in the scientific and medical communities regarding the study's validity and clinical importance.60,61,62,63 However, recent results from the United Kingdom Prospective Diabetes Study (UKPDS), a large, long-term (over 10 years) study in newly diagnosed type 2 diabetic patients, did not confirm an increase in cardiovascular events or mortality in the group treated intensively with sulfonylureas, insulin, or combination therapy compared with that in the group treated with less intensive conventional antidiabetic therapy.127,128,130,131

In the UKPD study, the overall aggregate rates of death from macrovascular diseases such as myocardial infarction, sudden death, stroke, or peripheral vascular disease were not appreciably different among either intensive therapies (stepwise introduction of chlorpropamide [no longer commercially available in the US] or glyburide then insulin, or an oral sulfonylurea and insulin, or insulin alone to achieve fasting plasma glucose concentrations of 108 mg/dL) or less intensive conventional therapy (diet and oral antidiabetic agents or insulin to achieve fasting plasma glucose concentrations below 270 mg/dL without symptoms of hyperglycemia).127,128 However, a trend in reduction in fatal and nonfatal myocardial infarction with intensive therapy was noted with sulfonylurea or insulin, and epidemiologic analysis of the data indicate that each 1% decrease in HbA_1c was associated with an 18% reduction of fatal and nonfatal myocardial infarction.128,131 Among the single end points, the incidence of angina increased among patients receiving chlorpropamide, and blood pressure also was higher with chlorpropamide compared with glyburide or insulin intensive therapies.127 As a result of these and other findings (e.g., beneficial effects on microvascular complications [retinopathy, nephropathy, and possibly neuropathy], confirmation of the beneficial effects of concomitant antihypertensive therapy and blood pressure lowering) of the UKPD study, the American Diabetes Association (ADA) has stated that the beneficial effects of intensive glycemic control with insulin or sulfonylureas and blood pressure control in diabetic patients outweigh the risks overall.128,144,234

Endocrine and Metabolic Effects

Hypoglycemia

Hypoglycemia, which may be severe1,2,67,68,69,74,105 and has occasionally been fatal,67,68,74,105 may occur in patients receiving glyburide alone or combined with other antidiabetic agents.66,67,68,69,73,74,77,105,158 In a controlled clinical trial in patients receiving initial therapy, symptoms of hypoglycemia (e.g., dizziness, shakiness, sweating, hunger) occurred in 21.3, 3.1, 11.4, or 37.7% of patients receiving glyburide (mean daily dosage: 5.3 mg), metformin hydrochloride (mean daily dosage: 1317 mg), glyburide in fixed combination with metformin hydrochloride (mean daily dosage: 2.78 mg of glyburide/557 mg of metformin hydrochloride), or glyburide in fixed combination with a higher dosage of metformin hydrochloride (mean daily dosage: 4.1 mg of glyburide/824 mg of metformin hydrochloride).158 Approximately 6.8% of patients experienced hypoglycemic symptoms while receiving the fixed combination of glyburide and metformin hydrochloride following inadequate control with sulfonylurea monotherapy.158 Appropriate patient selection and careful attention to dosage are important to avoid glyburide-induced hypoglycemia .1,2,67 (See Cautions: Precautions and Contraindications.)

Although not clearly established, it has been suggested that glyburide may be more likely than other sulfonylurea antidiabetic agents to produce severe hypoglycemia.62,66,67,69,74,77 In some clinical studies, hypoglycemia was the most frequent adverse effect of the drug.62,96 Hypoglycemia may occur as a result of excessive glyburide dosa 1,2,68,69 however, since the development of hypoglycemia is a function of many factors, including diet, or exercise without adequate caloric supplementation, this effect may occur in some patients receiving usual dosages of the drug.1,2,49,67,68,69,73,105 Severe hypoglycemia, sometimes fatal, has occurred in some patients receiving as little as 2.5-5 mg of glyburide daily.49,74,105 The risk of hypoglycemia is increased during concurrent use of other antidiabetic agents, certain other agents, or alcohol.158 (See: Drug Interactions.) In patients receiving glyburide in fixed combination with metformin, renal or hepatic insufficiency may increase the serum concentrations of both agents, and hepatic insufficiency may diminish gluconeogenic capacity; both of these conditions increase the risk of hypoglycemia.158 Debilitated, malnourished, or geriatric patients may be particularly susceptible to glyburide-induced hypoglycemia; this condition may be difficult to recognize in geriatric patients or in those receiving β-adrenergic blocking agents.1,105,158 (See Drug Interactions: β-Adrenergic Blocking Agents.) Glyburide-induced hypoglycemia may also occur in nontherapeutic situations (e.g., inadvertent or intentional ingestion).70,71,72,73,76,77,78,79

Management of glyburide-induced hypoglycemia depends on the severity of the reaction;1,2,67,69 patients with severe reactions require immediate hospitalization and treatment and observation until complete recovery is assured.1,2,67,69,105,106 Hypoglycemia is usually, but not always, readily controlled by administration of glucose.1,2,3,67,69,105 If hypoglycemia occurs during therapy with the drug, immediate reevaluation and adjustment of glyburide dosage and/or the patient's meal pattern are necessary.1,2,67,69

For further discussion of the pathogenesis, manifestations, and treatment of glyburide-induced hypoglycemia, see Acute Toxicity.

Other Endocrine and Metabolic Effects

Therapy with sulfonylureas, including glyburide, may be associated with weight gain.2,156,157,159 Although the exact mechanisms associated with such alterations in weight have not been established, suggested mechanisms include an increase in insulin secretion (which may increase appetite), stimulation of lipogenesis in fat tissue, or an increase in blood leptin concentrations.156,157,159 Data from the United Kingdom Prospective Diabetes Study (UKPDS) in patients receiving long-term (over 10 years) therapy with glyburide and other antidiabetic agents indicate that weight gain was greatest in those receiving intensive therapy (stepwise introduction of a sulfonylurea then insulin or an oral sulfonylurea and insulin, or insulin alone to achieve fasting glucose concentrations of 108 mg/dL) than conventional therapy (diet and oral antidiabetic agents or insulin to achieve fasting plasma glucose concentrations less than 270 mg/dL without symptoms of hyperglycemia), and weight gain was greatest in those initially receiving insulin or chlorpropamide (no longer commercially available in the US) compared with that in those receiving glyburide.127

Like other sulfonylureas, hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) have occurred in patients receiving glyburide.1,2 Hyponatremia appears to occur more often in patients who concurrently are receiving other medications or have medical conditions known to cause hyponatremia or an increased release of vasopressin.1,2

GI Effects

Adverse GI effects such as nausea, epigastric fullness, and heartburn are the most common adverse reactions to glyburide, occurring in about 1-2% of patients.1,2,3,62 Glyburide-induced adverse GI effects appear to be dose related and may subside following a reduction in dosage.1,2

Hepatic Effects

Cholestatic jaundice may occur rarely in patients receiving glyburide and is an indication for discontinuing the drug.1,2 Glyburide-induced cholestatic jaundice has occurred rarely in conjunction with other severe systemic adverse effects (e.g., visceral arteritis, cutaneous bullae).64,65 Liver function test abnormalities,1,2 including elevations in serum aminotransferase concentrations (which may subside with continued therapy),1,2,3 have been reported in patients receiving glyburide.1,2,3 Exacerbation of hepatic porphyria has been reported with other sulfonylurea antidiabetic agents, but has not been reported to date with glyburide.1,2

Dermatologic and Sensitivity Reactions

Allergic skin reactions including pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions occur in about 1.5% of patients receiving glyburide.1,2 Glyburide-induced adverse dermatologic effects generally subside rapidly following discontinuance of the drug,3 but may also disappear despite continued treatment;1,2,3 however, if adverse dermatologic effects persist with continued glyburide therapy, the drug should be discontinued.1,2 Cutaneous bullae occurred in conjunction with cholestatic jaundice in one patient receiving glyburide.65 Photosensitivity reactions have also been reported with glyburide,3 and porphyria cutanea tarda has been reported with other sulfonylurea antidiabetic agents.1,2

Nondermatologic allergic reactions to glyburide have included angioedema, arthralgia, myalgia, and vasculitis.1 A generalized hypersensitivity reaction with toxic erythema, cholestatic jaundice, eosinophilia, and visceral arteritis, resulting in death, has also been reported in one patient receiving the drug.64

Hematologic Effects

Like other sulfonylurea antidiabetic agents, glyburide may rarely cause leukopenia, thrombocytopenia, pancytopenia, agranulocytosis, aplastic anemia, and hemolytic anemia.1,2 Therapy with sulfonylurea agents in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency can lead to hemolytic anemia.1,124,158 Because glyburide is a sulfonylurea, it should be used with caution in patients with G6PD deficiency; use of a nonsulfonylurea antidiabetic drug should be considered.1,124,158 In postmarketing experience, hemolytic anemia also has been reported in patients receiving glyburide who did not have known G6PD deficiency.1,124,158 Thrombocytopenic purpura has been reported in one patient receiving glyburide.66

Macrovascular Outcomes

The manufacturer states that there are no clinical studies that conclusively establish macrovascular risk reduction with glyburide or any other antidiabetic drug.1,2,124

Other Adverse Effects

Although a causal relationship has not been established,101 paresthesia,77 joint pain,77 and nocturia80 have been reported in patients receiving glyburide. Changes in accommodation and/or blurred vision have been reported in patients receiving glyburide or other sulfonylureas and are thought to be related to fluctuations in blood glucose concentrations.1

Precautions and Contraindications

When glyburide is used in fixed combination with metformin, the cautions, precautions, and contraindications associated with metformin must be considered in addition to those associated with glyburide.158

Glyburide shares the toxic potentials of other sulfonylurea antidiabetic agents, and the usual precautions associated with their use should be observed.1,2,3,62 The diagnostic and therapeutic measures for managing diabetes mellitus that are necessary to ensure optimum control of the disease with insulin generally are necessary with glyburide.1,2,3,60 Glyburide should only be prescribed for carefully selected patients by clinicians who are familiar with the indications, limitations, and patient-selection criteria for therapy with oral sulfonylurea antidiabetic agents.1,2,3,4

Patients receiving glyburide should be monitored with regular clinical and laboratory evaluations, including blood and/or urine glucose determinations, to determine the minimum effective dosage and 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.1,2 Glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) measurements should also be performed periodically to monitor the patient's response to glyburide therapy.1,2 During the withdrawal period in patients in whom glyburide is replacing insulin, patients should be instructed to test their blood for glucose2,60,106 and their urine for glucose and/or ketones at least 3 times daily,1,2,124 and to report the results to their physician.1,2 Renal function should be evaluated prior to initiation of therapy with glyburide in fixed combination with metformin and at least annually thereafter.158 Care should be taken to avoid ketosis, acidosis, and coma during the withdrawal period in patients being switched from insulin to glyburide.100,101,106 If adequate lowering of blood glucose concentration is no longer achieved during maintenance therapy with glyburide, the drug should be discontinued.1,2 Alternatively, combined therapy with glyburide and metformin may be used in patients who do not have an adequate glycemic response to glyburide or metformin monotherapy.1,124,158 However, adequate adjustment of dosage and adherence to diet should be assessed before considering that secondary failure to oral antidiabetic therapy has occurred.1 When use of glyburide in asymptomatic type 2 diabetic patients is being considered, it should be recognized that control of blood glucose concentration in these patients has not been definitely established as effective for prevention of long-term cardiovascular or nervous system complications of the disease.1,2 There is limited evidence that sulfonylureas may reverse basement-membrane thickening of muscle capillaries in asymptomatic individuals with impaired glucose tolerance (chemical diabetes)107 and possibly reverse or retard the progression of microangiopathy in type 2 diabetic patients,115 but these findings require further evaluation.107,115

Patients should be fully and completely advised about the nature of diabetes mellitus, what they must do to prevent and detect complications, and how to control their condition.100,101,106 Patients should be informed of the potential risks and advantages of glyburide therapy and alternative forms of treatment .1,2 Patients should be instructed that dietary regulation is the principal consideration in the management of diabetes, and that glyburide therapy is only used as an adjunct to, and not a substitute for or a convenient means to avoid, proper dietary regulation.1,2 Patients should also 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.100,101,106 Primary and secondary failure to oral sulfonylurea antidiabetic agents should also be explained to patients.1,2

Patients and responsible family members should be informed of the risks of hypoglycemia, the symptoms and treatment of hypoglycemic reactions, and conditions that predispose to the development of hypoglycemic reactions, since these reactions may occur during therapy with glyburide.1,2 Appropriate patient selection and careful attention to dosage are important to avoid glyburide-induced hypoglycemia .1,2,67,106 Debilitated, malnourished, or geriatric patients and patients with mild disease or impaired hepatic or renal function should be carefully monitored and dosage of glyburide should be carefully adjusted in these patients, since they may be predisposed to developing hypoglycemia (sometimes severe).1,2,96,105,106 Renal or hepatic insufficiency may cause increased serum concentrations of glyburide1,2 and hepatic insufficiency may also diminish glyconeogenic capacity, both of which increase the risk of severe hypoglycemic reactions.1,2,62,67,105 Some clinicians recommend that glyburide generally not be used in patients with renal or hepatic impairment.67,106 Alcohol ingestion, severe or prolonged exercise, deficient caloric intake, use of more than one antidiabetic agent (e.g., glyburide and metformin), severe endocrine disorders, and adrenal or pituitary insufficiency may also predispose patients to the development of hypoglycemia.1,2,96,105 Hypoglycemia may be difficult to recognize in geriatric patients or in patients receiving β-adrenergic blocking agents.1,2 Intensive treatment (e.g., IV dextrose) and close medical supervision may be required in some patients who develop severe hypoglycemia during glyburide therapy.1,2,67,105 (See Acute Toxicity: Treatment.)

To maintain control of diabetes during periods of stress (e.g., fever of any cause, trauma, infection, surgery), temporary discontinuance of glyburide and administration of insulin may be required.1,2

If cholestatic jaundice occurs or if adverse dermatologic effects occur and persist during glyburide therapy, the drug should be discontinued.1,2

Glyburide alone or in fixed combination with metformin is contraindicated in patients with type 1 diabetes mellitus1,2,124 or diabetic ketoacidosis with or without coma.158 Diabetic ketoacidosis should be treated with insulin.1,2,124

Like other sulfonylureas, glyburide is generally contraindicated in patients with severe renal or hepatic impairment.62,100,114

Concomitant therapy with glyburide and bosentan is contraindicated. (See Drug Interactions: Bosentan.)

Glyburide is also contraindicated in patients with known hypersensitivity or allergy to any ingredient in the respective formulations.1,2,158

Pediatric Precautions

Safety and efficacy of glyburide in children have not been established.1,2 The manufacturer states that the drug is not recommended for use in this age group.1 The American Diabetes Association (ADA) states that most pediatric diabetologists use oral antidiabetic agents in children with type 2 diabetes mellitus because of greater patient compliance and convenience for the patient's family and a lack of evidence demonstrating better efficacy of insulin as initial therapy for type 2 diabetes mellitus.160

Mutagenicity and Carcinogenicity

It is not known if glyburide is mutagenic or carcinogenic in humans.100,101 The drug did not exhibit mutagenic activity in the Ames microbial mutagen test or the DNA damage/alkaline elution assay.1,2 Evidence of carcinogenicity was not observed in studies in rats receiving up to 300 mg/kg of glyburide daily for 18 months or in mice receiving the drug for 2 years.1,2

Pregnancy, Fertility, and Lactation

Pregnancy

When a glyburide dosage 6250 times the maximum recommended human dosage was given to rats, a shortening of long bones (humerus and femur) in rat pups was noted.2 These effects were observed during the period of lactation and not during organogenesis.2 Since abnormal maternal blood glucose concentrations during pregnancy may be associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain optimum control of blood glucose concentration.1,2,106 Use of glyburide in pregnant women is generally not recommended,1,106,114 and the drug should be used during pregnancy only when clearly necessary1,2 (e.g., when insulin therapy is infeasible) or when the potential benefit justifies the possible risks to the fetus.106 Glyburide has been used in some pregnant women without unusual adverse effects.81,186 In a prospective, comparative clinical trial in women with gestational diabetes, treatment with glyburide (mean daily dosage 9 mg, range 2.5-20 mg) initiated in the second trimester (11-33 weeks gestation) and continued until delivery resulted in similar degrees of glycemic control and perinatal outcomes as treatment with insulin human (mean daily dosage: 85 units).185,186 The incidence of hypoglycemia in neonates whose mothers received either insulin or glyburide therapy also was similar.186 Additional studies in a larger number of patients are needed to establish the safety of glyburide in gestational diabetes.185 In a retrospective study, hypoglycemia occurred and persisted for up to 2 days or longer in a few neonates whose mothers had received glyburide up to the time of delivery.81 Prolonged, severe hypoglycemia lasting 4-10 days has been reported in some neonates born to women who were receiving other sulfonylurea antidiabetic agents up to the time of delivery;1,2 this effect has been reported more frequently with the use of those agents having prolonged elimination half-lives.1,2 To minimize the risk of neonatal hypoglycemia if glyburide is used during pregnancy, the manufacturers recommend that the drug be discontinued at least 2 weeks before the expected delivery date.2,101

Fertility

Reproduction studies in rats and rabbits using glyburide doses up to 500 times the usual human dose have not revealed evidence of impaired fertility or harm to the fetus.1,2

Lactation

Although it is not known whether glyburide is distributed into milk, some sulfonylurea antidiabetic agents are distributed into milk.1,2 Because of the potential for hypoglycemia in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1,2 If glyburide is discontinued, and if dietary management alone is inadequate for controlling blood glucose concentration, administration of insulin should be considered.1,2

Drugs Affecting Hepatic Microsomal Enzymes

Glyburide is metabolized principally by cytochrome P-450 (CYP) isoenzyme 2C9.2 Potential interactions should be considered when glyburide is used concomitantly with inducers or inhibitors of CYP2C9.2

Protein-bound Drugs

Because glyburide is highly protein bound, it theoretically could be displaced from binding sites by, or could displace from binding sites, other protein-bound drugs such as oral anticoagulants, hydantoins, salicylate and other nonsteroidal anti-inflammatory agents, angiotensin-converting enzyme (ACE) inhibitors, disopyramide, fluoxetine, clarithromycin, chloramphenicol, monoamine oxidase (MAO) inhibitors, probenecid, β-adrenergic blocking agents, and sulfonamides.1,2,37,38,39,40,60,62,85 However, unlike the protein binding of some other sulfonylurea antidiabetic agents (e.g., acetohexamide, chlorpropamide, tolazamide [preceding 3 drugs no longer commercially available in the US], tolbutamide) and like that of glipizide, the protein binding of glyburide is principally nonionic;1,2,37,38,39,40 in addition, glyburide appears to bind to different but closely related sites on serum albumin and with a greater affinity than acetohexamide, chlorpropamide, or tolbutamide.38 Consequently, glyburide may be less likely to be displaced from binding sites by, or displace from binding sites, other highly protein-bound drugs whose protein binding is ionic in nature.37,40 In vitro studies indicate that glyburide is less susceptible to displacement from serum albumin by acidic drugs (e.g., phenylbutazone [no longer commercially available in the US], salicylate, warfarin) than is chlorpropamide or tolbutamide.40 Whether this difference in protein binding demonstrated in vitro will result in fewer clinically important drug interactions in vivo has not been established.1,2 There appears to be no clinically important interaction between tolmetin and glyburide.109 Patients receiving highly protein-bound drugs should be observed for adverse effects when glyburide therapy is initiated or discontinued and vice versa.1,2

Alcohol

Disulfiram-like reactions have occurred very rarely following the concomitant use of alcohol and glyburide.1,2,87

Azole Antifungal Agents

Concomitant use of certain azole antifungal drugs (i.e., miconazole, fluconazole) and oral antidiabetic agents has resulted in increased plasma concentrations of the oral antidiabetic agent and/or hypoglycemia.2,210 Clinically important hypoglycemia may be precipitated by concomitant use of oral hypoglycemic agents and fluconazole, and at least one fatality has been reported from hypoglycemia in a patient receiving glyburide and fluconazole concomitantly.211 (See Drug Interactions: Sulfonylurea Antidiabetic Agents, in Fluconazole 8:14.08.)

Beta-Adrenergic Blocking Agents

Several potential interactions between β-adrenergic blocking agents and sulfonylurea antidiabetic agents exist.60,62,85β-Adrenergic blocking agents may impair glucose tolerance;60,62,85 increase the frequency or severity of hypoglycemia;60,62,85 block hypoglycemia-induced tachycardia, but not hypoglycemic sweating which may actually be increased;62,85 delay the rate of recovery of blood glucose concentration following drug-induced hypoglycemia;60,62,85 alter the hemodynamic response to hypoglycemia, possibly resulting in an exaggerated hypertensive response;60,85 and possibly impair peripheral circulation.60,85 There is some evidence that many of these effects may be minimized by use of a β₁-selective adrenergic blocking agent rather than a nonselective β-adrenergic blocking agent.60,62,85 Acebutolol and propranolol have been shown to decrease the hypoglycemic action of glyburide in type 2 diabetic patients, presumably by decreasing insulin secretion.88 In another study in type 2 diabetic patients, insulin secretion during short-term atenolol therapy was reduced, but the hypoglycemic action of glyburide was not altered during short- or long-term atenolol administration.89 It generally is recommended that concomitant use of β-adrenergic blocking agents and sulfonylurea antidiabetic agents be avoided when possible;62,85 if concomitant therapy is necessary, use of a β₁-selective adrenergic blocking agent may be preferred.62 When glyburide and a β-adrenergic blocking agent are used concomitantly, the patient should be monitored closely for altered antidiabetic response.85

Bosentan

An increased risk of elevated serum aminotransferase concentrations has been observed in patients receiving glyburide and bosentan concomitantly.1,2,124,233 Therefore, concomitant use of glyburide and bosentan is contraindicated.233

Colesevelam

Concomitant administration of colesevelam and glyburide resulted in reductions in glyburide area under the concentration-time curve (AUC) and peak plasma concentration of 32 and 47%, respectively.1,2,124 The reductions in glyburide AUC and peak plasma concentration were 20 and 15%, respectively, when the drug was administered 1 hour before colesevelam, and were not substantially changed (decrease of 7% and increase of 4%, respectively) when glyburide was administered 4 hours before colesevelam.1,2,124 Therefore, glyburide should be given at least 4 hours prior to colesevelam.1,2,124

Metformin

Concomitant administration of metformin hydrochloride (single dose) resulted in highly variable decreases in AUC and peak plasma concentrations of glyburide (certain preparations) in patients with type 2 diabetes mellitus; no changes in metformin pharmacokinetics or pharmacodynamics were noted.1,124 The clinical importance of these effects is uncertain.1,124

Phenylbutazone

Phenylbutazone (no longer commercially available in the US) has been reported to potentiate the hypoglycemic effects of glyburide.84 The exact mechanism(s) of this interaction is not known.84 Phenylbutazone has been shown to decrease the renal excretion of glyburide metabolites without affecting metabolism of the sulfonylurea.84 If phenylbutazone is administered concomitantly with glyburide, the patient should be closely monitored for signs and symptoms of hypoglycemia;85 dosage adjustment of glyburide may be necessary when phenylbutazone therapy is initiated or discontinued.85

Thiazide Diuretics

Thiazide diuretics may exacerbate diabetes mellitus, resulting in increased requirements of sulfonylurea antidiabetic agents, temporary loss of diabetic control, or secondary failure to the antidiabetic agent.62,85,86 When thiazide diuretics are administered concomitantly with sulfonylurea antidiabetic agents, caution should be used.62,85,86

Topiramate

In a pharmacokinetic study in patients with type 2 diabetes mellitus, concomitant administration of glyburide (5 mg daily) and topiramate (150 mg daily) resulted in a 22% reduction in glyburide peak plasma concentration and a 25% reduction in glyburide AUC.1,124 Systemic exposure (AUC) of the active metabolites, 4-trans-hydroxyglyburide (M1) and 3-cis-hydroxyglyburide (M2), was also reduced by 13 and 15%, respectively, and peak plasma concentration was reduced by 18 and 25%, respectively.1,124 The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide.1,124

Other Drugs

Drugs that may enhance the hypoglycemic effect of sulfonylurea antidiabetic agents, including glyburide, include chloramphenicol,1,2,60,62,85 monoamine oxidase inhibitors,1,2,62,85 fluoroquinolone antibiotics (e.g., ciprofloxacin),1,2 and probenecid.1,2,62,85 When these drugs are administered or discontinued in patients receiving glyburide, the patient should be observed closely for hypoglycemia or loss of diabetic control, respectively.1,2

Drugs that may decrease the hypoglycemic effect of sulfonylurea antidiabetic agents (e.g., glyburide) include nonthiazide diuretics (e.g., furosemide),1,2,62,85 corticosteroids,1,2,62,85 phenothiazines,1,2,62,85 thyroid agents,1,2,62,85 estrogens,1,2,62 oral contraceptives,1,2,62,85 phenytoin,1,2,62 nicotinic acid,1,2,62 sympathomimetic agents,1,2,62 calcium-channel blocking agents,1,2,90 rifampin,2,62,85 and isoniazid.1,2 When these drugs are administered or discontinued in patients receiving glyburide, the patient should be observed closely for loss of diabetic control or hypoglycemia, respectively.1,2

Acute Toxicity

Pathogenesis

Acute glyburide toxicity may result from excessive dosage,1,2,67,68,69 and numerous conditions may predispose patients to the development of glyburide-induced hypoglycemia.1,2,67 (See Cautions: Precautions and Contraindications.) Acute glyburide toxicity may also result from inadvertent70,71,75,78 or intentional (e.g., attempted suicide)72,73,76,77 ingestion of the drug; glyburide, like other sulfonylurea antidiabetic agents, has also been used by some nondiabetic individuals to produce factitious hypoglycemia.79 Adults have survived intentional ingestions of up to 200 mg of glyburide,73 but death has occurred in some adults following severe hypoglycemia induced by as little as 2.5-5 mg of the drug.68,73,105

Manifestations

Acute glyburide overdosage is manifested principally as hypoglycemia, which may be severe1,2,67,68,69,74,105 and has occasionally been fatal.67,68,74,105 Severe hypoglycemia may result in loss of consciousness67,68,69,70,71,72,76,105 and seizures,71,75 with resultant neurologic sequelae.70,71,75,105 In 2 children 11 and 30 months of age who inadvertently ingested unknown amounts of glyburide, hypoglycemia occurred with seizures and apparently resulted in permanent cerebral dama 71,75 mental retardation could not be excluded.71,75 In another child 22 months of age who inadvertently ingested 10-15 mg of the drug, atrophy of the optic nerve with cerebral symptoms was reported.70 Severe hypoglycemic coma has been reported in one 79-year-old nondiabetic woman who inadvertently received a single 5-mg dose of glyburide.78 Although glyburide-induced hypoglycemia is generally not prolonged,96,105 hypoglycemia and/or loss of consciousness have persisted for up to 3-5 days in some cases (e.g., in geriatric patients).68,71,74,76,78,105 In some patients, hypoglycemia may persist despite continuous IV administration of dextrose, and in some fatalities, loss of consciousness persisted despite correction of hypoglycemia.105 Glyburide-induced hypoglycemia may be more severe and/or protracted in patients with renal and/or hepatic impairment.105

Treatment

Treatment of acute glyburide overdosage consists principally of administration of glucose and supportive therapy.1,2,67,69,71,72,78 The patient should be monitored closely until complete recovery is assured .1,2,69,78

Patients with mild hypoglycemic symptoms without loss of consciousness or adverse neurologic effects should be treated aggressively with orally administered glucose, and glyburide dosage and/or the patient's meal pattern should be appropriately adjusted.1,2,69 Severe glyburide-induced hypoglycemia with coma, seizures, or other neurologic impairment occurs infrequently, but constitutes a medical emergency requiring immediate hospitalization and treatment.1,2,67,105 If hypoglycemic coma is diagnosed or suspected, 50% dextrose injection (e.g., 50 mL) should be administered IV rapidly, followed immediately by a continuous IV infusion of 10% dextrose injection at a rate sufficient to maintain a blood glucose concentration exceeding 100 mg/dL.1,2,67 In some patients, subsequent administration of IV glucagon and/or corticosteroids may also be necessary.67 Blood glucose concentrations should be monitored at least every 3 hours during the first 24 hours and as often as necessary thereafter.67 Care should be taken to avoid inducing excessive hyperglycemia.73 Other symptomatic therapy (e.g., anticonvulsants) should be administered as necessary.71,72,75 Glyburide is effectively adsorbed by activated charcoal in vitro.82 Experimental studies using chlorpropamide (no longer commercially available in the US) suggest that if sulfonylurea overdosage is the result of an acute ingestion, administration of activated charcoal within several hours of the ingestion may be effective in reducing sulfonylurea absorption.83 Since hypoglycemia may occur after apparent clinical recovery, patients must be closely monitored for at least 24-72 hours;1,2,67,69,78,105 glyburide-induced hypoglycemia has persisted for longer periods in some patients,74 and recurring hypoglycemia after apparently successful treatment has resulted in death in at least one patient.73

Pharmacology

Antidiabetic Effect

Like other sulfonylurea antidiabetic agents, glyburide lowers blood glucose concentration in diabetic and nondiabetic individuals.3,4,8,9,10,11 Although the hypoglycemic action of the various sulfonylureas is generally similar, the drugs may differ quantitatively and/or possibly qualitatively in the extent to which they produce specific effects, and the effects may vary as a function of duration of treatment.4,8,9,10,11,12 On a weight basis, glyburide is one of the most potent of the sulfonylurea antidiabetic agents;4,8 although an exact dosage relationship does not exist, a daily glyburide dosage of 5 mg controls blood glucose concentration to approximately the same degree as daily dosages of glipizide 5-10 mg8,14,100,101 or tolbutamide 1-1.5 g.1,2

The precise mechanism(s) of hypoglycemic action of sulfonylurea antidiabetic agents has not been clearly established, but the drugs, including glyburide, initially appear to lower blood glucose concentration principally by stimulating secretion of endogenous insulin from the beta cells of the pancreas.1,2,3,4,8,9,10,11,12,124 Sulfonylureas bind to the sulfonylurea receptor in the pancreatic β-cell plasma membrane, leading to closure of the ATP-sensitive potassium channel, thereby stimulating the release of insulin.158 Other mechanisms of the hypoglycemic action associated with short-term glyburide therapy appear to include reduction of basal hepatic glucose production9,12,121 and enhancement of peripheral insulin action at postreceptor (probably intracellular) site(s).9,12,13,16,48,121 Following short-term administration of glyburide, an increase in insulin binding has been demonstrated in monocytes obtained from healthy individuals,17 but not in adipocytes obtained from diabetic patients.9 Like other sulfonylureas, glyburide alone is ineffective in the absence of functioning beta cells.1,2,4,124

The mechanism(s) of action of glyburide during prolonged administration has not been fully established.1,2,4,8,9,10,11,12,15,16,17,124 Glyburide-induced improvement in glucose tolerance during long-term therapy persists despite a gradual decline in glucose- or meal-stimulated secretion of endogenous insulin towards pretreatment levels.1,2,4,8,9,10,11,12,124 During prolonged administration of sulfonylureas, including glyburide, extrapancreatic effects appear to substantially contribute to the hypoglycemic action of the drugs.4,8,9,10,11,12,15,16,17,110,111,112,121 Many extrapancreatic effects of the drugs have been proposed and/or studied, but the principal effects appear to include enhanced peripheral sensitivity to insulin and reduction of basal hepatic glucose production;4,8,9,12,110,111,112,121 however, the nature of the long-term hypoglycemic effect and the mechanism(s) involved remain to be fully elucidated.4,8,9,10,11,12,15,16,17,110,111,112 There is evidence that glyburide enhances the peripheral action of insulin at postreceptor (probably intracellular) site(s)9,12,48,112,121 and reduces basal hepatic glucose production9,12,112,121 during long-term administration. An increase in insulin binding and/or number of insulin receptors has also been demonstrated in monocytes16 and adipocytes9 obtained from diabetic patients receiving long-term therapy with the drug.

Other Effects

Glyburide produces a mild diuresis by enhancing renal free water clearance.1,2,18,19,20,45,46,124 The diuretic effect has been demonstrated in healthy individuals,18,19,45 diabetic patients,18 and patients with neurohypophyseal diabetes insipidus;19,20,46 the drug apparently has no diuretic effect in patients with nephrogenic diabetes insipidus.19 Glyburide has been shown to reduce the duration of antidiuresis induced by IV desmopressin46 in patients with neurohypophyseal diabetes insipidus; IV desmopressin inhibits the diuretic effect of glyburide in these patients.46 The exact mechanism by which glyburide enhances renal free water clearance is not known.18,19,20,45,46 The diuretic action apparently is not mediated through an effect on the release of vasopressin (antidiuretic hormone) from the posterior pituitary or on the action of vasopressin at the renal collecting ducts.18,19,20 It has been suggested that glyburide inhibits reabsorption of sodium in the proximal renal tubule18 or nonvasopressin-dependent reabsorption of water in the distal renal tubule.19,20

Glyburide has been reported to inhibit in vitro platelet aggregation induced by epinephrine or collagen and to normalize in vitro platelet aggregation induced by adenosine diphosphate (ADP) in individuals with type 2 diabetes mellitus;21 however, conflicting results have also been reported,22 and further evaluation is needed to determine the effect of glyburide on platelet function.21,22

Pharmacokinetics

Absorption

Currently available tablet formulations of glyburide appear to be reliably and almost completely absorbed following oral administration.4,23,24,94 Bioavailability studies have demonstrated that micronized glyburide and nonmicronized (conventional) glyburide tablets are not bioequivalent; therefore, patients switching from micronized to nonmicronized tablets or vice versa should have their dosage retitrated.124 (See Dosage: Type 2 Diabetes Mellitus, under Dosage and Administration.) Food apparently does not affect the rate or extent of absorption of glyburide.27,28,94

Following oral administration of a single 5-mg dose of glyburide, the drug appears in plasma or serum within 15-60 minutes and average peak plasma or serum concentrations of approximately 140-350 ng/mL usually are attained within 2-4 hours (range: 2-8 hours).1,24,25,26,27,29,30,31,32,47,94 The area under the serum concentration-time curve (AUC) for glyburide increases in proportion to increasing doses.1,2,32,124 Substantial interindividual variations in steady-state serum concentration have been reported in diabetic patients receiving the same dosage of glyburide.27,95

Following single oral doses of glyburide in nonfasting diabetic or healthy individuals, plasma insulin concentration generally begins to increase within 15-60 minutes4,27,28,29,33,34 and is maximal within 1-2 hours;4,27,28,29,34 in diabetic patients, increases in plasma insulin concentration may persist for up to 24 hours.4,33,49 Following single oral doses of the drug in fasting healthy individuals, the degree and duration of lowering of blood glucose concentration are proportional to the dose administered and the AUC;1,2,32,124 the hypoglycemic action generally begins within 45-60 minutes and is maximal within 1.5-3 hours.4,27,32,49 In nonfasting diabetic patients, the hypoglycemic action of a single morning dose of glyburide may persist for up to 24 hours.1,2,33,124 There is some evidence that a serum glyburide concentration of approximately 30-50 ng/mL is required to lower blood glucose concentration.32,35 A correlation between blood concentrations of the drug and fasting blood glucose concentration in diabetic patients receiving long-term glyburide therapy has not been established.1,2,27,124

Distribution

Distribution of glyburide into human body tissues and fluids has not been fully characterized.30,34,36 Following oral or IV administration in animals, highest concentrations of the drug are attained in the liver, kidneys, and small and large intestines, with lower concentrations in the stomach, pancreas, spleen, mesenteric lymph nodes, mesenteric and retroperitoneal fat, heart, lungs, gonads, skeletal muscle, and brain.3,36 In humans, glyburide is distributed in substantial amounts into bile.1,2,3,25,26,36,124 Glyburide appears to cross the placenta,81,101 since prolonged hypoglycemia has occurred in neonates born to women who received the drug up to the time of delivery.81 It is not known if the drug is distributed into milk.1,2,124

In healthy adults, the volume of distribution of glyburide during the elimination phase averages 0.155 L/kg41,97 and the apparent steady-state volume of distribution averages 0.125 L/kg.41 Serum glyburide concentration-time curves in diabetic individuals receiving multiple doses of the drug have been shown to be similar to those following single doses, suggesting that glyburide does not accumulate in tissue depots;1,2,124 however, other pharmacokinetic data have suggested that the drug may accumulate in a deep tissue compartment following continuous administration.27

At a concentration of 0.05-10 mcg/mL in vitro, glyburide is more than 99% bound to serum proteins7,25,37 and its major metabolite, 4- trans -hydroxyglyburide, is more than 97% bound to serum proteins.25 Glyburide has a higher affinity for binding to serum albumin than does glipizide or tolbutamide.37,38 Unlike the protein binding of some other sulfonylurea antidiabetic agents (e.g., tolbutamide) and like that of glipizide, the protein binding of glyburide is principally nonionic;1,2,37,38,39,40,124 consequently, glyburide may be less likely to be displaced from binding sites by, or displace from binding sites, other highly protein-bound drugs whose protein binding is ionic in nature.37,40 (See Drug Interactions: Protein-Bound Drugs.)

Elimination

Serum concentrations of glyburide appear to decline in a biphasic manner.1,2,25,32,124 In studies in healthy adults using assays relatively specific for unchanged glyburide, the terminal elimination half-life has reportedly averaged 1.4-1.8 hours (range: 0.7-3 hours);24,27,29,41,97 when assays that also measured metabolites of the drug were used, the terminal elimination half-life has averaged about 10 hours (range: 5-26 hours).25,30,31,32,124 Serum glyburide concentrations may be increased in patients with renal1,2,27,124 or hepatic1,2,124 insufficiency.124 Data are limited, but the half-life may be prolonged in patients with severe renal impairment.42,43 In one study in patients with normal hepatic function and impaired renal function given a single oral dose of radiolabeled glyburide, the plasma half-life of total radioactivity was 2-5 hours in those with creatinine clearances of 29-131 mL/minute per 1.73 m² and 11 hours in one patient with a creatinine clearance of 5 mL/minute per 1.73 m²; in those patients with creatinine clearances of 29-131 mL/minute per 1.73 m², no relationship between plasma half-life and creatinine clearance was observed.42,102

Glyburide appears to be completely metabolized,25,26,31,36 probably in the liver.31 The drug is metabolized at the cyclohexyl ring principally to -hydroxyglyburide trans 4-;1,2,25,26,31,36,124 the 4- trans -hydroxy metabolite has only 0.25% of the hypoglycemic activity of glyburide following oral administration in rabbits,1,2,36,124 but has about 15% of the hypoglycemic activity of the parent compound following intraperitoneal administration in rats.44,98 Glyburide is also metabolized to the 3- cis -hydroxy derivative and to another unidentified metabolite;25,26,31 the 3- cis -hydroxy metabolite has 2.5% of the hypoglycemic activity of glyburide following oral administration in rabbits.1,2,36 The hypoglycemic activity of glyburide metabolites is generally considered clinically unimportant;1,2,36,124 however, results of studies in rats indicate that retention of the 4- trans -hydroxy metabolite in the presence of renal insufficiency may enhance and prolong the hypoglycemic effect of the drug.98,99

Unlike other currently available sulfonylurea antidiabetic agents which are excreted principally in urine,1,2,8,124 glyburide is excreted as metabolites in urine and feces in approximately equal proportions.1,2,23,25,26,30,31,47,124 Fecal excretion appears to occur almost completely via biliary elimination;25,26,30 only small amounts may be excreted in feces as unabsorbed drug following oral administration.30 Most urinary excretion occurs within the first 6-24 hours after oral administration of the drug.25,26,30,31,47 Following oral administration of a single 5-mg dose of glyburide in healthy individuals, approximately 30-50% of the dose is excreted in urine as metabolites within 24 hours;30,31 about 80% of the urinary excretion occurs as the 4- trans -hydroxy metabolite, 15% as the 3- cis -hydroxy metabolite, and 5% as an unidentified metabolite.25,26 Fecal excretion occurs more slowly, but a single oral dose of the drug is completely excreted in urine and feces within 3-5 days in healthy individuals.25,30

Total plasma clearance of glyburide reportedly averages 78 mL/hour per kg in healthy adults.41,97 The effects of renal impairment on the elimination of glyburide and its metabolites have not been fully evaluated.42,43,98 Limited data indicate that renal excretion of glyburide metabolites98 and plasma clearance of glyburide42,43 may be substantially decreased in patients with severe renal impairment.

Glyburide appears to be only minimally removed by hemodialysis.42

Chemistry and Stability

Chemistry

Glyburide is a sulfonylurea antidiabetic agent.1,2,3,4,124 The drug is structurally similar to acetohexamide (no longer commercially available in the US) and glipizide.4 Although chemically related to sulfonamides, glyburide has no antibacterial activity.5 Glyburide is commercially available alone and in fixed combination with metformin hydrochloride.158

Glyburide occurs as a white1,2 or almost white,6 odorless or almost odorless,6 crystalline powder.1,2,6,124 The solubility of glyburide in water increases with increasing pH;7 the solubility of the drug in water is approximately 4 mcg/mL at pH 4 and 600 mcg/mL at pH 9.7 Glyburide has a solubility of approximately 3 mg/mL in alcohol.6 The drug has a pK_a of 6.8.7

Stability

Depending on the specific preparation, glyburide tablets should be stored in well-closed containers at 252 or 20-25°C;1,124 with some preparations,1,2 temperature may range between 15-30°C. Fixed-combination preparations containing glyburide and metformin hydrochloride should be stored in light-resistant containers at a controlled room temperature up to 25°C.158

1. Cadilla Pharmaceuticals Ltd. Glyburide tablets prescribing information. District - Ahmedabad, Gujarat, India; 2020 Jan.

2. Sanofi-Aventis. Diaβeta^® (glyburide tablets) prescribing information. Bridgewater, NJ; 2017 Jan.

3. Anon. Glibenclamide: a review. Drugs . 1971; 1:116-40. [PubMed 5004340]

4. Jackson JE, Bressler R. Clinical pharmacology of sulphonylurea hypoglycaemic agents: part 1. Drugs . 1981; 22:211-45. [PubMed 7021124]

5. Vomel VW, Sauer W. Zur Frage einer antimikrobiellen Wirkung des neuen oralen Antidiabeticums HB 419. (German; with English abstract) Arzneim-Forsch . 1969; 19:1491-4.

6. The British pharmacopoeia. London: Her Majesty's Stationery Office; 1980:210.

7. Hadju VP, Kohler KF, Schmidt FH et al. Physikalisch-chemische und analytische Unter suchungen an HB 419. (German; with English abstract) Arzneim-Forsch . 1969; 19:1381-6.

8. Skillman TG, Feldman JM. The pharmacology of sulfonylureas. Am J Med . 1981; 70:361-72. [PubMed 6781341]

9. Kolterman OG, Gray RS, Shapiro G et al. The acute and chronic effects of sulfonylurea therapy in type II diabetic subjects. Diabetes . 1984; 33:346-54. [PubMed 6423429]

10. Duckworth WC, Solomon SS, Kitabchi AE. Effect of chronic sulfonylurea therapy on plasma insulin and proinsulin levels. J Clin Endocrinol Metab . 1972; 35:585-91. [PubMed 5052977]

11. Feldman JM, Lebovitz HE. Endocrine and metabolic effects of glybenclamide: evidence for an extrapancreatic mechanism of action. Diabetes . 1971; 20:745-55.

12. DeFronzo RA, Ferrannini E, Koivisto V. New concepts in the pathogenesis and treatment of noninsulin-dependent diabetes mellitus. Am J Med . 1983; 74(Suppl 1A):52-81. [PubMed 6337486]

13. Lockwood DH, Maloff BL, Nowak SM et al. Extrapancreatic effects of sulfonylureas: potentiation of insulin action through post-binding mechanisms. Am J Med . 1983; 74(Suppl 1A):102-8. [PubMed 6401922]

14. Brogden RN, Heel RC, Pakes GE et al. Glipizide: a review of its pharmacological properties and therapeutic use. Drugs . 1979; 18:329-53. [PubMed 389600]

15. Kolterman OG, Prince MJ, Olefsky JM. Insulin resistance in noninsulin-dependent diabetes mellitus: impact of sulfonylurea agents in vivo and in vitro. Am J Med . 1983; 74(Suppl 1A):82-101. [PubMed 6401923]

16. Beck-Nielsen H, Pedersen O, Lindskov HO. Increased insulin sensitivity and cellular insulin binding in obese diabetics following treatment with glibenclamide. Acta Endocrinol . 1979; 90:451-62. [PubMed 106617]

17. Hjollund E, Richelsen B, Beck-Nielsen H et al. The effect of glibenclamide on insulin receptors in normal man: comparative studies of insulin binding to monocytes and erythrocytes. J Clin Endocrinol Metab . 1983; 57:1257-62. [PubMed 6415086]

18. Moses AM, Howanitz J, Miller M. Diuretic action of three sulfonylurea drugs. Ann Intern Med . 1973; 78:541-4. [PubMed 4632790]

19. Rado JP, Borbély L, Szende L et al. Investigation of the diuretic effect of glibenclamide in healthy subjects and in patients with pituitary and nephrogenic diabetes insipidus. Horm Metab Res . 1974; 6:289-92. [PubMed 4213198]

20. Rado JP, Szende L. Inhibition of clofibrate-induced antidiuresis by glybenclamide in patients with pituitary diabetes insipidus. J Clin Pharmacol . 1974; 14:290-5. [PubMed 4208361]

21. Klaff LJ, Kernoff L, Vinik AI et al. Sulfonylureas and platelet function. Am J Med . 1981; 70:627-30. [PubMed 6782875]

22. Blumenthal SA. Sulfonylureas and platelet function. Am J Med . 1983; 74:795. [PubMed 6404166]

23. Rupp W, Christ O, Fulberth W. Untersuchungen zur Bioavailability von Glibenclamid. (German; with English abstract) Arzneim-Forsch . 1972; 22:471-3.

24. Ings RMJ, Lawrence JR, McDonald A et al. Glibenclamide pharmacokinetics in healthy volunteers: evidence for zero-order drug absorption. Br J Clin Pharmacol . 1982; 13:264-5P.

25. Christ OE, Heptner W, Rupp W. Investigations on absorption, excretion and metabolism in man after administration of¹⁴C-labelled HB 419. Horm Metab Res Suppl Ser . 1969; 1:51-4.

26. Rupp VW, Christ O, Heptner W. Resorption, Ausscheidung and Metabolismus nach intravenoser und oraler Gabe von HB 419-¹⁴C an Menschen. (German; with English abstract) Arzneim-Forsch . 1969; 19:1428-34.

27. Sartor G, Melander A, Scherstén B et al. Serum glibenclamide in diabetic patients, and influence of food on the kinetics and effects of glibenclamide. Diabetologia . 1980; 18:17-22. [PubMed 6767639]

28. Sartor G, Lundquist I, Melander A et al. Improved effect of glibenclamide on administration before breakfast. Eur J Clin Pharmacol . 1982; 21:403-8. [PubMed 6804245]

29. Sartor G, Melander A, Scherstén B et al. Comparative single-dose kinetics and effects of four sulfonylureas in healthy volunteers. Acta Med Scand . 1980; 208:301-7. [PubMed 6778079]

30. Fucella LM, Tamassia V, Valzelli G. Metabolism and kinetics of the hypoglycemic agent glipizide in man—comparison with glibenclamide. J Clin Pharmacol . 1973; 13:68-75.

31. Balant L, Fabre J, Zahnd GR. Comparison of the pharmacokinetics of glipizide and glibenclamide in man. Eur J Clin Pharmacol . 1975; 8:63-9. [PubMed 823030]

32. Ko H, Royer ME, Molony BA. Relationships between circulating glyburide/metabolite concentrations, serum glucose lowering, and dose of glyburide in man. In: Rifkin H, ed. Micronase^® (glyburide): pharmacological and clinical evaluation. Amsterdam: Excerpta Medica; 1975:20-30.

33. Groop L, Harno K. Diurnal pattern of plasma insulin and blood glucose during glibenclamide and glipizide therapy in elderly diabetics. Acta Endocrinol Suppl . 1980; 239:44-52.

34. Balant L, Zahnd GR, Weber F et al. Behaviour of glibenclamide on repeated administration to diabetic patients. Eur J Clin Pharmacol . 1977; 11:19-25. [PubMed 401739]

35. Schmidt FH, Hrstka VE. Radio-immunoassay of glibenclamide: minimum effective dose levels and pharmacodynamics. XII^e Congrès International de Thérapeutique, Genève, 1973.

36. Kaiser DG, Forist AA. A review of glyburide metabolism in man and laboratory animals. In: Rifkin H, ed. Micronase^® (glyburide): pharmacological and clinical evaluation. Amsterdam: Excerpta Medica; 1975:31-43.

37. Crooks MJ, Brown KF. The binding of sulphonylureas to serum albumin. J Pharm Pharmacol . 1974; 26:304-11. [PubMed 4153105]

38. Hsu P, Ma JKH, Luzzi LA. Interactions of sulfonylureas with plasma proteins. J Pharm Sci . 1974; 63:570-3. [PubMed 4208196]

39. Brown KF, Crooks MJ. Binding of sulfonylureas to serum albumin. II. The influence of salt and buffer compositions on tolbutamide and glyburide. Can J Pharm Sci . 1974; 9:75-7.

40. Brown KF, Crooks MJ. Displacement of tolbutamide, glibenclamide and chlorpropramide from serum albumin by anionic drugs. Biochem Pharmacol . 1976; 25:1175-8. [PubMed 820348]

41. Morrison PJ, Rogers HJ, Spector RG et al. Effect of pirprofen on glibenclamide kinetics and response. Br J Clin Pharmacol . 1982; 14:123-6. [PubMedCentral][PubMed 6809024]

42. Raehl CL, Goersch WA, Craig WA et al. The pharmacokinetics of¹⁴C-glyburide (Micronase^®) in patients with reduced renal function. In: Official Program and Abstracts of Papers presented before the APhA Academy of Pharmaceutical Sciences. Washington, DC: American Pharmaceutical Association; 1983; 13(2):205. Abstract.

43. Balant L, Zahnd G, Petitpierre B et al. Influence of renal failure on the pharmacokinetics and hypoglycemic effect of sulfonylureas. Diabetologia . 1973; 9:59.

44. Balant L, Fabre J, Loutan L et al. Does 4-trans-hydroxy-glibenclamide show hypoglycemic activity? Arzneim-Forsch . 1979; 29:162-3.

45. Rado JP, Borbély L. Inhibition of the antidiuretic effect of 1-deamino-8d-arginine vasopressin (DDAVP) by glibenclamide in water-loaded healthy subjects. Endokrinologie . 1975; 66:88-93. [PubMed 817889]

46. Rado JP, Szende L, Marosi J. Influence of glyburide on the antidiuretic response induced by 1-deamino-8-d-arginine vasopressin (DDAVP) in patients with pituitary diabetes insipidus. Metabolism . 1974; 23:1057-63. [PubMed 4214480]

47. Anderson J, Stephenson RJ, Tomlinson RWS et al. Studies with¹⁴C-labelled glibenclamide. Postguard Med J . 1970; 46(Dec Suppl):42-5.

48. Larner J. Mediators of postreceptor action of insulin. Am J Med . 1983; 74(Suppl 1A):38-51. [PubMed 6297300]

49. Davidson M, Lewis AAG, de Mowbray RR. Metabolic and clinical effects of glibenclamide. Lancet . 1970; 1:57-61. [PubMed 4188623]

50. Johnson BF, Bhatia CK, Rzeszotarski WJ et al. Preliminary clinical evaluation of glybenclamide in treatment of diabetes mellitus. Diabetes . 1970; 19:579-84. [PubMed 4915447]

51. Clarke BF, Campbell IW. Long-term comparative trial of glibenclamide and chlorpropamide in diet-failed, maturity-onset diabetics. Lancet . 1975; 1:246-8. [PubMed 8667857]

52. Hamblin JJ, Ismay G, Good MS et al. A comparative study of glibenclamide and chlorpropamide (preliminary report). Postgrad Med J . 1970; 46(Dec Suppl):92-4. [PubMedCentral][PubMed 5416512]

53. Mogensen EF, Worm J, Mikkelsen BO. Clinical comparison between glibornuride (Glutril^®) and glibenclamide in maturity-onset diabetes: a controlled double-blind trial. Curr Ther Res . 1976; 19:599-64.

54. Blohmé G, Waldenstrom J. Glibenclamide and glipizide in maturity onset diabetes. Acta Med Scand . 1979; 206:263-7. [PubMed 116480]

55. Frederiksen PK, Mogensen EF. A clinical comparison between glipizide (Glibenese^®) and glibenclamide (Daonil^®) in the treatment of maturity onset diabetes: a controlled doudle-blind cross-over study. Curr Ther Res . 1982; 32:1-7.

56. Allen GS. The comparative effectiveness of glyburide and tolazamide in patients with mild diabetes. In: Rifkin H, ed. Micronase^® (glyburide): pharmacological and clinical evaluation. Amsterdam: Excerpta Medica; 1975:150-6.

57. Bryan JB, Inchaustegui HJ. Clinical impressions of Micronase^® (glyburide) in a private practice. In: Rifkin H, ed. Micronase^® (glyburide): pharmacological and clinical evaluation. Amsterdam: Excerpta Medica; 1975:225-34.

58. Murphey AT, Peskin H. Glyburide compared to previous therapy or tolbutamide. In: Rifkin H, ed. Micronase^® (glyburide): pharmacological and clinical evaluation. Amsterdam: Excerpta Medica; 1975:204-10.

59. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care . 2009; 32 Suppl 1:S62-7.

60. Carlisle BA, Kroon LA, Koda-Kimble MA,. Diabetes mellitus. In: Koda-Kimble MA, Young LY, eds. Applied therapeutics: the clinical use of drugs. 8th ed.Philadelphia, PA: Lippincott Williams & Wilkins, Inc; 2005: 50-1-50-86.

61. Scientific Advisory Panel of the Executive Committee, American Diabetes Association. Policy statement: the UGDP controversy. Diabetes . 1979; 28:168-70.

62. Jackson JE, Bressler R. Clinical pharmacology of sulphonylurea hypoglycaemic agents: part 2. Drugs . 1981; 22:295-320. [PubMed 7030708]

63. Food and Drug Administration. Labeling for oral hypoglycemic drugs of the sulfonylurea class. [Docket No. 75N-0062] Fed Regist . 1984; 49:14303-31.

64. Clarke BF, Campbell IW, Ewing DJ et al. Generalized hypersenstivity reaction and visceral arteritis with fatal outcome during glibenclamide therapy. Diabetes . 1974; 23:739-42. [PubMed 4213123]

65. Wongpaitoon V, Mills PR, Russell RI et al. Intrahepatic cholestasis and cutaneous bullae associated with glibenclamide therapy. Postgrad Med J . 1981; 57:244-6. [PubMedCentral][PubMed 6794018]

66. Krans HMJ. Insulin, glucagon and oral hypoglycaemic drugs. In: Dukes MNG, ed. Side effects of drugs. Annual 2. New York: Elsevier/North Holland Inc; 1978:345.

67. Seltzer HS. Severe drug-induced hypoglycemia: a review. Compr Ther . 1979; 5(4):21-9. [PubMed 445986]

68. Gottesburen H, Gerdes H, Littman KP et al. Severe hypoglycemia after glibenclamide. Lancet . 1970; 2:576.

69. Howard FM. Hypoglycemia in diabetics treated with Micronase^® (glyburide). In: Rifkin H, ed. Micronase^® (glyburide): pharmacological and clinical evaluation. Amsterdam: Excerpta Medica: 1975:164-71.

70. Krans HMJ. Insulin, glucagon and oral hypoglycaemic drugs. In: Dukes MNG, ed. Side effects of drugs. Annual 1. New York: Elsevier/North Holland Inc; 1977:319.

71. Sillence DO, Court JM. Glibenclamide-induced hypoglycaemia. Br Med J . 1975; 3:490-1. [PubMedCentral][PubMed 808247]

72. Kullavanijaya P. Recovery from overdose with glibenclamide. Br Med J . 1970; 4:53-4. [PubMedCentral][PubMed 5470446]

73. Krans HMJ. Insulin, glucagon and oral hypoglycaemic drugs. In: Dukes MNG, ed. Side effects of drugs. Annual 3. New York: Elsevier/North Holland Inc; 1979:347.

74. Krans HMJ. Insulin, glucagon and oral hypoglycaemic drugs. In: Dukes MNG, ed. Side effects of drugs. Annual 4. New York: Elsevier/North Holland Inc; 1980:303.

75. Krans HMJ. Insulin, glucagon and oral hypoglycaemic drugs. In: Dukes MNG, ed. Side effects of drugs. Annual 6. New York: Elsevier/North Holland Inc.; 1982:370.

76. Krans HMJ. Insulin, glucagon and oral hypoglycaemic drugs. In: Dukes MNG, ed. Side effects of drugs. Annual 7. New York: Elsevier/North Holland Inc.; 1983:409.

77. Pannekoek JH. Insulin, glucagon and oral hypoglycaemic drugs. In: Dukes MNG, ed. Meyler's side effects of drugs. 8th ed. Amsterdam: Excerpta Medica; 1975:914-5.

78. Sketris I, Wheeler D, York S. Hypoglycemic coma induced by inadvertent administration of glyburide. Drug Intell Clin Pharm . 1984; 18:142-3. [PubMed 6421558]

79. Walfish PG, Kashyap RP, Greenstein S. Sulfonylurea-induced factitious hypoglycemia in a nondiabetic nurse. Can Med Assoc J . 1975; 112:71-2. [PubMedCentral][PubMed 803250]

80. Shaw KM, Bulpitt CJ, Bloom A. Side effects of therapy in diabetes evaluated by a self-administered questionnaire. J Chron Dis . 1977; 30:39-48. [PubMed 401821]

81. Coetzee EJ, Jackson WPU. Pregnancy in established non-insulin-dependent diabetics: a five-and-a-half year study at Groote Schuur Hospital. S Afr Med J . 1980; 58:795-802. [PubMed 6777880]

82. Kannisto H, Neuvonen PJ. Adsorption of sulfonylureas onto activated charcoal in vitro. J Pharm Sci . 1984; 73:253-6. [PubMed 6707896]

83. Neuvonen PJ, Karkkainen S. Effects of charcoal, sodium bicarbonate, and ammonium chloride on chlorpropamide kinetics. Clin Pharmacol Ther . 1983; 33:386-93. [PubMed 6297841]

84. Shulz E, Koch K, Schmidt FH. Ursachen der Potenzierung der hypoglykamischen Wirkung von Sulfonylharstoff-Derviaten durch Medikamente. II. Pharmakokinetik und Metabolismus von Glibenclamide (HB 419) in Gegenwart von Phenylbutazon. (German; with English abstract) Eur J Clin Pharmacol . 1971; 4:32-7.

85. Hansten PD. Drug interactions. 4th ed. Philadelphia: Lea & Febiger; 1979:14, 93-109.

86. The Upjohn Company. Orinase^® prescribing information. In: Huff BB, ed. Physicians' desk reference. 38th ed. Oradell, NJ: Medical Economics Company Inc.; 1984:2041-3.

87. Wardle EN, Richardson GO. Alcohol and glibenclamide. Br Med J . 1971; 3:309. [PubMedCentral]

88. Zaman R, Kendall MJ, Biggs PI. The effect of acebutolol and propranolol on the hypoglycaemic action of glibenclamide. Br J Clin Pharmacol . 1982; 13:507-12. [PubMedCentral][PubMed 6802160]

89. Hausmann L, Goebel KM. Atenolol in orally treated diabetic patients. Drugs . 1983; 25(Suppl 2):71-3.

90. De Marinis L, Barbarino A. Calcium antagonists and hormone release. I. Effects of verapamil on insulin release in normal subjects and patients with islet-cell tumor. Metabolism . 1980; 29:599-604. [PubMed 6247604]

91. O'sullivan DJ, Cashman WF. Blood glucose variations and clinical experience with glibenclamide in diabetes mellitus. Br Med J . 1970; 2:572-4. [PubMedCentral][PubMed 5526612]

92. Molony BA, Crim JA, Hearron AE Jr. Micronase^® (glyburide): a comparison of single and divided daily dose treatment schedules. In: Rifkin H, ed. Micronase^® (glyburide): pharmacological and clinical evaluation. Amsterdam: Excerpta Medica; 1975:248-53.

93. Owens DR, Wragg KG, Shetty KT et al. Glibenclamide, acute-long-term response in m.o. diabetics. Horm Metab Res . 1979; 11:411-2. [PubMed 112018]

94. The Upjohn Company. Pharmacokinetic profile: Micronase^® tablets (glyburide). Kalamazoo, MI; 1983 Oct.

95. Huupponen R, Viikari J, Saarimaa H. Chlorpropamide and glibenclamide serum concentrations in hospitalized patients. Ann Clin Res . 1982; 14:119-22. [PubMed 6814340]

96. The Upjohn Company. Therapeutic profile: Micronase^® tablets (glyburide). Kalamazoo, MI; 1984 May.

97. Rogers HJ, Spector RG, Morrison PJ et al. Pharmacokinetics of intravenous glibenclamide investigated by a high performance liquid chromatographic assay. Diabetologia . 1982; 23:37-40. [PubMed 6811355]

98. Fabre J, Balant L, Loutan L et al. Hypoglycemic activity of the main metabolite of glibenclamide: influence of renal insufficiency. Kidney Int . 1978; 13:435.

99. Loutan L, Samimi H, Balant L et al. Metabolites of hypoglycemic sulfonylureas in renal insufficiency. Experiences with glibenclamide. (German) Schweiz Med Wochenschr . 1978; 108:1782-6.

100. Gurwich EL (The Upjohn Company, Kalamazoo, MI): Personal communication; 1984 Jun 25.

101. Roney JV (Hoechst-Roussel Pharmaceuticals Inc., Somerville, NJ): Personal communication; 1984 Jun 18.

102. Raehl CL (University of Wisconsin School of Pharmacy, Madison, WI): Personal communication; 1984 Jun 28.

103. Lebovitz HE. Clinical utility of oral hypoglycemic agents in the management of patients with noninsulin-dependent diabetes mellitus. Am J Med . 1983; 75(Suppl 5B):94-9. [PubMed 6369972]

104. Adetuyibi A, Ogundipe OO. A comparative trial of glipizide, glibenclamide and chlorpropamide in the management of maturity-onset diabetes mellitus in Nigerians. Curr Ther Res . 1977; 21:485-90.

105. Asplund K, Wiholm BE, Lithner F. Glibenclamide-associated hypoglycemia: a report on 57 cases. Diabetologia . 1983; 24:412-7. [PubMed 6411511]

106. Reviewers' comments (personal observations); 1984 Jun.

107. Camerini-Davalos RA, Velasco C, Glasser M et al. Drug-induced reversal of early diabetic microangiopathy. N Engl J Med . 1983; 309:1551-6. [PubMed 6656850]

109. Kritz H, Najemnik C, Irsigler K. Sulfinpyrazone and glibenclamide study of interaction in diabetics of type II. Wien Med Wochenschr . 1983; 133:237-43. [PubMed 6408808]

110. Best JD, Judzewitsch RG, Pfeifer MA et al. The effect of chronic sulfonylurea therapy on hepatic glucose production in non-insulin-dependent diabetes. Diabetes . 1982; 31:333-8. [PubMed 6759249]

111. Pfeifer MA, Halter JB, Judzewitsch RG et al. Acute and chronic effects of sulfonylurea drugs on pancreatic islet function in man. Diabetes Care . 1984; 7(Suppl 1):25-34. [PubMed 6376026]

112. DeFronzo RA, Simonson DC. Oral sulfonylurea agents suppress hepatic glucose production in non-insulin-dependent diabetic individuals. Diabetes Care . 1984; 7(Suppl 1):72-80. [PubMed 6428844]

113. Skyler JS. Non-insulin-dependent diabetes mellitus: a clinical strategy. Diabetes Care . 1984; 7(Suppl 1):118-29. [PubMed 6376024]

114. Asmal AC, Marble A. Oral hypoglycaemic agents: an update. Drugs . 1984; 28:62-78. [PubMed 6378583]

115. Holmes B, Heel RC, Brogden RN et al. Gliclazide: a preliminary review of its pharmacodynamic properties and therapeutic efficacy in diabetes mellitus. Drugs . 1984; 27:301-27. [PubMed 6373223]

116. Lotz N, Lacher F, Bachmann W. Combination of sulfonylureas (SU) and insulin (I) in the treatment of type-II-diabetes with “secondary failure” of SU-therapy (DSF). Diabetes . 1984; 33(Suppl 1):24A.

117. Simonson DC, Castellino P, Delprato S. Effect of glyburide on glucose control and metabolism in insulin treated diabetics. Diabetes . 1984; 33(Suppl 1):38A.

118. Rost CR, Brown JL. Combined insulin-sulfonylurea therapy in noninsulin-dependent diabetes mellitus (NIDDM). Diabetes . 1984; 33(Suppl 1):87A.

119. Groop L, Harno K, Nikkila EA et al. The combination of insulin and sulfonylurea (glibenclamide) in the treatment of non-insulin dependent diabetes poorly controlled with insulin alone: evaluation of its metabolic effects. Acta Endocrinol Suppl . 1983; 257:20.

120. Bachmann W, Sieger C, Haslbeck M et al. Combination of insulin and glibenclamide (gl) in the treatment of adult-onset diabetes (Type 2). Diabetologia . 1981; 21:245.

121. Simonson DC, Ferrannini E, Bevilacqua S et al. Mechanism of improvement in glucose metabolism after chronic glyburide therapy. Diabetes . 1984; 33:838-45. [PubMed 6432610]

122. Sonksen PH, Lowy C, Perkins JR et al. Hormonal and metabolic effects of chlorpropamide, glibenclamide and placebo in a cross-over study in diabetics not controlled by diet alone. Diabetologia . 1981; 20:22-30. [PubMed 6781962]

124. Pharmacia & Upjohn. Glynase^® PresTab^® (micronized glyburide) tablets prescribing information. Kalamazoo, MI; 2017 Aug.

127. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet . 1998; 352:837-53. [PubMed 9742976]

128. American Diabetes Association. Implications of the United Kingdom Prospective Diabetes Study. Diabetes Care . 1999; 22(Suppl 1):S27-31.

129. Matthews DR, Cull CA, Stratton RR et al. UKPDS 26: sulphonylurea failure in non-insulin-dependent diabetic patients over 6 years. Diabet Med . 1998; 15:297-303. [PubMed 9585394]

130. Genuth P. United Kingdom prospective diabetes study results are in. J Fam Pract . 1998; 47:(Suppl 5):S27.

131. Bretzel RG, Voit K, Schatz H et al. The United Kingdom Prospective Diabetes Study (UKPDS): implications for the pharmacotherapy of type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes . 1998; 106:369-72. [PubMed 9831300]

132. Schmitt JK, Moore JR. Hypertension secondary to chlorpropamide with amelioration by changing to insulin. Am J Hypertens . 1993; 6:317-9. [PubMed 8507452]

133. Genuth S, Brownless MA, Kuller LH et al. Consensus development conference on insulin resistance: Novermber 5-6 1997. Diabetes Care . 1998; 21:310-4. [PubMed 9540000]

134. Henry RR. Glucose control and insulin resistance in non-insulin-dependent diabetes mellitus. Ann Intern Med . 1996; 124:97-103. [PubMed 8554221]

135. Lebovitz HE. Stepwise and combination drug therapy for the treatment of NIDDM. Diabetes Care . 1994; 17:1542-4. [PubMed 7882832]

136. Nathan DM. Some answers, more controversy, from UKDS. Lancet . 1998; 352:832-3. [PubMed 9742972]

137. Reviewers' comments (personal observations) on metformin.

138. American Diabetes Association. Standards of medical care in diabetes--2009. Diabetes Care . 2009; 32 Suppl 1:S13-61.

139. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med . 1993; 329:977-86. [PubMed 8366922]

140. Klein R, Klein BEK, Moss SE et al. Glycosylated hemoglobin predicts the incidence and progression of diabetic retinopathy. JAMA . 1988; 260:2864-71. [PubMed 3184351]

141. American Diabetes Association. Implications of the diabetes control and complications trial. Diabetes Care . 1996; 19:50-2S.

142. Ohkubo Y, Kishikawa H, Araki E et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus; a randomized prospective 6-year study. Diabetes Res Clin Pract . 1995; 28:103-17. [PubMed 7587918]

143. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metfromin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet . 1998; 352:854-65. [PubMed 9742977]

144. American Diabetes Association. The United Kingdom Prosepective Diabetes Study (UKPDS) for type 2 diabetes: what you need to know about the results of a long-term study. Washington, DC; September 15, 1998. From American Diabetes Association web site. [Web]

145. Davis TM. United Kingdom Prospective Diabetes Study: the end of the beginning? Med J Aust . 1998; 169:511-2.

146. Watkins PJ. UKPDS: a message of hope and a need for change. Diabet Med . 1998; 15:895-6. [PubMed 9827842]

147. Turner RC, Cull CA, Frighi V et al. Glycemic control with diet, sulfonlyurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirements for multiple therapies (UKPDS 49). JAMA . 1999; 281:2005-12. [PubMed 10359389]

148. August K, Brooks L (California Department of Health and Human Services). State health director warns consumers about prescription drugs in herbal products. Rockville, MD; 2000 Feb 15. News release No. 09-00. News release from FDA web site ([Web]).

149. American Diabetes Association. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care . 2000; 23(Suppl 1):S4-19.

150. DeFronzo RA. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes . 1988; 37:667-87. [PubMed 3289989]

151. Polonsky KS, Sturis J, Bell GI. Non-insulin-dependent diabetes mellitus-a genetically programmed failure of the beta cell to compensate for insulin resistance. N Engl J Med . 1996; 334:777-83. [PubMed 8592553]

152. Swislocki A. Insulin resistance and hypertension. Am J Med Sci . 1990; 300:104-15. [PubMed 2206054]

153. United Kingdom Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ . 1998; 317:703-13. [PubMedCentral][PubMed 9732337]

154. UK Prospective Diabetes Study (UKPDS) Group. Efficacy of atenolol and captopril in reducing risk of macrovascular complications in type 2 diabetes mellitus: UKPDS 39. BMJ . 1998; 317:713-20. [PubMedCentral][PubMed 9732338]

155. Davis TM. United Kingdom Prospective Diabetes Study: the end of the beginning? Med J Aust . 1998; 169:511-2.

156. Haffner SM, Hanefeld M, Fischer S et al. Glibenclamide, but not acarbose, increase leptin concentrations parallel to changes in insulin in subjects with NIDDM. Diabetes Care . 1997; 20: 1430-4. [PubMed 9283792]

157. Shi H, Moustaid-Moussa N, Wilkison WO et al. Role of the sulfonylurea receptor in regulating human adipocyte metabolism. FASEB J . 1999; 13:1833-8. [PubMed 10506587]

158. Actavis Pharma. Glyburide and metformin hydrochloride tablets prescribing information. Parsippany, NJ; 2020 May.

159. Cheskin LJ, Bartlett SJ, Zayas R et al. Prescription medications: a modifiable contributor to obesity. South Med J . 1999; 92:898-904. [PubMed 10498166]

160. American Diabetes Association. Type 2 diabetes in children and adolescents. Pediatrics . 2000; 105:671-80. [PubMed 10699131]

161. American Diabetes Association. Office guide to diagnosis and classification of diabetes mellitus and other categories of glucose intolerance. Diabetes Care . 1995; 18(Suppl 1):4.

162. Williams G. Management of non-insulin-dependent diabetes mellitus. Lancet . 1994; 343:95-100. [PubMed 7903785]

163. Genuth S. Exogenous insulin administration and cardiovascular risk in non-insulin-dependent and insulin-dependent diabetes mellitus. Ann Intern Med . 1996;124(1 Part 2):104-9. [PubMed 8554200]

164. USP DI: drug information for the health care professional. 20th ed. Englewood, CO: Micromedex, Inc; 2000;1:306.

165. Chow CC, Sorensen JP, Tsang LWW et al. Comparison of insulin with or without continuation of oral hypoglycemic agents in the treatment of secondary failure in NIDDM patients. Diabetes Care . 1995; 18:307-14. [PubMed 7555472]

166. Zimmerman B, Espenshade J, Fujimoto W et al. The pharmacological treatment of hyperglycemia in NIDDM. Diabetes Care . 1996; 19:1510-18.

167. Landstedt-Hallin L, Bolinder J, Adamson U et al. Comparison of bedtime NPH or preprandial regular insulin combined with glibenclamide in secondary sulfonylurea failure. Diabetes Care . 1995; 18:1183-6. [PubMed 7587856]

168. Expert Committee of the Canadian Diabetes Advisory Board. Clinical practice guidelines for treatment of diabetes mellitus. Can Med Assoc J . 1992; 147:697-712.

169. Raskin P. Combination therapy in NIDDM N Engl J Med . 1992; 327:1453-4. Editorial.

170. Pugh JA, Ramirez G, Wagner ML et al. Is combination sulfonylurea and insulin therapy useful in NIDDM patients? A metaanalysis. Diabetes Care . 1992; 15:953-9. [PubMed 1387073]

171. Buse J. Combining insulin and oral agents. Am J Med . 2000; 108(Suppl 6A):23S-32S. [PubMed 10764847]

172. Johnson JL, Wolf SL, Kabadi UM. Efficacy of insulin and sulfonylurea combination therapy in type II diabetes: a meta-analysis of the randomized placebo-controlled trials. Arch Intern Med . 1996; 156:259-64. [PubMed 8572835]

173. Yki-Jarvinen H, Dressler A, Ziemen M et al. Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime HPH insulin during insulin combination therapy in type 2 diabetes. Diabetes Care . 2000; 23:1130-6 (IDIS 451244)

174. Trischitta V, Italia S, Mazzarino S et al. Comparison of combined therapies in treatment of secon dary failure to glyburide. Diabetes Care . 1992; 15:539-42. [PubMed 1499473]

175. Florence JA, Yeager BF. Treatment of type 2 diabetes mellitus. Am Fam Physician . 1999; 59:2835-44. [PubMed 10348076]

176. Bastyr EJ, Johnson ME, Trautman ME et al. Insulin lispro in the treatment of patients with type 2 diabetes mellitus after oral agent failure. Clin Ther . 1999; 21:1703-4. [PubMed 10566566]

177. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med . 1999; 131:281-303. [PubMed 10454950]

178. Krentz AJ, Ferner RE, Bailey CJ. Comparative tolerability profiles of oral antidiabetic agents. Drug Safety . 1994; 11:223-41. [PubMed 7848543]

179. Anon. Diabetes mellitus. NIH Cons Dev Conf Statement . 1986; 6:1-7.

180. Blake GH. Control of type II diabetes: reaping the rewards of exercise and weight loss. Postgrad Med . 1992; 92:129-32. [PubMed 1437899]

181. Kerr CP. Improving outcomes in diabetes: a review of the outpatient care of NIDDM patients. J Fam Pract . 1995; 40:63-75. [PubMed 7807040]

182. Bailey C, Turner R. Metformin. N Engl J Med . 1996; 334:574-9. [PubMed 8569826]

183. Turner R, Cull C, Holman R et al. United Kingdom Prospective Diabetes Study 17: a 9-year update of a randomized, controlled trial on the effect of improved metabolic control on complications in non-insulin-dependent diabetes mellitus. Ann Intern Med . 1996; 124(1 Pt 2):136-45. [PubMed 8554206]

184. Zoetica. Glycron^® (glyburide) micronized tablets prescribing information. Princeton, NJ; 1999 Apr.

185. American Diabetes Association. Gestational diabetes mellitus. Diabetes Care . 2002; 25(Suppl 1):S94-6.

186. Langer O, Conway DL, Berkus MD et al. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med . 2000; 343:1134-8. [PubMed 11036118]

187. Albengres E, Le Louet H, Tillement JP. Systemic antifungal agents. Drug interactions of clinical significance. Drug Saf . 1998; 18:83-97. [PubMed 9512916]

188. Hermann LS, Scherstén B, Bitzén PO et al. Therapeutic comparison of metformin and sulfonylurea, alone and in various combinations. Diabetes Care . 1994; 17:1100-9. [PubMed 7821128]

189. Hermann L. Biguanides and sulfonylureas as combination therapy in NIDDM. Diabetes Care . 1990; 13:37-41. [PubMed 2209342]

193. United Kingdom prospective diabetes study group. United Kingdom prospective diabetes study (UKPDS) 16: overview of 6 years' therapy of type II diabetes: a progressive disease. Diabetes . 1995; 44:1240-58.

194. Bristol-Myers Squibb, Princeton, NJ: personal communication on metformin.

195. Wolffenbuttel BHR, Gomist R, Squatrito S et al. Addition of low-dose rosiglitazone to sulphonylurea therapy improves glycaemic control in type 2 diabetic patients. Diabet Med . 2000; 17:40-7. [PubMed 10691158]

196. Takeda Pharmaceuticals America. Actos^® (pioglitazone hydrochloride) tablets prescribing information. Lincolnshire, IL; 2002 July.

197. SmithKline Beecham. Avandia^® (rosiglitazone maleate) tablets prescribing information. Philadelphia, PA; 2002 May

198. Kipnes MS, Krosnick a, Rendell MS et al. Pioglitazone hydrochloride in combination with sulfonylurea therapy improves glycemic control in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study. Am J Med . 2001; 111:10-7. [PubMed 11448655]

199. Pfizer Inc. Glucotrol XL^®(glipizide) extended release tablets prescribing information. New York, NY; 2000 Oct.

200. Chiasson J, Josse R, Hunt J et al. The efficacy of acarbose in the treatment of patients with non-insulin-dependent diabetes mellitus. Ann Intern Med . 1994; 121:929-935.

201. Coniff RF, Shapiro JA, Seaton TB et al. Multicenter, placebo-controlled trial comparing acarbose (BAY g 5421) with placebo, tolbutamide, and tolbutamide-plus-acarbose in non-insulin-dependent diabetes mellitus. Am J Med . 1995; 98:443-51. [PubMed 7733122]

202. Calle-Pascual AL, Garcia-Honduvilla J, Martin-Alvarez PJ et al. Comparison between acarbose, metformin, and insulin treatment in type 2 diabetic patients with secondary failure to sulfonylurea treatment. Diabetes Metab . 1995; 21:256-60.

203. Klein W. Sulfonylurea-metformin-combination versus sulfonylurea-insulin-combination in secondary failures of sulfonylurea monotherapy. Diab Metab. 1991; 17(Suppl 1):235-40.

205. Hermann LS, Melander A. Biguanides: basic aspects and clinical use. In: Alberti KGMM, DeFronzo RA, Keen H et al, eds. International textbook of diabetes mellitus. New York: John Wiley & Sons; 1992; 773-95.

206. Moses R, Carter J, Slobodniuk R et al. Effect of repaglinide addition to metformin monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care . 1999; 22:119-24. [PubMed 10333912]

207. Fonseca V, Rosenstock J, Patwardhan R et al. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. JAMA . 2000; 283:1695-702. [PubMed 10755495]

208. Bristol-Myers Squibb. Metaglip^® (glipizide and metformin hydrochloride) prescribing information. Princeton, NJ; 2002 Oct.

209. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA . 2002; 287:2563-9. [PubMedCentral][PubMed 12020338]

210. Pfizer Inc. Glucotrol XL^®(glipizide) extended release tablets prescribing information. New York, NY; 2001 Apr.

211. Pfizer. Diflucan^® (fluconazole) tablets, for oral suspension, and injection prescribing information. New York, NY; 1998 Jun.

212. Bayer. Precose^® (acarbose) tablets prescribing information. West Haven, CT; 2003 Mar.

213. Nathan DM, Buse JB, Davidson MB et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care . 2006; 29:1963-72. [PubMed 16873813]

214. American Diabetes Association. Preconception care of women with diabetes. Diabetes Care . 2004; 27(Suppl 1):S76-78.

215. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2003 clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes . 2003; 27(Suppl 2):S1-152.

216. Clark CM Jr. Where do we go from here? Ann Intern Med . 1996; 124(1 Part 2):184-6. Editorial.

217. Bloomgarden ZT. New and traditional treatment of glycemia in NIDDM. Diabetes Care . 1996; 19:295-9. [PubMed 8742586]

218. Klein S, Allison DB, Heymsfield SB et al. Waist circumference and cardiometabolic risk: a consensus statement from shaping America's health: Association for Weight Management and Obesity Prevention; NAASO, the Obesity Society; the American Society for Nutrition; and the American Diabetes Association. Diabetes Care . 2007; 30:1647-52. [PubMed 17360974]

219. American Diabetes Association. Summary of revisions for the 2009 clinical practice recommendations. Diabetes Care . 2009; 32:S3-S5. [PubMedCentral][PubMed 19118287]

220. Skyler JS, Bergenstal R, Bonow RO et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Diabetes Care . 2009; 32:187-92. [PubMedCentral][PubMed 19092168]

221. Ismail-Beigi F, Moghissi ES. Glycemia management and cardiovascular risk in type 2 diabetes: an evolving perspective. Endocr Pract . 2008 Jul-Aug; 14:639-43.

222. , Patel A, MacMahon S et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med . 2008; 358:2560-72. [PubMed 18539916]

223. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med . 2008; 358:2545-59. [PubMedCentral][PubMed 18539917]

224. Duckworth W, Abraira C, Moritz T et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med . 2009; 360:129-39. [PubMed 19092145]

225. American Diabetes Association. Aspirin therapy in diabetes: position statement. Diabetes Care . 2001; 24(Suppl.1):S62-3. [PubMedCentral]

226. Zimmerman BR. Preventing long term complications: implications for combination therapy with acarbose. Drugs . 1992; 44(Suppl 3):54-60. [PubMed 1280578]

227. Laakso M. Glycemic control and the risk for coronary heart disease in patients with non-insulin-dependent diabetes mellitus: the Finnish studies. Ann Intern Med . 1996; 124:127-30. [PubMed 8554204]

228. DluhyRG, McMahon GT. Intensive glycemic control in the ACCORD and ADVANCE trials. N Engl J Med . 2008; 358:2630-33. Editorial.

229. Stratton IM, Adler AI, Neil HA et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ . 2000; 321:405-12. [PubMedCentral][PubMed 10938048]

230. Weiss IA, Valiquette G, Schwarcz MD. Impact of glycemic treatment choices on cardiovascular complications in type 2 diabetes. Cardiol Rev . 2009; 17(4):165-75. [PubMed 19525678]

231. Holman RR, Paul SK, Bethel MA et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med . 2008; 359:1577-89. [PubMed 18784090]

232. Nathan DM, Cleary PA, Backlund JY et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med . 2005; 353:2643-53. [PubMedCentral][PubMed 16371630]

233. Actelion Pharmaceuticals US. Tracleer^® (bosentan) tablets prescribing information. South San Francisco, CA; 2011 Feb.

234. American Diabetes Association. Standards of medical care in diabetes--2009. Diabetes Care . 2009; 32 Suppl 1:S13-61.

698. Garber AJ, Handelsman Y, Grunberger G et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm 2020 executive summary. Endocr Pract . 2020; 26:107-139. [PubMed 32022600]

699. Zelniker TA, Wiviott SD, Raz I et al. Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus. Circulation . 2019; 139:2022-2031. [PubMed 30786725]

702. American Diabetes Association. 6. Glycemic targets: Standards of Medical Care in Diabetes—2020. Diabetes Care . 2020; 43(Suppl 1):S66-S76.

704. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes-2020 . Diabetes Care . 2020; 43:S98-S110. [PubMed 31862752]

705. American Diabetes Association. 10. Cardiovascular disease and risk management: Standards of Medical Care in Diabetes-2020 . Diabetes Care . 2020; 43:S111-S134. [PubMed 31862753]

706. American Diabetes Association. 11. Microvascular complications and foot care: Standards of Medical Care in Diabetes-2020 . Diabetes Care . 2020; 43:S135-S151. [PubMed 31862754]