VA Class:HS502

ATC Class:A10BB07

AHFS Class:

• Sulfonylureas 68:20.20

Generic Name(s):

• glipiZIDE

Chemical Name:

• 1-Cyclohexyl-3-[[ p -[2-(5-methylpyrazinecarboxamideo)ethyl]phenyl]sulfonyl]urea

Molecular Formula:

• C₂₁H₂₇N₅O₄S

Glipizide is a sulfonylurea antidiabetic agent.1,2,3

Type 2 Diabetes Mellitus

Glipizide is used as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.1,2,3,19,27,50,51,52,53,54,55,56,57,58,59,60,95 Sulfonylureas, including glipizide, 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.120,127,128,129,130,139,154,155,157,158,161,159,160,161,162,164 Glipizide is commercially available in fixed combination with metformin for use as initial therapy in patients with type 2 diabetes mellitus whose hyperglycemia cannot be controlled by diet and exercise alone and as second-line therapy in patients with type 2 diabetes who are inadequately controlled with either sulfonylurea or metformin monotherapy.153

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.698,704 While addition of a GLP-1 receptor agonist may successfully control hyperglycemia, many patients will eventually require insulin therapy.698 Early introduction of insulin therapy should be considered when hyperglycemia is severe (e.g., blood glucose of at least 300 mg/dL or HbA_1c exceeding 9-10%), especially in the presence of catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis) or symptoms of hyperglycemia.698,704 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.

The manufacturer states that glipizide is not recommended for use in patients with type 1 diabetes mellitus or diabetic ketoacidosis.95,707

Glipizide Monotherapy

Glipizide may be useful in some patients with type 2 diabetes mellitus who have primary or secondary failure to other sulfonylurea antidiabetic agents; however, primary or secondary failure to glipizide also may occur.2,50,51,53,55 Patients with secondary failure to one oral antidiabetic agent occasionally may respond to another agent.62

Secondary failure to sulfonylurea antidiabetic agents is characterized by progressively decreasing diabetic control1,62 following 1 month to several years of good control.62,66 Interim data from a substudy (UKPD 26) of the UKPD study 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.97,98 The failure rate at 6 years was 48% among patients receiving glyburide and about 40% among patients receiving chlorpropamide.98 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.96,97,98,99,105,112,115,116 In another substudy (UKPD 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.116 At diagnosis, risk factors predisposing toward sulfonylurea failure included higher fasting plasma glucose concentrations, younger age, and lower pancreatic β-cell reserve.98,116

In some type 2 diabetic patients who are being treated with insulin, glipizide alone may be effective alternative therapy.1,2,52,54

Combination Therapy with Metformin or Other Oral Antidiabetic Agents

Sulfonylureas 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.153,154,155,156,157,158,161,159,160,164,698,704 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.

Glipizide is used in fixed combination 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.153 In a comparative study in such patients, therapy with the fixed combination of glipizide and metformin was more effective in improving glycemic control (as determined by HbA_1c values, fasting plasma glucose concentrations) than monotherapy with either component.153 A greater percentage of patients receiving the fixed combination achieved strict glycemic control (HbA_1c values below 7%) than did those receiving metformin or glipizide monotherapy.107,153

Glipizide also is used in fixed combination with metformin as second-line therapy in patients with type 2 diabetes whose hyperglycemia is inadequately controlled with either sulfonylurea or metformin monotherapy.153 In a comparative study, greater glycemic control (as determined by HbA_1c values and fasting plasma glucose concentrations) was achieved with the fixed combination of glipizide and metformin than with either drug as monotherapy.153 Strict glycemic control (e.g., HbA_1c values less than 7%)138 also was achieved in a greater percentage of patients receiving the fixed combination of glipizide and metformin.107,153

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.120,127,128,129,130,139,173 Concomitant therapy with insulin (e.g., given as intermediate- or long-acting insulin at bedtime or rapid-acting insulin at meal times)127,128,131,132,134,136,141,173 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.120,127,128,131,132,133,134,135,136,137,138 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 agents.132 However, such combined therapy may increase the risk of hypoglycemic reactions.128,129,132,134,140

Administration

Glipizide is administered orally.1,95 The extended-release tablets should be swallowed whole and should not be divided, chewed, or crushed.95 Patients receiving the extended-release tablets may occasionally notice a tablet-like substance in their stools; this is normal since the tablet containing the drug is designed to remain intact and slowly release the drug from a nonabsorbable shell during passage through the GI tract.95

Extended-release tablets of glipizide are administered once daily, generally with breakfast or the first main meal of the day.95 Conventional (immediate-release) tablets of the drug usually are administered initially as a single daily dose given each morning before breakfast.1 It is generally recommended that glipizide be administered approximately 30 minutes before a meal to achieve the maximum reduction in postprandial blood glucose concentration.1,11,32

Once-daily dosing of glipizide at dosages up to 15-20 mg daily has been shown to provide adequate control of blood glucose concentration throughout the day in most patients with usual meal patterns;1,2,39,40,41,42,43,44 however, some patients may have a more satisfactory response when the drug is administered in 2 or 3 divided doses daily as immediate-release tablets.1,2,11,44,50,51,52,53,54,57,58,59,60 When glipizide dosage exceeds 15-20 mg daily as immediate-release tablets, the drug usually should be administered in divided doses before meals of sufficient caloric content.1,2,59 When a divided-dosing regimen as immediate-release tablets is employed in patients receiving more than 15 mg of glipizide daily, the doses and schedule of administration should be individualized according to the patient's meal pattern and response.1,2,11,44,50,51,52,53,54,57,58,59,60 The manufacturer states that dosages greater than 30 mg daily have been given safely in twice-daily dosing regimens for prolonged periods.1

When given concomitantly with colesevelam, glipizide should be administered at least 4 hours prior to colesevelam.1,95 (See Drug Interactions: Colesevelam.)

Dosage

Type 2 Diabetes Mellitus

Dosage of glipizide must be based on blood and urine glucose determinations and must be carefully individualized to obtain optimum therapeutic effect.1 If appropriate glipizide dosage regimens are not followed, hypoglycemia may be precipitated .27,71

Patients receiving glipizide should be monitored carefully to determine the need for continued therapy and to ensure that the drug continues to be effective; some clinicians state that if adequate lowering of blood glucose concentration is no longer achieved during maintenance therapy, the drug should be discontinued.92 In patients usually well controlled by dietary management alone, short-term therapy with glipizide may be sufficient during periods of transient loss of diabetic control.1

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 recommended initial adult dosage of glipizide as immediate-release or extended-release tablets is 5 mg daily.1,95 In patients who may be predisposed to hypoglycemia (e.g., debilitated, malnourished, or geriatric patients; those with hepatic disease or renal impairment; patients taking other antidiabetic drugs), an initial dosage of 2.5 mg daily is recommended.1,27,71 (See Cautions: Precautions and Contraindications.) Subsequent dosage should be adjusted according to the patient's tolerance and therapeutic response;1 dosage adjustments in increments of 2.5-5 mg daily at intervals of at least several days1 (usually 3-7 days)2,51,54,59,60 are recommended when immediate-release tablets are used.1

Initial Dosage in Patients Transferred from Immediate-release to Extended-release Glipizide Tablets

Patients receiving immediate-release glipizide tablets may be switched to extended-release glipizide tablets by giving the nearest equivalent total daily dose once daily.95

Initial Dosage in Patients Transferred from Other Oral Antidiabetic Agents

A transition period generally is not required when transferring from other oral antidiabetic agents to glipizide, and administration of the other agent may be abruptly discontinued.1 Because of the prolonged elimination half-life of chlorpropamide (no longer commercially available in the US), it has been recommended that patients being transferred from chlorpropamide to glipizide be closely monitored for the occurrence of hypoglycemia during the initial 1-2 weeks of the transition period due to the potential for an overlapping drug effect.1 A drug-free interval of 2-3 days has been advised before glipizide therapy is initiated as immediate-release tablets in patients being transferred from chlorpropamide, particularly if blood glucose concentration was adequately controlled with chlorpropamide.90,92 An initial or loading dose of glipizide is not necessary when transferring from other sulfonylurea antidiabetic agents to glipizide.90,92 The transfer should be performed conservatively.90,92

For the management of type 2 diabetes mellitus in patients previously receiving other sulfonylurea antidiabetic agents, the usual initial dosage of glipizide is 5-10 mg daily, but the initial dosage is variable and must be carefully individualized.90,92 Subsequent dosage is adjusted according to the patient's tolerance and therapeutic response.1 Although an exact dosage relationship between glipizide and other sulfonylurea antidiabetic agents does not exist, approximate dosage equivalencies have been estimated.2,5,15 (See Pharmacology: Antidiabetic Effect.)

Initial Dosage in Patients Transferred from Insulin

In general, patients who were previously maintained on insulin dosages up to 20 units daily may be transferred directly to the usual recommended initial dosage of glipizide, and administration of insulin may be abruptly discontinued.1,95 In patients requiring insulin dosages greater than 20 units daily, the usual recommended initial dosage of glipizide should be started and insulin dosage reduced by 50%.1,95 Subsequently, insulin is withdrawn gradually and dosage of glipizide is adjusted at intervals of at least several days according to the patient's tolerance and therapeutic response.1 During the period of insulin withdrawal, patients should test their urine at least 3 times daily for glucose and ketones, and should be instructed to report the results to their clinician so that appropriate adjustments in therapy may be made, if necessary;1,95 when feasible, patient or laboratory monitoring of blood glucose concentration is preferable.73,94 The presence of persistent ketonuria with glycosuria,93 ketosis,84 and/or inadequate lowering or persistent elevation of blood glucose concentration84 indicates that the patient requires insulin therapy.84,93 In some patients, especially those requiring greater than 40 units of insulin daily, the manufacturer suggests that it may be advisable to consider hospitalization during the transition from insulin to glipizide;1,95 however, some clinicians believe that hospitalization should rarely be necessary.92

Maintenance Dosage

The adult maintenance dosage of glipizide for the management of type 2 diabetes mellitus varies considerably, ranging from 2.5-40 mg daily.1,2,7,27,39,40,41,42,43,44,50,51,52,53,54,56,57,58,59,60 Dosage should be adjusted based on the patient's glycemic control.1,95 Most patients appear to require 5-25 mg daily as immediate-release tablets27,39,40,41,42,43,44,50,51,52,53,54,56,57,58,59,60 or 5-10 mg daily as extended-release tablets, but some clinicians report that higher dosages may be necessary in many patients.7,25,95

Maintenance dosage of glipizide should be conservative in debilitated, malnourished, or geriatric patients; patients receiving other antidiabetic drugs; or patients with impaired renal or hepatic function because of an increased risk of hypoglycemia in these patients.1 (See Cautions: Precautions and Contraindications.) The maximum recommended dosage is 40 mg daily as immediate-release tablets1 or 20 mg daily as extended-release tablets.95

Combination Therapy with Other Oral Antidiabetic Agents

Glipizide may be used in combination with other oral antidiabetic agents if glycemic control is inadequate with glipizide, either upon initiation of therapy or after a period of effectiveness.95,154,155,158,157 The second oral antidiabetic agent should be added to glipizide at the lowest recommended dosage, and patients should be observed carefully.95,154,155 Titration of the additional oral antidiabetic agent should be based on clinical judgment.95

When glipizide is added to therapy with other antidiabetic agents, glipizide extended-release tablets should be initiated at a dosage of 5 mg daily.95 Initiation of therapy with glipizide extended-release tablets at a lower dosage may be appropriate in patients who may be more sensitive to oral hypoglycemic agents.95

If the fixed combination of glipizide and metformin is used as initial therapy, the recommended initial dosage is 2.5 mg of glipizide and 250 mg of metformin hydrochloride once daily with a meal.153 In patients with more severe hyperglycemia (i.e., fasting plasma glucose concentrations of 280-320 mg/dL), an initial dosage of 2.5 mg of glipizide and 500 mg of metformin hydrochloride twice daily may be considered.153 Dosage may be increased in increments of one tablet153 (using the tablet strength at which therapy was initiated, either 2.5 mg glipizide/250 mg metformin hydrochloride or 2.5 mg glipizide/500 mg metformin hydrochloride)163 daily every 2 weeks until the minimum effective dosage required to achieve adequate glycemic control or a maximum daily dosage of 10 mg of glipizide and 2 g of metformin hydrochloride given in divided doses is reached.153 A total daily dosage exceeding 10 mg of glipizide and 2 g of metformin hydrochloride has not been evaluated in clinical trials in patients receiving the fixed-combination preparation as initial therapy.153 The efficacy of glipizide in fixed combination with metformin hydrochloride has not been established in patients with fasting plasma glucose concentrations exceeding 320 mg/dL.153

When the commercially available fixed-combination preparation is used as second-line therapy in patients with type 2 diabetes mellitus whose blood glucose is not adequately controlled by therapy with a sulfonylurea antidiabetic agent or metformin alone, the recommended initial dosage in previously treated patients is 2.5 or 5 mg of glipizide and 500 mg of metformin hydrochloride twice daily with the morning and evening meals.153 In order to minimize the risk of hypoglycemia, the initial dosage of glipizide and metformin hydrochloride in fixed combination should not exceed the daily dosage of glipizide or metformin hydrochloride already being taken.153 The dosage of glipizide and metformin hydrochloride in fixed combination should be titrated upward in increments not exceeding 5 mg of glipizide and 500 mg of metformin hydrochloride until adequate glycemic control or a maximum daily dosage of 20 mg of glipizide and 2 g of metformin hydrochloride is reached.153

For patients being switched from combination therapy using separate preparations of glipizide (or another sulfonylurea antidiabetic agent) and metformin, the initial dosage of the fixed-combination preparation should not exceed the daily dosages of glipizide (or equivalent dosage of another sulfonylurea) and metformin hydrochloride currently being taken.153,158 Such patients should be monitored for signs and symptoms of hypoglycemia following the switch.153 In the transfer from previous antidiabetic therapy to the fixed combination of glipizide and metformin hydrochloride, the decision to switch to the nearest equivalent dosage or to titrate dosage is based on clinical judgment.153 Hypoglycemia or hyperglycemia is possible in such patients, and any change in the therapy of patients with type 2 diabetes mellitus should be undertaken with appropriate monitoring.153 The safety and efficacy of switching from combined therapy with separate preparations of glipizide (or another sulfonylurea antidiabetic agent) and metformin hydrochloride to the fixed-combination preparation containing these drugs have not been established in clinical studies.153

When glipizide is used in fixed combination with metformin, the cautions, precautions, and contraindications associated with metformin must be considered in addition to those associated with glipizide.153

Cardiovascular Effects

Several large, long-term studies have evaluated the cardiovascular risks associated with the use of oral sulfonylurea antidiabetic agents.1,95,60,61,62,63,96,97,100,113 In 1970, the University Group Diabetes Program (UGDP) reported that administration of oral antidiabetic agents (i.e., tolbutamide or phenformin [no longer commercially available in the US]) was associated with increased cardiovascular mortality as compared to treatment with dietary regulation alone or with dietary regulation and insulin.1,75,95 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;1,75,95 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.1,75,95 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.62,64,72,75 However, results from the United Kingdom Prospective Diabetes (UKPD) study, 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 less intensive conventional antidiabetic therapy.96,97,99,100

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).96,97 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.97,100 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.96 As a result of these and other findings (e.g., beneficial effects on microvascular [retinopathy, nephropathy, and possibly neuropathy] complications, confirmation of the beneficial effects of concomitant antihypertensive therapy and blood pressure lowering) of the UKDP study, the American Diabetes Association (ADA) currently considers the beneficial effects of intensive glycemic control with insulin or sulfonylureas and blood pressure control in diabetic patients to outweigh the risks overall.97,107,113

Hypoglycemia

Hypoglycemia may occur in patients receiving glipizide alone or in fixed combination with metformin.1,2,27,50,54,58,60,70,95,153 Hypoglycemia (defined as blood glucose of less than 60 mg/dL or symptoms associated with hypoglycemia) occurred in 3.4% of patients receiving glipizide extended-release tablets in clinical trials.95 Appropriate patient selection and careful attention to dosage are important to avoid glipizide-induced hypoglycemia .1,27,71 (See Cautions: Precautions and Contraindications.) Hypoglycemia may occur as a result of excessive glipizide dosa 1,27 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.1,2,27,50,54,58,60,71 Although glipizide-induced hypoglycemia has been reported infrequently and has usually been mild,2,27,50,58,59,60 severe hypoglycemia has occurred, principally in patients with predisposing conditions (e.g., impaired renal and/or hepatic function).27,70

Management of glipizide-induced hypoglycemia depends on the severity of the reaction;1,71 patients with severe reactions require immediate hospitalization and treatment and observation until complete recovery is assured.1,70,71 Because of glipizide's elimination characteristics, the risk of prolonged hypoglycemia is likely to be low.90,91 Hypoglycemia is usually,1,27,50 but not always,70 readily controlled by administration of glucose. If hypoglycemia occurs during therapy with the drug, immediate reevaluation and adjustment of glipizide dosage and/or the patient's meal pattern are necessary.1,2,27

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

Other Endocrine and Metabolic Effects

Therapy with sulfonylureas, including glipizide, may be associated with weight gain.142,143,144 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.142,143,144 Data from the United Kingdom Prospective Diabetes (UKPD) study in patients receiving long-term therapy (over 10 years) 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 those receiving glyburide.96

GI Effects

Adverse GI effects such as nausea,1,50 anorexia,50 vomiting,50 pyrosis,50 gastralgia,1 diarrhea,1 and constipation1 are the most common adverse reactions to glipizide immediate-release tablets, occurring in about 1-2% of patients.1,2,50 Diarrhea or flatulence occurred in 5 or 3%, respectively, of patients receiving extended-release glipizide tablets in controlled clinical trials.95 Diarrhea was reported in 2.3-5.2 or 8.5% of patients receiving the fixed combination of glipizide and metformin or metformin monotherapy, respectively, as initial therapy for type 2 diabetes mellitus, and in 18.4 or 17.3% of patients receiving the fixed combination of glipizide and metformin or metformin monotherapy, respectively, as second-line therapy.153 Abdominal pain occurred in 5.7 or 6.7% of patients receiving the fixed combination of glipizide and metformin or metformin monotherapy, respectively, in clinical trials as second-line therapy for type 2 diabetes mellitus;153 abdominal pain also has been reported with extended-release glipizide during postmarketing experience.95 Nausea, dyspepsia, constipation, or vomiting occurred in less than 3% of patients receiving extended-release glipizide tablets in clinical trials.95 Anorexia, thirst, or trace blood in the stool has been reported in less than 1% of patients receiving extended-release glipizide in clinical trials; GI irritation or bleeding also has been reported with the extended-release tablets during postmarketing experience.95 Nausea or vomiting was reported in 0.6-1.7 or 5.1% of patients receiving the fixed combination of glipizide and metformin or metformin monotherapy, respectively, as initial therapy for type 2 diabetes mellitus, and in 8% of patients receiving either the fixed combination of glipizide and metformin or metformin monotherapy as second-line therapy.153 Glipizide-induced adverse GI effects appear to be dose related and may subside following a reduction in dosage or administration of the drug in divided doses.1,2

Dermatologic Effects

Allergic skin reactions including pruritus, erythema, eczema, urticaria, and morbilliform or maculopapular eruptions occur in about 1.5% of patients receiving glipizide immediate-release tablets.1,50 Urticaria has been reported in less than 1.5% of patients receiving extended-release glipizide tablets in clinical trials but more often with glipizide treatment than with placebo; rash has also been reported.95 Glipizide-induced adverse dermatologic effects may be transient and disappear despite continued therapy; however, if adverse dermatologic effects persist with continued glipizide therapy, the drug should be discontinued.1,95 Photosensitivity reactions and porphyria cutanea tarda have been reported with other sulfonylurea antidiabetic agents.1

Hepatic Effects

Cholestatic and hepatocellular forms of liver injury accompanied by jaundice have been reported rarely during postmarketing experience; glipizide should be discontinued if such adverse effects occur.1,95 Although a causal relationship has not been established, mild to moderate increases in serum LDH, AST (SGOT), and alkaline phosphatase concentrations have occurred occasionally in patients receiving glipizide.1 Hepatic porphyria and disulfiram-like reactions have been reported with extended-release glipizide during postmarketing experience.95

Hematologic Effects

Like other sulfonylurea antidiabetic agents, glipizide may rarely cause leukopenia, thrombocytopenia, pancytopenia, agranulocytosis, aplastic anemia, and hemolytic anemia.1,95 Patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency who receive sulfonylureas (e.g., glipizide) may develop hemolytic anemia.1 In patients with G6PD deficiency, a non-sulfonylurea antidiabetic agent should be considered.1 Hemolytic anemia also has been reported with glipizide therapy during postmarketing experience in patients who did not have known G6PD deficiency.1

Nervous System Effects

Dizziness, drowsiness, and headache have been reported in about 2% of patients receiving glipizide immediate-release tablets,1,90 usually as manifestations of mild hypoglycemia.90 Asthenia, headache, dizziness, nervousness, pain, or tremor has been reported in 10, 9, 7, or 4% of patients receiving glipizide extended-release tablets in controlled clinical trials.95 Headache has been reported in 12.6 or 5.3% of patients receiving the fixed combination of glipizide and metformin or metformin monotherapy, respectively, as second-line therapy for type 2 diabetes mellitus.153 Dizziness has been reported in 1.7-5.2 or 1.1% of patients receiving the fixed combination of glipizide and metformin or metformin monotherapy, respectively, in clinical trials as initial therapy for type 2 diabetes mellitus.153 Insomnia, paresthesia, anxiety, depression, and hypoesthesia have been reported in less than 3% of patients receiving glipizide extended-release tablets in clinical trials.95 Chills, hypertonia, confusion, vertigo, somnolence, or gait abnormality has been reported in less than 1% of patients receiving extended-release glipizide in clinical trials.95

Macrovascular Outcomes

The manufacturer states that there are no clinical studies that conclusively establish macrovascular risk reduction with glipizide or any other antidiabetic drug.95

Other Adverse Effects

Arthralgia, leg cramps, or myalgia has been reported in less than 3% of patients receiving extended-release glipizide in clinical trials.95 Musculoskeletal pain has been reported in 8 or 6.7% of patients receiving the fixed combination of glipizide and metformin or metformin monotherapy, respectively, as second-line therapy for type 2 diabetes mellitus. 153 Syncope has been reported in less than 3%, and arrhythmia, migraine, flushing, hypertension, or edema has been reported less than 1% of patients receiving extended-release glipizide tablets in clinical trials.95 Hypertension has been reported in 2.9-3.5 or 5.6 % of patients receiving glipizide in fixed combination with metformin or metformin alone, respectively, as initial therapy for type 2 diabetes mellitus. 153 Rhinitis has reported in less than 3%, and pharyngitis or dyspnea has been reported in than 1% of patients receiving extended-release glipizide tablets in clinical trials.95 Upper respiratory tract infection was reported in 8.1-9.9 or 8.5% of patients receiving the fixed combination of glipizide and metformin or metformin monotherapy, respectively, as initial therapy for type 2 diabetes mellitus, and in 10.3 or 10.7% of patients receiving the fixed combination of glipizide and metformin or metformin monotherapy, respectively, as second-line therapy.153 Blurred vision has been reported in less than 3%, and ocular pain, conjunctivitis, or retinal hemorrhage has been reported in less than 1% of patients receiving extended-release glipizide tablets in clinical trials.95 Although a causal relationship has not been established, mild to moderate increases in BUN and serum creatinine concentration have occurred occasionally in patients receiving glipizide.1 Urinary tract infection has been reported in 1.1 or 8% of patients receiving the fixed combination of glipizide and metformin or metformin monotherapy, respectively, as second-line therapy for type 2 diabetes mellitus. 153 Decreased libido or polyuria has been reported in less than 3%, and dysuria has been reported in less than 1% of patients receiving extended-release glipizide tablets in clinical trials.95

Like other sulfonylureas, hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) have occurred in patients receiving glipizide.1,95

Precautions and Contraindications

Glipizide shares the toxic potentials of other sulfonylurea antidiabetic agents, and the usual precautions associated with their use should be observed.1,2,3,72 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 glipizide.1,2,3,62 Glipizide 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.1,2,3,65

Patients receiving glipizide should be monitored with regular clinical and laboratory evaluations, including blood and 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 Glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) measurements may also be useful for monitoring the patient's response to glipizide therapy.1 During the withdrawal period in patients in whom glipizide is replacing insulin, patients should be instructed to test their urine for glucose and ketones at least 3 times daily, and to report the results to their physician;1 when feasible, patient or laboratory monitoring of blood glucose concentration is preferable.62,73,94 Care should be taken to avoid ketosis, acidosis, and coma during the withdrawal period in patients being switched from insulin to glipizide.84 If adequate lowering of blood glucose concentration is no longer achieved during maintenance therapy with glipizide, the drug should be discontinued.1 When use of glipizide 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 There is limited evidence that sulfonylureas may reverse basement-membrane thickening of muscle capillaries in asymptomatic individuals with impaired glucose tolerance and possibly reverse or retard the progression of microangiopathy in type 2 diabetic patients.68,74

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.84 Patients should be informed of the potential risks and advantages of glipizide 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 glipizide therapy is only used as an adjunct to, and not a substitute for or a convenient means to avoid, proper dietary regulation.1 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.84 Primary and secondary failure to oral sulfonylurea antidiabetic agents should also be explained to patients.1

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 occasionally occur during therapy with glipizide.1 Appropriate patient selection and careful attention to dosage are important to avoid glipizide-induced hypoglycemia .1,27,71 Debilitated, malnourished, or geriatric patients and patients with impaired hepatic or renal function should be carefully monitored and dosage of glipizide should be carefully adjusted in these patients, since they may be predisposed to developing hypoglycemia (sometimes severe).1,27,71 Renal or hepatic insufficiency may cause increased serum concentrations of glipizide and hepatic insufficiency may also diminish gluconeogenic capacity, both of which increase the risk of severe hypoglycemic reactions.1,71 Alcohol ingestion, severe or prolonged exercise, deficient caloric intake, use of more than one antidiabetic agent, and adrenal or pituitary insufficiency may also predispose patients to the development of hypoglycemia.1 The patient's ability to concentrate or react may be impaired as a result of hypoglycemia.95 Hypoglycemia may be difficult to recognize in geriatric patients or in patients receiving β-adrenergic blocking agents.1 In such situations, severe hypoglycemia may occur before the patient is aware of the condition.95 Severe hypoglycemia can lead to unconsciousness or seizures and may result in temporary or permanent impairment of brain function or death.95 Intensive treatment (e.g., IV dextrose) and close medical supervision may be required in some patients who develop severe hypoglycemia during glipizide therapy.1,70 (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 glipizide and administration of insulin may be required.1,2

Obstructive symptoms have been reported in patients with known GI strictures in association with ingestion of another drug with the nondissolvable extended-release formulation used in glipizide extended-release tablets.95 Use of extended-release glipizide tablets should be avoided in patients with severe preexisting GI narrowing (pathologic or iatrogenic).95

The inert portion of glipizide extended-release tablets is not absorbed and is excreted in feces where it may be noticeable.95

Glipizide is contraindicated in patients with known hypersensitivity to the drug1,95 or any ingredients in the formulation95 or to sulfonamide derivatives.95

Pediatric Precautions

The manufacturer states that safety and efficacy of glipizide alone or in fixed combination with metformin in children have not been established.1,153 However, 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.117

Geriatric Precautions

Safety and efficacy of glipizide extended-release tablets in geriatric patients have not been specifically studied to date; however, in clinical studies of the drug, approximately 33% of patients were 65 years of age or older.95 It has not been determined whether clinical trials of glipizide immediate-release tablets did not include sufficient numbers of patients 65 years and older to determine whether they respond differently than younger adults.1 Although no overall differences in safety or efficacy were observed between geriatric and younger patients in clinical studies of glipizide extended-release tablets, the possibility that some older patients may exhibit increased sensitivity cannot be ruled out. 95 Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in geriatric patients, the manufacturer suggests that patients in this age group receive initial dosages of the drug in the lower end of the usual range.1 Geriatric patients should be carefully monitored and dosage of glipizide should be conservative and carefully adjusted in these patients, since they may be predisposed to developing hypoglycemia (sometimes severe).1,27,71,95

Mutagenicity and Carcinogenicity

It is not known if glipizide is mutagenic or carcinogenic in humans. The drug did not exhibit mutagenic activity in the Ames microbial mutagen test1,90 or in vivo in animal tests.1,76 Evidence of carcinogenicity was not observed in rats or mice receiving up to 75 times the maximum human dosage of glipizide daily for 20 or 18 months, respectively.1

Pregnancy, Fertility, and Lactation

Pregnancy

The manufacturer states that available data from a small number of published studies and postmarketing experience with use of extended-release glipizide in pregnancy over decades have not identified any drug-associated risks for major birth defects, miscarriage, or adverse maternal outcomes.95 Glipizide has been shown to be mildly fetotoxic in rats when given at doses of 5-50 mg/kg; the fetotoxic effect is perinatal and similar to that of some other sulfonylureas, and is believed to be directly related to the hypoglycemic effect of the drug.1 There were no effects on embryofetal development following administration of glipizide to pregnant rats and rabbits during organogenesis at doses 833 and 8 times, respectively, the human dose based on body surface area.95 No teratogenic effects were observed in reproduction studies in rats or rabbits.1 However, increased pup mortality was observed in rats given glipizide from gestation day 15 throughout lactation at dosages twice the maximum human dose based on body surface area.95

Poorly controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, miscarriage, preterm delivery, stillbirth, and delivery complications.95 In addition, poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity.95 Many experts recommend that insulin be used during pregnancy to maintain optimum control of blood glucose concentration.1 Use of glipizide in pregnant women is generally not recommended,2,65 and the drug should be used during pregnancy only when clearly necessary1 (e.g., when insulin therapy is infeasible).

Neonates born to women with gestational diabetes that was treated with sulfonylureas during pregnancy may be at increased risk for neonatal intensive care admission and may develop respiratory distress, hypoglycemia, or birth injury; they also may be large for gestational age.95 Sulfonylureas, including glipizide, cross the placenta and have been associated with neonatal adverse reactions such as hypoglycemia.95 Prolonged, severe hypoglycemia lasting 4-10 days has been reported in some neonates born to women who were receiving sulfonylurea antidiabetic agents up to the time of delivery; this effect has been reported more frequently with the use of those agents having prolonged elimination half-lives.1 To minimize the risk of neonatal hypoglycemia if glipizide is used during pregnancy, the manufacturer recommends that the drug be discontinued at least 2-4 weeks before the expected delivery date.1 Neonates should be observed for symptoms of hypoglycemia and respiratory distress and managed accordingly.95

Fertility

Reproduction studies in rats using glipizide doses up to 75 times the usual human dose have not revealed evidence of impaired fertility.1

Lactation

Although it is not known whether glipizide is distributed into milk in humans, some sulfonylurea antidiabetic agents are distributed into milk.1 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 If glipizide is used during breast-feeding, infants should be monitored for signs of hypoglycemia (e.g., jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, seizures).95 If glipizide is discontinued, and if dietary management alone is inadequate for controlling blood glucose concentration, administration of insulin should be considered.1

Protein-bound Drugs

Because glipizide 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, and sulfonamides.1,2,47,72,80 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 glyburide, the protein binding of glipizide is principally nonionic;46,47 in addition, glipizide appears to bind to different but closely related sites on serum albumin than does tolbutamide.47 Consequently, glipizide 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.46 In vitro studies indicate that glipizide does not displace dicumarol or salicylate from plasma proteins.1 Whether any differences in protein binding demonstrated in vitro will result in fewer clinically important drug interactions in vivo has not been established.1 There appears to be no clinically important interaction between indoprofen and glipizide.81,82 Patients receiving highly protein-bound drugs should be observed for adverse effects when glipizide therapy is initiated or discontinued and vice versa.1

Drugs That May Alter the Hypoglycemic Effect of Sulfonylureas

Drugs that may enhance the hypoglycemic effect of sulfonylurea antidiabetic agents, including glipizide, include other antidiabetic agents,95 angiotensin-converting enzyme (ACE) inhibitors,95 angiotensin II receptor antagonists,95 chloramphenicol,1,2,62,72,80,95 coumarins,95 disopyramide,95 fibric acid derivatives,95 fluoxetine,95 histamine H₂-receptor antagonists,95 monoamine oxidase (MAO) inhibitors,1,2,72,80 nonsteroidal anti-inflammatory agents (NSAIAs),95 pentoxifylline,95 pramlintide,95 probenecid,1,72,80,95 propoxyphene,95 quinolones,95 salicylates,95 somatostatin analogs (e.g., octreotide),95 sulfonamide antibiotics,95 and voriconazole.95 When these drugs are administered or discontinued in patients receiving glipizide, the patient should be observed closely for hypoglycemia or loss of diabetic control, respectively.1 When glipizide was administered to counter the hyperglycemic effect of diazoxide in several severely hypertensive nondiabetic patients with impaired renal function, hypoglycemic reactions resulted, prompting some clinicians to recommend that the drugs not be used concomitantly in such circumstances.87

Drugs that may decrease the hypoglycemic effect of sulfonylurea antidiabetic agents, including glipizide, include atypical antipsychotic agents (e.g., olanzapine, clozapine),95 calcium-channel blockers,1 corticosteroids,1,72,80,95 danazol,95 diuretics (e.g., furosemide),1,72,80,95 estrogens,1,72 glucagon,95 isoniazid,1 niacin,1,72 oral contraceptives,1,72,80 phenothiazines,1,72,80 progestogens,95 protease inhibitors,95 somatropin,95 sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline),1,72 thyroid hormones,1,72,80,95 phenytoin,1,72 and rifampin.72,80 When these drugs are administered or discontinued in patients receiving glipizide, the patient should be observed closely for loss of diabetic control or hypoglycemia, respectively.1,95

Preliminary data suggest that glipizide may reduce the rate and/or extent of absorption of concomitantly administered oral xylose in type 2 diabetic patients.88

Alcohol, β-adrenergic blockers (see Drug Interactions: β-Adrenergic Blocking Agents), clonidine, or reserpine may either potentiate or weaken the hypoglycemic effect of glipizide.95 In addition, the signs of hypoglycemia may be reduced or absent in patients receiving sympatholytic drugs such as β-adrenergic blocking agents, clonidine, guanethidine, or reserpine.95 An increased frequency of monitoring may be required when glipizide is given concomitantly with these drugs.95

Beta-Adrenergic Blocking Agents

Several potential interactions between β-adrenergic blocking agents and sulfonylurea antidiabetic agents exist.62,72,80β-Adrenergic blocking agents may impair glucose tolerance;62,72,80 increase the frequency or severity of hypoglycemia;62,72,80 block hypoglycemia-induced tachycardia, but not hypoglycemic sweating which may actually be increased;72,80 delay the rate of recovery of blood glucose concentration following drug-induced hypoglycemia;62,72,80 alter the hemodynamic response to hypoglycemia, possibly resulting in an exaggerated hypertensive response;62,80 and possibly impair peripheral circulation.62,80 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.62,72,80 In one study in type 2 diabetic patients, tolbutamide-induced insulin secretion was not affected by short-term propranolol therapy, but the hypoglycemic action of a single dose of glipizide in conjunction with an oral glucose load appeared to be slightly reduced.86 It generally is recommended that concomitant use of β-adrenergic blocking agents and sulfonylurea antidiabetic agents be avoided when possible;72,80 if concomitant therapy is necessary, use of a β₁-selective adrenergic blocking agent may be preferred.62,72 When glipizide and a β-adrenergic blocking agent are used concomitantly, the patient should be monitored closely for altered antidiabetic response.80

Alcohol

Disulfiram-like reactions have occurred very rarely following the concomitant use of alcohol and glipizide.1,58,85

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 glipizide and/or hypoglycemia.95 In a study in healthy individuals, the area under the plasma concentration-time curve (AUC) of glipizide increased by 57% following concomitant administration with fluconazole (100 mg daily for 7 days).95 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.165 (See Drug Interactions: Sulfonylurea Antidiabetic Agents in Fluconazole in 8:14.08).

Cimetidine

Preliminary data indicate that cimetidine may potentiate the hypoglycemic effects of glipizide.83 The exact mechanism(s) of this interaction is not known, but cimetidine may inhibit hepatic metabolism of the sulfonylurea.83 Oral cimetidine has been shown to substantially increase the area under the plasma glipizide concentration-time curve and was associated with a substantial reduction in the postprandial increase in blood glucose concentration in diabetic patients receiving the drugs concomitantly.83 If cimetidine is administered concomitantly with glipizide, the patient should be closely monitored for signs and symptoms of hypoglycemia;83 dosage adjustment of glipizide may be necessary when cimetidine therapy is initiated or discontinued.

Colesevelam

Concomitant administration of colesevelam and extended-release glipizide in healthy individuals has resulted in reductions in glipizide AUC and peak plasma concentrations of 12 and 13%, respectively.1 Substantial changes in AUC and peak plasma concentrations were not observed when extended-release glipizide was administered 4 hours prior to colesevelam.1 The manufacturer states that glipizide should be administered at least 4 hours prior to colesevelam to avoid reductions in glipizide absorption.1

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.72,80,84 When thiazide diuretics are administered concomitantly with sulfonylurea antidiabetic agents, caution should be used.72,80,84

Acute Toxicity

Pathogenesis

There is no well documented experience to date with glipizide overdosage.1 The oral LD₅₀ of the drug was greater than 4 g/kg in all animal species tested.1 Acute glipizide toxicity may result from excessive dosage,1,27 and numerous conditions may predispose patients to the development of glipizide-induced hypoglycemia.1,27,71 (See Cautions: Precautions and Contraindications.) Severe glipizide-induced hypoglycemia has reportedly occurred almost exclusively in patients with predisposing conditions (e.g., impaired renal and/or hepatic function).27,70

Manifestations

Acute glipizide overdosage is manifested principally as hypoglycemia, which is usually mild2,27,50,58,59,60 but occasionally may be severe.1,27,70 Severe sulfonylurea-induced hypoglycemia may result in loss of consciousness1,27,70,71 and seizures,1 with resultant neurologic sequelae.1 Because of glipizide's elimination characteristics, the risk of prolonged hypoglycemia is likely to be low.90,91 In some cases, hypoglycemia may persist despite continuous IV administration of dextrose.70

Treatment

Treatment of acute glipizide overdosage consists principally of administration of glucose and supportive therapy.1,27,70,71 The patient should be monitored closely until complete recovery is assured .1,70,71

Patients with mild hypoglycemic symptoms without loss of consciousness or adverse neurologic effects should be treated aggressively with orally administered glucose, and glipizide dosage and/or the patient's meal pattern should be appropriately adjusted.1,2,27 Severe glipizide-induced hypoglycemia with coma, seizures, or other neurologic impairment occurs infrequently, but constitutes a medical emergency requiring immediate hospitalization and treatment.1,70,71 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 greater than 100 mg/dL.1,71 In some patients, subsequent administration of IV glucagon and/or corticosteroids may also be necessary.70,71 Blood glucose concentrations should be monitored at least every 3 hours during the first 24 hours and as often as necessary thereafter.71 Care should be taken to avoid inducing excessive hyperglycemia.77 Other symptomatic therapy (e.g., anticonvulsants) should be administered as necessary. Glipizide is effectively adsorbed by activated charcoal in vitro.78 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.79 Because glipizide is highly protein bound, dialysis is not likely to enhance elimination of the drug.1 Since hypoglycemia may occur after apparent clinical recovery, patients must be closely monitored for at least 24-48 hours;1,70,90 in patients with substantial renal or hepatic dysfunction, longer periods of monitoring may be necessary.90

Pharmacology

Antidiabetic Effect

Like other sulfonylurea antidiabetic agents, glipizide lowers blood glucose concentration in diabetic and nondiabetic individuals.2,3,5,6,7,8,9,10,11,12,13 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.3,5,7,10,11,12,13,14 On a weight basis, glipizide is one of the most potent of the sulfonylurea antidiabetic agents;2,3,5 although an exact dosage relationship does not exist, a daily glipizide dose of 5 mg controls blood glucose concentration to approximately the same degree as daily doses of glyburide 2.5-5 mg2,5,15 or tolbutamide 0.5-1 g.2,5

The precise mechanism(s) of hypoglycemic action of sulfonylurea antidiabetic agents has not been clearly established, but the drugs, including glipizide, initially appear to lower blood glucose concentration principally by binding to the sulfonylurea receptor in the pancreatic beta cell plasma membrane, leading to closure of the ATP-sensitive potassium channel and stimulating the release of insulin.1,2,3,5,7,8,9,10,11,12,13,95 Glipizide also appears to enhance peripheral insulin action7,10,12 at postreceptor (probably intracellular) site(s)16,17,18 during short-term therapy. Like other sulfonylureas, glipizide alone is ineffective in the absence of functioning beta cells.1,3

The mechanism(s) of action of glipizide during prolonged administration has not been fully established.1,2,3,7,8,10,12,13,16 The glipizide-induced increase in glucose- or meal-stimulated secretion of endogenous insulin appears to be sustained during prolonged administration1,10,12,95 and has persisted in most diabetic patients for up to at least 2 years.12,55 The prolonged effect of glipizide on secretion of endogenous insulin is unlike that of most other sulfonylureas, but its clinical importance in the long-term efficacy of the drug remains to be clearly determined;7,8,12,55,66 while this effect likely contributes to the improvement in glucose tolerance in many patients during prolonged glipizide therapy,7,8,12,55 it alone does not appear to be sufficient for a long-term, effective response to the drug55 and glucose tolerance can improve in some patients without an increase in insulin secretion.12 Fasting plasma insulin concentrations are usually not increased during prolonged glipizide therapy1,19 but have been reported to be slightly increased in some patients.7,8 The drug generally does not appear to alter glucagon secretion.20,21,22 During prolonged administration of sulfonylureas, including glipizide, extrapancreatic effects appear to substantially contribute to the hypoglycemic action of the drugs.3,5,7,8,10,12,13,14,16,17,23,24 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;3,5,7,8,13,14,16,17,23,24 however, the nature of the long-term hypoglycemic effect and the mechanism(s) involved remain to be fully elucidated.3,5,7,8,10,12,13,14,16,17,18,23,24 There is evidence that glipizide enhances the peripheral action of insulin7,8,10,12,13 at postreceptor (probably intracellular) site(s)16,17,18 during long-term administration, and this appears to be a principal mechanism of action during prolonged therapy.7,8,10,12,13 An increase in insulin binding in erythrocytes obtained from diabetic patients receiving long-term therapy with the drug has also been reported.21

Other Effects

In patients with type 2 diabetes mellitus, glipizide-induced improvement in plasma glucose concentration is associated with a reduction in plasma total2,8,25 and very low-density lipoprotein (VLDL)8,25 triglyceride concentrations and plasma low-density lipoprotein (LDL) cholesterol concentration;8,25 mean serum or plasma total,2,8,25,26,27 LDL,8,25 and high-density lipoprotein (HDL)8,25 cholesterol concentrations generally do not appear to be changed during therapy with the drug, but the ratio of plasma HDL cholesterol to total cholesterol may be slightly increased.8,25 The effects of glipizide on plasma lipids are apparently secondary to improved control of plasma glucose concentration.8,25,90

Glipizide has been reported to slightly enhance renal free water clearance in healthy individuals, possibly by increasing electrolyte reabsorption in the loop of Henle.28

In vitro, glipizide reportedly inhibits platelet aggregation induced by collagen or adenosine diphosphate (ADP).29 The effect, if any, of the drug on platelet aggregation in vivo has not been determined to date.

Pharmacokinetics

Absorption

Glipizide is rapidly and essentially completely absorbed from the GI tract.1,30,31,32,33,34,35,36,37,38 First-pass metabolism of glipizide appears to be minimal,1,30 and the absolute oral bioavailability of the drug is reported to be 80-100%.30,31 Food delays the absorption of glipizide but does not affect peak serum concentrations achieved or the extent of absorption of the drug.32,33

Following oral administration of a single 5-mg dose of glipizide as conventional (immediate-release) tablets in fasting and nonfasting individuals, the drug appears in plasma or serum within 15-30 minutes and average peak plasma or serum concentrations of approximately 310-450 ng/mL usually are attained within 1-3 hours (range: 1-6 hours).9,30,31,32,33,34,35,36,39 Peak serum concentrations generally are delayed 20-40 minutes in the nonfasting state compared with the fasting state.32,33 A few reports indicate that biphasic peak serum concentrations may occur in some patients, suggesting that the drug may undergo enterohepatic circulation.30,39 The area under the serum concentration-time curve (AUC) for glipizide increases in proportion to increasing doses.30,31,38 Time to reach steady-state plasma glipizide concentrations following administration of glipizide extended-release tablets was delayed by 1-2 days in geriatric patients compared with younger patients.95

Following administration of glipizide extended-release tablets in men with type 2 diabetes mellitus and patients younger than 65 years of age, steady-state plasma glipizide concentrations were achieved by at least the fifth day of dosing.95

Following single oral doses of glipizide as immediate-release tablets in nonfasting diabetic or healthy individuals, plasma insulin concentration generally begins to increase within 10-30 minutes and is maximal within 0.5-2 hours;11,32,33,36,38,39 increased plasma insulin concentrations generally do not persist beyond the time of the meal challenge.1,32,33,36,39 Following single oral doses in fasting healthy individuals, the hypoglycemic action of glipizide generally begins within 15-30 minutes and is maximal within 1-2 hours.6,32,33 In nonfasting diabetic patients, the hypoglycemic action of a single morning dose of the drug may persist for up to 24 hours.1,39,40,41,42,43,44 Although a correlation between the plasma concentration of glipizide and its hypoglycemic effect has not been established, plasma insulin concentration was increased only when the plasma glipizide concentration was 200 ng/mL or higher in one study.9

Distribution

Distribution of glipizide into human body tissues and fluids has not been fully characterized.2,30,34,37 Following IV administration of glipizide in mice, highest concentrations of the drug were attained in the liver and blood, with lower concentrations in the lungs, kidneys, adrenals, myocardium, salivary glands, and retroscapular fat; the drug was not detected in the brain or spinal cord.45 In humans, small amounts of glipizide are apparently distributed into bile30,34,37 and very small amounts are distributed into erythrocytes and saliva.30 Although glipizide apparently did not cross the placenta in mice in one study,1,45 the drug was detected in the fetuses of pregnant rats given the drug.1,2 It is not known if glipizide is distributed into milk in humans.1

Following IV administration in humans, glipizide undergoes rapid distribution.30,31,37 Following IV administration of the drug, the volumes of distribution in the central compartment and at steady-state average 4.2-4.6 L (range: 3.5-13.2 L) and 10.2-11.7 L (range: 4.6-15.1 L), respectively,30,31 suggesting that the drug is distributed principally within extracellular fluid.1,30,31,35,36 Although pharmacokinetic data from one single-dose study suggest that glipizide might accumulate in a deep tissue compartment,35 data from other single-dose studies suggest that the drug does not accumulate in tissue depots.30,31

At a concentration of 9-612 ng/mL, glipizide is approximately 92-99% bound to plasma proteins.30,34,36,46 Glipizide has a lower affinity for binding to serum albumin than does glyburide.47 Unlike the protein binding of some other sulfonylurea antidiabetic agents (e.g., tolbutamide) and like that of glyburide, the protein binding of glipizide appears to be principally nonionic;46,47 consequently, glipizide 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.46 (See Drug Interactions: Protein-Bound Drugs.)

Elimination

Following IV administration, serum concentrations of glipizide decline in a biphasic manner.30,31,35,36 Following IV administration of glipizide in healthy individuals or diabetic patients with normal renal and hepatic function, the half-life of the drug averages 8.4-36 minutes (range: 4-36 minutes) in the initial phase and 2.1-3.6 hours (range: 1.1-3.7 hours) in the terminal phase.30,31,35,36 Following oral administration in healthy individuals or diabetic patients with normal renal and hepatic function, the terminal elimination half-life of glipizide averages 3-4.7 hours (range: 2-7.3 hours).9,30,31,32,33,34,35,38,39,48 The terminal elimination half-life of total glipizide metabolites reportedly ranges from 2-6 hours in patients with normal renal and hepatic function.37 Serum glipizide concentrations may be increased in patients with renal or hepatic insufficiency.1 Data are limited, but the terminal elimination half-life of unchanged glipizide does not appear to be substantially increased in patients with impaired renal function.37 The terminal elimination half-life of total glipizide metabolites may be prolonged to greater than 20 hours in patients with impaired renal function;37 however, since glipizide metabolites are considered essentially inactive,37,49 this is probably of little clinical importance,2,90 at least in patients with moderate renal impairment.2

Glipizide is almost completely metabolized,30,34,35,36,37 mainly in the liver.1 The drug is metabolized principally at the cyclohexyl ring to 4- trans -hydroxyglipizide; the drug is also metabolized to the 3- cis -hydroxy derivative, N -(2-acetylaminoethylphenylsulfonyl)- N '-cyclohexyl urea (DCDA), and at least 2 unidentified metabolites.34,36 There is no information regarding the effects of hepatic impairment on the disposition of glipizide.95 However, since glipizide is highly protein bound and hepatic biotransformation is the predominant route of elimination, the pharmacokinetics and/or pharmacodynamics of glipizide may be altered in patients with hepatic impairment.95 If hypoglycemia occurs in such patients, it may be prolonged and appropriate management should be instituted.95 (See Cautions: Hypoglycemia.)

Glipizide and its metabolites are excreted principally in urine.30,34,35,36,37 The drug and its metabolites are also excreted in feces,30,34,35,37 apparently almost completely via biliary elimination;30,35,36,37 only small amounts may be excreted in feces as unabsorbed drug following oral administration.34 Most urinary excretion occurs within the first 6-24 hours after oral administration of the drug.30,34,35,36,37 Following oral administration of a single 5-mg dose of glipizide in individuals with normal renal and hepatic function, approximately 60-90% of the dose is excreted in urine as unchanged drug and metabolites within 24-72 hours and about 5-20% is excreted in feces within 24-96 hours;30,34,35,37 less than 10% of a dose is excreted in urine as unchanged drug within 24 hours, about 20-60% as the 4- trans -hydroxy metabolite, 10-15% as the 3- cis -hydroxy metabolite, 1-2% as DCDA, and the remainder as unidentified metabolites.34,36

Total plasma or serum clearance of glipizide reportedly averages 21-38 mL/hour per kg in individuals with normal renal and hepatic function.30,34,38,39,48 Renal clearance of unchanged glipizide increases substantially with increasing urinary pH, but is only about 5% of total plasma clearance at urinary pH of 5-6; the low renal clearance indicates that the drug undergoes renal tubular reabsorption.30 The effects have not been fully evaluated, but elimination of glipizide may be reduced in patients with impaired renal and/or hepatic function.1,37,95 Limited data indicate that renal excretion and terminal elimination half-life of glipizide metabolites are substantially decreased and increased, respectively, in patients with severe renal impairment.37

Following single-dose administration in older diabetic patients, there were no differences in glipizide pharmacokinetics compared with that in younger healthy individuals.95

Chemistry and Stability

Chemistry

Glipizide is a sulfonylurea antidiabetic agent.1,2,3 The drug is structurally similar to glyburide.3 Glipizide occurs as a whitish powder1,4 and is practically insoluble in water and in alcohol.4 The drug has a pK_a of 5.9.1

Stability

Glipizide tablets should be stored in tight, light-resistant containers.90,95 Conventional (immediate-release) tablets of the drug should be stored at a temperature between 20-25°C.1 Glipizide extended-release tablets should be stored at controlled room temperatures of 20-25°C but may be exposed to temperatures ranging from 15-30°C; the extended-release tablets should be protected from moisture and humidity.95

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