Glipizide is used as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus.1, 2, 3, 19, 27, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 95 In clinical studies in adults, glipizide was evaluated as monotherapy and in combination with other antidiabetic agents (e.g., metformin, thiazolidinedione).127, 153, 156, 157, 158, 166
Glipizide is commercially available as a single entity preparation and in fixed combination with metformin hydrochloride.1, 95, 153 The fixed combination of glipizide and metformin hydrochloride is used 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
The manufacturer states that glipizide is not recommended for use in patients with type 1 diabetes mellitus or diabetic ketoacidosis.1, 95
When given as monotherapy for the management of type 2 diabetes mellitus, glipizide improves glycemic control as evidenced by reductions in fasting and postprandial glucose and glycosylated hemoglobin (hemoglobin A1c; HbA1c).95 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
Secondary failure to sulfonylurea antidiabetic agents is characterized by progressively decreasing diabetic control following 1 month to several years of good control.1, 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 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 an effective alternative therapy.1, 2, 52, 54
Sulfonylureas may be used in combination with one or more other oral antidiabetic agents (e.g., metformin, GLP-1 receptor agonists, sodium-glucose cotransporter 2 [SGLT2] inhibitors, dipeptidyl peptidase-4 [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, 156, 157, 158, 161, 159, 160, 708, 709
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 HbA1c values, fasting plasma glucose concentrations) than monotherapy with either component.153 A greater percentage of patients receiving the fixed combination achieved strict glycemic control (HbA1c values below 7%) than did those receiving metformin or glipizide monotherapy.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 HbA1c 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., HbA1c values less than 7%)138 also was achieved in a greater percentage of patients receiving the fixed combination of glipizide and metformin.153
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.1, 120, 127, 130, 139 Concomitant therapy with insulin (e.g., given as intermediate- or long-acting insulin at bedtime or rapid-acting insulin at meal times)127, 131, 132, 134, 136 and one or more oral antidiabetic agents improves 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, 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.132, 134, 140
The American Diabetes Association (ADA) publishes an annual guideline on diabetes management, which provides clinical practice recommendations for glucose-lowering therapies in patients with type 2 diabetes mellitus.708 The current 2025 ADA guideline states that in adults with type 2 diabetes mellitus, pharmacologic strategies that provide sufficient effectiveness to achieve and maintain the intended treatment goals should be used and guided by a person-centered shared decision-making approach.708 In general, higher-efficacy approaches have a greater likelihood of achieving glycemic goals.708 Weight management should be included as a distinct treatment goal, and healthy lifestyle behaviors should also be considered.708 When selecting an appropriate treatment regimen, clinicians should be guided by factors such as cardiovascular and renal comorbidities, drug efficacy and adverse effects, hypoglycemic risk, presence of overweight or obesity, cost, access, and patient preferences.708 Sulfonylureas do not have additive beneficial effects on cardiovascular or renal outcomes and are associated with an increased risk of weight gain and hypoglycemia.708 Therefore, their use should be limited or discontinued; when used, these guidelines recommend the lowest possible dosage.708
The American Association of Clinical Endocrinology (AACE) also publishes guidelines for the management of type 2 diabetes.709 The principles of diabetes management outlined in these guidelines are similar to those recommended by the ADA.709 The AACE guidelines state that in adult patients with type 2 diabetes, sulfonylureas are associated with a higher risk of hypoglycemia and weight gain and therefore are not preferred; however, sulfonylureas may remain a treatment option in those patients with access or cost barriers to other antidiabetic agents.709
Dispensing and Administration Precautions
Glipizide is administered orally.1, 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
Extended-release tablets of glipizide are administered once daily, generally with breakfast or the first main meal of the day.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
When given concomitantly with colesevelam, glipizide should be administered at least 4 hours prior to colesevelam.1, 95
The fixed combination of glipizide with metformin hydrochloride should be taken once or twice daily with food.153 See the full prescribing information for additional administration instructions for the combination product.153
Store glipizide immediate-release tablets at 20—25°C in a tight, light-resistant container.1 Store glipizide extended-release tablets at 20—25°C (excursions permitted to 15—30°C) protected from moisture and humidity.95
Dosage of glipizide must be based on blood and urine glucose determinations and must be carefully individualized to obtain optimum therapeutic effect.1
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 orally once 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 orally once daily is recommended.1, 27, 71 Subsequent dosage should be adjusted according to the patient's tolerance and therapeutic response in increments of 2.5-5 mg at intervals of at least several days when immediate-release tablets are used.1, 2, 51, 54, 59, 60 Dosages utilizing immediate-release tablets above 15 mg daily should ordinarily be divided; total daily dosages above 30 mg have safely been given twice daily.1
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
A transition period generally is not required when transferring from other oral antidiabetic agents to glipizide immediate-release tablets.1 Patients being transferred from longer half-life sulfonylureas to glipizide should be closely monitored for hypoglycemia during the initial 1-2 weeks of the transition period due to the potential for an overlapping drug effect.1 When 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
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
The maximum recommended dosage is 40 mg daily as immediate-release tablets or 20 mg daily as extended-release tablets.1, 95
Glipizide/Metformin Hydrochloride Fixed-combination Therapy
Dosage of the commercially available fixed combination of glipizide and metformin hydrochloride should be individualized for effectiveness and tolerance.153
When the commercially available fixed-combination preparation 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 orally 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 orally twice daily may be considered.153 Dosage may be increased in increments of one tablet 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 orally 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
Patients previously treated with combination therapy using separate preparations of glipizide (or another sulfonylurea antidiabetic agent) and metformin may be switched to glipizide 2.5 or 5 mg and metformin 500 mg tablets; 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 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
Transitioning from Insulin Therapy
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.94 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
Immediate release: The manufacturer recommends an initial starting dosage of 2.5 mg for patients with hepatic impairment; initial and maintenance dosage should be conservative to avoid hypoglycemic reactions.1
Extended release: The manufacturer recommends an initial starting dosage of 2.5 mg for patients with hepatic impairment.95
Glipizide/Metformin Hydrochloride Fixed-combination Therapy
The manufacturer recommends to avoid use in patients with clinical or laboratory evidence of hepatic disease.153
Immediate release: The manufacturers makes no specific dosage recommendations for patients with renal impairment; initial and maintenance dosage should be conservative to avoid hypoglycemic reactions.1
Extended release: The manufacturers makes no specific dosage recommendations for patients with renal impairment.95
Glipizide/Metformin Hydrochloride Fixed-combination Therapy
Glipizide in fixed combination with metformin hydrochloride should not be initiated in patients with an estimated glomerular filtration rate (eGFR) between 30—45 mL/minute per 1.73 m2.153 Use is contraindicated in patients with an eGFR less than 30 mL/minute per 1.73 m2.153 In patients taking glipizide in fixed combination with metformin hydrochloride whose eGFR falls below 45 mL/minute per 1.73 m2, assess the benefits and risks of continuing therapy.153 Discontinue glipizide in fixed combination with metformin hydrochloride if the patient's eGFR falls below 30 mL/minute per 1.73 m2.153
Immediate release: The manufacturer recommends an initial dosage of 2.5 mg for geriatric patients.1 In general, dosage selection for a geriatric patient should be conservative, usually starting at the low end of the dosage range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy, to avoid hypoglycemic reactions.1
Extended release: The manufacturer recommends an initial dosage of 2.5 mg for geriatric patients.95
Glipizide/Metformin Hydrochloride Fixed-combination Therapy
The manufacturer makes no specific dosage recommendations but states that geriatric patients should not be titrated to the maximum dosage of glipizide and metformin hydrochloride to avoid the risk of hypoglycemia.153 In general, initial and maintenance dosage selection for a geriatric patient should be conservative, usually starting at the low end of the dosage range, reflecting the greater frequency of decreased renal function.153
Increased Risk of Cardiovascular Mortality
The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin.1, 95
Several large, long-term studies have evaluated the cardiovascular risks associated with the use of oral sulfonylurea antidiabetic agents.1, 95, 60, 96, 97, 100, 113 In 1970, the University Group Diabetes Program (UGDP) reported that administration of oral antidiabetic agents 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.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 HbA1c 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
Although only one drug in the sulfonylurea class was included in the UGDP study, it is prudent from a safety standpoint to consider that this warning may also apply to other hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.1, 95 The patient should be informed of the potential risks and advantages of glipizide and of alternative therapies.1, 95
The manufacturer states that there are no clinical studies that conclusively establish macrovascular risk reduction with glipizide or any other antidiabetic drug.1, 95
The metabolism and excretion of glipizide may be slowed in patients with renal and/or hepatic impairment.1 If hypoglycemia occurs in such patients, it may be prolonged and appropriate management should be instituted.1
All sulfonylurea drugs, including glipizide, are capable of causing severe hypoglycemia.1, 95 Hypoglycemia may occur in patients receiving glipizide alone or when used in combination with other antidiabetic agents; concomitant use of glipizide with other antidiabetic agents increases the risk of hypoglycemia.1, 2, 27, 50, 54, 58, 60, 70, 95, 153 The patient's ability to concentrate and react may be impaired as a result of hypoglycemia.95 These impairments may present a risk in situations where these abilities are especially important, such as driving or operating machinery.95 Severe hypoglycemia can lead to unconsciousness or convulsions and may result in temporary or permanent impairment of brain function or death.95 Early warning signs of hypoglycemia may be different or less pronounced in patients with autonomic neuropathy, in geriatric patients, and in patients who are taking β-adrenergic blocking agents.95 These situations may result in severe hypoglycemia before the patient is aware of the hypoglycemia.95
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 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.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
Appropriate patient selection and careful attention to dosage are important to avoid glipizide-induced hypoglycemia .1, 27, 71, 95 A lower dosage of glipizide may be required to minimize the risk of hypoglycemia when used concomitantly with other antidiabetic agents.95 Patients should be educated to recognize and manage hypoglycemia.95
When a patient stabilized on any antidiabetic regimen is exposed to stress (e.g., fever, trauma, infection, or surgery), a loss of glycemic control may occur.1 At such times, it may be necessary to discontinue glipizide and administer insulin.1
The effectiveness of any oral hypoglycemic drug, including glipizide, in lowering blood glucose to a desirable level decreases in many patients over a period of time as a result of progression of disease severity or from diminished responsiveness to the drug.1
Patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency who receive sulfonylureas (e.g., glipizide) may develop hemolytic anemia.1, 95 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, 95
There have been reports of obstructive symptoms in patients with known strictures in association with the ingestion of another drug with a non-dissolvable extended release formulation.95 Avoid use of extended-release glipizide tablets (Glucotrol XL®) in patients with preexisting gastrointestinal narrowing (pathologic or iatrogenic).95
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
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 necessary (e.g., when insulin therapy is infeasible).1
Neonates born to women with gestational diabetes that were 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, 95 To minimize the risk of neonatal hypoglycemia if glipizide is used during pregnancy, the manufacturer recommends that the drug be discontinued at least 2 weeks before the expected delivery date.95 Neonates should be observed for symptoms of hypoglycemia and respiratory distress and managed accordingly.95
Although it is not known whether glipizide is distributed into milk in humans, some sulfonylurea antidiabetic agents are distributed into human milk.1 There are no data on the effects of glipizide on milk production.95 The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for glipizide and any potential adverse effects on the breast-fed child from glipizide or from the underlying maternal condition.95 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
Safety and effectiveness of glipizide in pediatric patients have not been established.1, 95
There are no overall differences in safety or effectiveness between younger and older patients receiving glipizide, but greater sensitivity of some individuals cannot be ruled out.1, 95 Geriatric patients are particularly susceptible to the hypoglycemic action of antidiabetic agents; hypoglycemia may be difficult to recognize in these patients.95 In general, dosage selection for a geriatric patient should be cautious, usually starting at the low end of the dosage range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.1
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
The pharmacokinetics of glipizide have not been evaluated in patients with varying degrees of renal impairment.95 Limited data indicate that glipizide biotransformation products may remain in circulation for a longer time in subjects with renal impairment than that seen in normal renal function.95
The most common adverse effects of glipizide (>3% of patients) are dizziness, diarrhea, nervousness, tremor, hypoglycemia, and flatulence.95
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 (NSAIAs), and sulfonamides.1, 2, 47, 72 However, unlike the protein binding of some other sulfonylurea antidiabetic agents, and like that of glyburide, the protein binding of glipizide is 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 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, 95 coumarins,95 disopyramide,95 fibric acid derivatives,95 fluoxetine,95 histamine H2-receptor antagonists,95 monoamine oxidase (MAO) inhibitors,1, 2, 72 NSAIAs,95 pentoxifylline,95 pramlintide,95 probenecid,1, 72, 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 glycemic 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 blocking agents,1 corticosteroids,1, 72, 95 danazol,95 diuretics (e.g., furosemide),1, 72, 95 estrogens,1, 72 glucagon,95 isoniazid,1 niacin,1, 72 hormonal contraceptives,1, 72 phenothiazines,1, 72 progestogens,95 protease inhibitors,95 somatropin,95 sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline),1, 72 thyroid hormones,1, 72, 95 phenytoin,1, 72 and rifampin.1, 72 When these drugs are administered or discontinued in patients receiving glipizide, the patient should be observed closely for loss of glycemic 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 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.1, 62, 72, 95β-Adrenergic blocking agents may impair glucose tolerance;62, 72 increase the frequency or severity of hypoglycemia;62, 72 block hypoglycemia-induced tachycardia, but not hypoglycemic sweating which may actually be increased;72 delay the rate of recovery of blood glucose concentration following drug-induced hypoglycemia;62, 72 alter the hemodynamic response to hypoglycemia, possibly resulting in an exaggerated hypertensive response;62 and possibly impair peripheral circulation.62 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 It generally is recommended that concomitant use of β-adrenergic blocking agents and sulfonylurea antidiabetic agents be avoided when possible;72 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.1, 95
Disulfiram-like reactions have occurred very rarely following the concomitant use of alcohol and glipizide.1, 58, 85
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 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 Monitor patients closely for hypoglycemia when glipizide is administered with azole antifungal drugs (i.e., miconazole, fluconazole).1, 95
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; dosage adjustment of glipizide may be necessary when cimetidine therapy is initiated or discontinued.83
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, 95 Substantial changes in AUC and peak plasma concentrations were not observed when extended-release glipizide was administered 4 hours prior to colesevelam.1, 95 The manufacturer states that glipizide should be administered at least 4 hours prior to colesevelam to avoid reductions in glipizide absorption.1, 95
Thiazide diuretics may exacerbate diabetes mellitus, resulting in increased requirements of sulfonylurea antidiabetic agents, temporary loss of glycemic control, or secondary failure to the antidiabetic agent.72 When thiazide diuretics are administered concomitantly with sulfonylurea antidiabetic agents, caution should be used.72
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 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.1, 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 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 mg.2, 5
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, 95 Food delays the absorption of glipizide but does not affect peak serum concentrations achieved or the extent of absorption of the drug.1, 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 within 15-30 minutes and average peak plasma concentrations are attained within 1-3 hours (range: 1-6 hours).1, 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.1, 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 AUC for glipizide increases in proportion to increasing doses.30, 31, 38 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.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
Distribution of glipizide into human body tissues and fluids has not been fully characterized.2, 30, 34, 37 In humans, small amounts of glipizide are apparently distributed into bile30, 34, 37 and very small amounts are distributed into erythrocytes and saliva.30 It is not known if glipizide is distributed into milk in humans.1 Glipizide is approximately 92-99% bound to plasma proteins.30, 34, 36, 46 Unlike the protein binding of some other sulfonylurea antidiabetic agents 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 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 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 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 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 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
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 5 mg* | ||
10 mg* | glipiZIDE Tablets | |||
Tablets, extended-release | 2.5 mg* | |||
5 mg* | glipiZIDE Tablets ER | |||
Glucotrol XL® | Pfizer | |||
10 mg* | glipiZIDE Tablets ER | |||
Glucotrol XL® | Pfizer |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 2.5 mg with 250 mg Metformin Hydrochloride* | ||
2.5 mg with 500 mg Metformin Hydrochloride* | glipiZIDE with Metformin Hydrochloride Tablets | |||
5 mg with 500 mg Metformin Hydrochloride* | glipiZIDE with Metformin Hydrochloride Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions June 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
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