Article Author:
Ricardo Correa
Article Editor:
Thomas Nappe
2/28/2019 3:47:57 PM
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Glipizide is a second generation sulfonylurea that is FDA-approved for the treatment of adults with diabetes mellitus type 2. It is to be administered as an adjunct to diet and exercise. Second-generation sulfonylureas are considered to be more potent by weight when compared to the first-generation agents. Sulfonylureas were discovered in 1942 and had been widely used in type 2 diabetes mellitus treatment since the 1960s.

Glipizide is available in doses of 2.5 mg, 5 mg, and 10 mg. Glipizide is only indicated for type 2 diabetics.

Other drug classes used in the treatment of diabetes mellitus type 2 include alpha-glucosidase inhibitors, biguanides, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, glinides, and thiazolidinediones.

Mechanism of Action

Glipizide is a sulfonylurea. It promotes insulin release from the pancreatic beta cells and reduces glucose output from the liver. It also improves insulin sensitivity at peripheral target sites.

The molecular mechanisms of glipizide involve a partial block of the potassium channels in the beta cells of the pancreatic islets. This potassium channel blockade results in cell depolarization, which opens up the voltage-gated calcium channels, causing insulin secretion.


Glipizide is administered orally. Patients are generally started on the lowest dose, with urine, and blood sugar regularly monitored to determine dosing efficacy. In many patients with type 2 diabetes, glipizide as sole therapy is inadequate to achieve blood sugar control. Glipizide is often used with other oral hypoglycemics for maximal benefit. Hemoglobin glycosylation (HbA1c) should be monitored every 3 to 6 months to ensure therapeutic patient compliance. In patients with mild hyperglycemia, glipizide may be used as monotherapy with changes in diet and exercise.

The immediate release dosage form should be administered 30 minutes prior to meals to achieve the greatest reduction in postprandial hyperglycemia. The extended-release dosage form should be administered with breakfast or the first meal of the day. Practitioners should instruct patients to swallow the tablets whole and not to chew, split, or crush the tablets.

The dose should be increased by 2.5 to 5 mg in a response dependent manner, and several days should elapse between any dose changes. In some patients, dividing the dose twice a day may help, but this may also result in reduced compliance. The maximum recommended dose of glipizide is 40 mg daily. Failure to achieve a satisfactory therapeutic response at the highest dose is indicative of therapeutic failure, and a different oral hypoglycemic agent should be considered.

In elderly patients, those who are malnourished, severely ill patients, and those with impaired liver or renal function, glipizide should be initiated at a lower dose, and higher doses should be avoided, as this can lead to hypoglycemic episodes.

Glipizide can be used concomitantly with insulin, but the dose of glipizide will typically need to be at the lower end of the dose range to prevent hypoglycemia. If insulin needs to be discontinued, then the patient's urine and blood sugars should be monitored at least three times a day. Patients whose treatment regimen consists of 40 units of insulin plus glipizide may require hospital admission to safely discontinue insulin therapy. Severe bouts of hyperglycemia and hypoglycemia can occur when insulin is withdrawn while taking glipizide.

Adverse Effects

The primary adverse effects of glipizide include hypoglycemia and weight gain. The most common adverse reactions are gastrointestinal and include nausea and diarrhea. In rare cases, cholestatic jaundice may result from glipizide therapy, and this requires immediate discontinuation of the medication.

Allergic reactions to glipizide are rare but can occur. They may present with erythema, pruritis, and eczema. If these symptoms are severe or persistent, the drug should be discontinued; this will typically result in cessation of allergic symptoms.

Hepatic porphyria has been reported in some patients. Additionally, some patients may develop a disulfiram-like reaction, but at present, this is only referenced anecdotally in the literature.

Rarely, glipizide may cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and hyponatremia. This adverse effect is also known to occur with several other sulfonylurea agents.

In general, glipizide is a relatively safe oral hypoglycemic, and the risk of adverse reactions is very low.


Glipizide is contraindicated in patients with hypersensitivity to sulfa drugs and patients with type 1 diabetes mellitus.


The administration of sulfonylureas has been reportedly associated with a slight increase in adverse cardiac events as compared to patients being treated with insulin and diet. This caution is not unique to glipizide, but also to several classes of oral hypoglycemic agents (e.g., tolbutamide) that were studied in the University Group Diabetes Program. If a patient is to initiate glipizide therapy, they should be informed of the potential risks, benefits, and possible complications.


Monitor fasting plasma glucose and A1c at three months in patients taking glipizide. Some experts recommend monitoring liver enzymes and renal function in patients who are prescribed glipizide for more than 2 months. There are reports that the drug can cause mild elevations in SGOT, LDH, and creatinine levels. Actual liver damage is very rare, but if the liver enzymes remain persistently high, the drug should be discontinued.


The sulfonylureas, like glipizide, can interact with several other drugs and induce hypoglycemia. The use of nonsteroidal anti-inflammatory drugs, some azole antifungals, sulfonamides, probenecid, monoamine oxidase inhibitors, beta blockers, quinolones, and salicylates can potentiate hypoglycemia in the presence of glipizide. Patients who are prescribed any of these drugs while taking glipizide need close monitoring of their blood sugars to prevent hypoglycemic attacks.  

Conversely, with use of drugs like thiazide diuretics, corticosteroids, thyroid hormone, phenothiazines, phenytoin, estrogen-containing contraceptives, calcium channel blockers, and nicotinic acid, there is the potential for hyperglycemia in patients taking glipizide. In some patients, a sudden loss of blood glucose control may occur. Further, if these medications are withdrawn, there is a risk of hypoglycemia. If a patient declines the use of glipizide, an alternate oral hypoglycemic drug may be considered, or they may need to be switched to insulin therapy.

All patients with diabetes mellitus should be encouraged to exercise regularly, discontinue smoking, eat a healthy diet, and control their body weight. There is ample evidence today showing that reduction in body weight leads to better blood glucose control and decreased need for oral hypoglycemics.


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