Glipizide


Article Author:
Ricardo Correa
Bryan Quintanilla Rodriguez


Article Editor:
Thomas Nappe


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes
Kavin Sugumar


Updated:
5/27/2019 3:46:40 PM

Indications

Glipizide is a second generation sulfonylurea that is FDA-approved for the treatment of adults with diabetes mellitus type 2. Its use is to be as an adjunct to diet and exercise. It is usable in combination with metformin, a biguanide, to reach goal HbA1c in patients with not adequate metabolic control in 3 months, despite compliance with diet, exercise, and medication. In a specific context, it can be a monotherapy in cases of intolerance or a contraindication to use metformin. Given its lower cost, availability, and efficacy to control type 2 diabetes, glipizide and the other sulfonylureas are common choices for physicians.[1]

Second-generation sulfonylureas are considered to be more potent by weight when compared to the first-generation agents. Sulfonylureas were discovered in 1942 and have enjoyed extensive use in type 2 diabetes mellitus treatment since the 1960s.

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.[1]

Dosing Forms:

Glipizide is available in doses of immediate-release tablets of 5 mg, and 10 mg, and extended-release tablets of 2.5mg, 5mg, and 10mg.  Glipizide is only indicated for type 2 diabetics.[2][3][4]

Immediate-release tabs: Start with 5mg PO daily initially, increase dosage 2.5 to 5mg based on blood glucose tolerance response. Maintenance dose range: 2.5  to 20mg PO daily or every 12 hours. The maximum dose is 40mg/day.Extended-release tabs: Initially: 5mg PO daily, given with breakfast. Dose adjusted according to patient tolerance response and blood glucose.

Switching from insulin to glipizide:Patients with low insulin doses around less than 20 Units: The recommendation is to discontinue insulin and initiate glipizide at an appropriate dose.Patients with a moderate insulin dose using more than 20 Units: The recommendation is to decrease the insulin dose around 50% of the current dose, and start glipizide at the appropriate doses. Then begin reducing insulin dose according to patient response.Dosis adjustments:Hepatic failure: Start dose at 2.5mg PO daily, immediate release tabs.Renal failure: In patients with a GFR of less than 50 ml/min, decrease the dose by 50%.[2][3][4]

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 extrapancreatic effect of sulfonylureas results from an increase in the deficient number of insulin receptors in the muscle, fat, or liver cells.[5]

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 from the pancreatic beta cells.

The 2nd generation sulfonylureas have a more nonpolar side chain; this results in a higher potency hypoglycemic effect.[6]

In comparison with the other sulfonylureas, glipizide has the fastest absorption and onset of action, as well as the shortest half-life and effect-duration. Thus the risk of long-lasting hypoglycemia is minute.[7]

The initial onset effect takes around 30 minutes, and the duration is approximately 12 to 24 hours. 99% of the drug is protein bound. Glipizide undergoes hepatic metabolism and excretion is primarily in the urine with a small percentage in the feces.[8]

Administration

Glipizide is an orally administered drug. Patients generally start 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, monotherapy with glipizide may be sufficient with changes in diet and exercise.[9][10]

The immediate release dosage form should be administered 30 minutes before meals to achieve the greatest reduction in postprandial hyperglycemia. Administration of the extended-release dosage form should be 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 merits consideration of a different oral hypoglycemic agent.

In elderly patients, those who are malnourished, severely ill patients, and those with impaired liver, adrenal or renal function, glipizide should be initiated at a lower dose, and higher doses avoided, as this can lead to hypoglycemic episodes. Patients using beta blockers can impair patient to distinguish hypoglycemia symptoms.

It is recommended to use sulfonylureas like glipizide carefully in patients with glucose 6 phosphate dehydrogenase deficiency. They can develop hemolytic anemia when treated with sulfonylureas. Consider switching to another hypoglycemic agent.

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 discontinuation of insulin becomes necessary, 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 discontinue insulin therapy safely. Severe bouts of hyperglycemia and hypoglycemia can occur when withdrawing insulin while taking glipizide.[8][9][10]

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.

Reports exist of hepatic porphyria 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.[11][12]

Contraindications

Contraindications to glipizide include patients with hypersensitivity to sulfa drugs and patients with type 1 diabetes mellitus, diabetic ketoacidosis, and hyperosmolar hyperglycaemic state (HHS).[13][14]

The administration of sulfonylureas reportedly correlates with a slight increase in adverse cardiac events as compared to patients treated with insulin and diet. This caution is not unique to glipizide, but also several classes of oral hypoglycemic agents (e.g., tolbutamide) studied in the University Group Diabetes Program. If a patient is to initiate glipizide therapy, they should receive information regarding the potential risks, benefits, and possible complications.[15]

Glipizide and sulfonylureas cross the placenta and have correlations in some cases with neonatal hypoglycemia. It is suggested to discontinue this drug two weeks before expected delivery.

Limited information suggests that levels of glipizide are low in lactation; results are not conclusive. In some instances, an alternative drug may be preferable, particularly while nursing preterm or a newborn. The recommendation is to monitor for hypoglycemia symptoms in breastfed infants whose mother is taking glipizide or other sulfonylureas. In some cases, a newborn with clinical symptoms of hypoglycemia needs the supervision of blood glucose during the time the mother is taking sulfonylureas.[5][7][16]

Monitoring

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 infrequent, but if the liver enzymes remain persistently high, discontinue the drug.

Regular weight measurings are a recommendation given glipizide's potential side effect of weight gain.[13][14]

Toxicity

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. Patients with low blood glucose secondary to glipizide can be managed with IV dextrose or oral glucose tablets, depending on the severity of the clinical presentation. The management of the drug toxic effect is to restore and maintain euglycemia.

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, upon withdrawal of these medications, there is a risk of hypoglycemia. If a patient declines the use of glipizide, an alternate oral hypoglycemic drug may be an option, or they may need to switch 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.[16]

Enhancing Healthcare Team Outcomes

Nurse practitioners, primary care physicians, internists, and endocrinologists all commonly prescribe glipizide. The drug is useful for the treatment of type 2 diabetes and relatively safe. However, healthcare workers, including nurses and pharmacists, must warn the patient that the drug can cause mild hypoglycemia and how to manage it. Also, since the medication can cause weight gain, patients should be instructed to exercise and eat a healthy diet. Recommendations are to monitor fasting plasma glucose, HbA1c, renal, and liver function tests in patients using this drug.

GLipizide therapy requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level V]


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Glipizide - Questions

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A 48-year-old female patient with a past medical history of hypertension, hyperlipidemia, and obesity presents to the emergency department complaining of being confused, increased urinary frequency, increased thirst, and increased hunger. She was previously diagnosed a couple of years ago with type 2 diabetes. Her medications include: losartan 100mg, metformin 1000mg, and simvastatin 10mg. She is compliant with her medication apparently, as per her daughter. She follows a strict diet and exercises 3 to 5 days a week. Vital signs show sat02: 94% BP 100/65 mmHg, pulse 93 beats per minute, respiratory rate 18 per minute. Physical exam reveals: mucosas are dry, crackles at the base of the right lung, rest of the physical exam is unremarkable. Labs are reported as shown: hemoglobin A1C: 8.9 %, creatinine: 0.9 mg/dL, BUN: 12 mg/dL, AST: 30 U/L, ALT: 30 U/L, WBC: 14,000/mm3, Beta-hydroxybutyrate: Positive, urinalysis: positive for ketones, arterial blood gases: Bicarbonate: 14 mEq/L. Chest x-ray shows the presence of infiltrates in the lower lobe of the right lung. She is admitted, and started on supplemental oxygen, IV normal saline, IV ceftriaxone, and PO Azythromycin. Given her current condition, which of the following will be contraindicated in the management of this patient at this moment?



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A 28-year-old male patient with an unremarkable past medical history presents to the outpatient clinic complaining of increased urinary frequency, increased thirst, increased hunger, weight loss, and dizziness. His medications include a daily multivitamin. He denies allergies to food and medications. Physical exam BP 137/89 mmHg, pulse 85 per minute, respiratory rate 18 per minute, rest of the physical exam is unremarkable. Labs are reported as shown: fasting plasma glucose: 180 mg/dL, HbA1C: 7.5%, oral glucose tolerance test: 220 mg/dL, creatinine: 0.9 mg/dL , BUN: 12 mg/dL, GAD-65 antibodies: positive. Which of the following medications is contraindicated in the management of this patient?



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A 48-year-old female patient with a past medical history of hypertension, hypercholesterolemia, and obesity presents complaining of increased urinary frequency, increased thirst, and increased hunger. She was previously diagnosed a couple of years ago with type 2 diabetes mellitus. Her medications include metformin 1500mg. She is compliant with her medication. She started a diet and exercise regimen a couple of months ago. Physical exam reveals BP 138/88 mmHg, pulse 80 beats per minute, and respiratory rate 18 per minute, while the rest of the physical exam is unremarkable. Labs show a hemoglobin A1C of 8.9 %. She is started on a new medication to address her hyperglycemia. She presents to a follow-up appointment 3 months later, with no symptoms of polydipsia, polyphagia, or polyuria. However, she is gaining more weight. New labs show a hemoglobin A1c of 7.0 %, Creatinine: 0.9 mg/dL, BUN: 12 mg/dL. Her physician addressed it is caused by the new medication. What is the mechanism of action of the drug causing her weight gain?



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Sergei is a 55-year-old white male with a history of type 2 diabetes, hypertension, and hypercholesterolemia. He works as a security guard at a warehouse near his home. His medications are as follows: metformin 500 mg bid (with morning and evening meals), glipizide XL 5 mg daily (with evening meal), hydrochlorothiazide (HCTZ) 25 mg every morning, and atorvastatin 20 mg at bedtime. He reports being compliant with his medications, except his HCTZ because it makes him urinate too often during his long shifts at the warehouse. He checks his blood glucose fairly regularly and reports recent increased incidents of hypoglycemia when testing. He also reports that he has been eating more fresh fruit and vegetables since a farmers' market has opened near where he lives, so he has been purchasing food there and stopped eating processed and fast food. What might be a prudent next step in managing this patient's case?



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A 54-year-old male with a history of type 2 diabetes, hypertension, and hypercholesterolemia presented to the clinic for follow-up. His medications include metformin, hydrochlorothiazide (HCTZ), and simvastatin. He reports being compliant with his medications. He checks his blood glucose fairly regularly and reports recently increased incidents of hyperglycemia when testing. His fasting blood glucose is found to be 160 mg/dL and hemoglobin A1c 8%. He is prescribed a new medication for better glycemic control. The next day the patient presents to the emergency department with a rash and hives localized in multiple sections of the body. He reports no food allergies. However, he suffers an allergy to trimethoprim/sulfamethoxazole. Which of the following medications is most likely responsible for his symptoms?



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A 45-year-old male with a history of type 2 diabetes, hypertension, obesity, glucose-6-phosphate dehydrogenase (G6PD) deficiency presented to the clinic for follow up. His medications include metformin, losartan, and atorvastatin. He reported being adherent to his medications. His fasting blood glucose was 165 mg/dL, and hemoglobin A1c was 8.1%. A new medication was added to his regimen for better glycemic control. The next week, the patient presents to the emergency department with jaundice, weakness, and fatigue. Laboratory workup shows a total bilirubin of 4.0 mg/dL, indirect bilirubin 3.5 mg/dL, LDH 450 IU/L, hemoglobin 9 g/dL and platelets 200000/microL. Which of the following medications is most likely responsible for the patient's condition?



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Glipizide - References

References

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Lo C,Toyama T,Wang Y,Lin J,Hirakawa Y,Jun M,Cass A,Hawley CM,Pilmore H,Badve SV,Perkovic V,Zoungas S, Insulin and glucose-lowering agents for treating people with diabetes and chronic kidney disease. The Cochrane database of systematic reviews. 2018 Sep 24;     [PubMed]
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Nasri H,Rafieian-Kopaei M, Diabetes mellitus and renal failure: Prevention and management. Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences. 2015 Nov;     [PubMed]
Kalra S,Aamir AH,Raza A,Das AK,Azad Khan AK,Shrestha D,Qureshi MF,Md Fariduddin,Pathan MF,Jawad F,Bhattarai J,Tandon N,Somasundaram N,Katulanda P,Sahay R,Dhungel S,Bajaj S,Chowdhury S,Ghosh S,Madhu SV,Ahmed T,Bulughapitiya U, Place of sulfonylureas in the management of type 2 diabetes mellitus in South Asia: A consensus statement. Indian journal of endocrinology and metabolism. 2015 Sep-Oct;     [PubMed]
Skillman TG,Feldman JM, The pharmacology of sulfonylureas. The American journal of medicine. 1981 Feb     [PubMed]
Melander A,Wåhlin-Boll E, Clinical pharmacology of glipizide. The American journal of medicine. 1983 Nov 30     [PubMed]
Lebovitz HE, Glipizide: a second-generation sulfonylurea hypoglycemic agent. Pharmacology, pharmacokinetics and clinical use. Pharmacotherapy. 1985 Mar-Apr     [PubMed]
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