Continuing Education Activity

Glipizide is a second-generation sulfonylurea that is FDA-approved for the treatment of adults with diabetes mellitus type 2. It is administered as an adjunct to diet and exercise. It can be combined with metformin to reach goal HbA1c in patients with not adequate metabolic control in 3 months, despite compliance with diet, exercise, and medication. This activity will highlight the indications, mechanism of action, contraindications, adverse event profile, and potential toxicity of glipizide pertinent for members of the interprofessional team in the management care of patients with diabetes using glipizide.

Objectives:

• Identify the mechanism of action of glipizide.
• Describe the adverse effects of glipizide.
• Summarize the appropriate monitoring of glipizide.
• Explain the importance of sulfonylureas, particularly glipizide, and how it affects type 2 diabetes mellitus management as it pertains to improving care coordination among the interprofessional team when initiating a sulfonylurea like glipizide and improving outcomes.

Indications

Glipizide is a second-generation sulfonylurea that is FDA-approved for the treatment of adults with diabetes mellitus type 2. Its use is 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 2.5 mg, 5 mg, and 10 mg. Glipizide is only indicated for type 2 diabetes.[2][3][4]

Immediate-release tabs: Start with 5 mg PO daily initially, increase dosage 2.5 to 5 mg based on blood glucose tolerance response. Maintenance dose range: 2.5  to 20 mg PO daily or every 12 hours. The maximum dose is 40 mg/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.Dose adjustments:Hepatic failure: Start dose at 2.5 mg 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 second-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 most significant 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 may have an impaired ability to recognize 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 clinician should discontinue the drug; 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 two 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. The management of patients with low blood glucose secondary to glipizide can be 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 the 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 is best when performed by a collaborative interprofessional team approach. The treating physician (MD, DO, NP, or PA) will determine whether to initiate glipizide therapy. Nursing can assist with counseling about medication administration, use of glucose monitors, and answer any patient questions. The pharmacist also can counsel in all these areas, as well as verifying dosing and checking for drug-drug interactions, contacting the prescribing clinician with any concerns. Nursing can monitor treatment effectiveness on followup visits, as well as check for any medication adverse effects, letting the managing physician know about any issues so they can make necessary changes in therapy.

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]

Review Questions

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References

1.

Costello RA, Nicolas S, Shivkumar A. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Jul 12, 2023. Sulfonylureas. [PubMed: 30020597]

2.

Saharan P, Bahmani K, Saharan SP. Preparation, Optimization and In vitro Evaluation of Glipizide Nanoparticles Integrated with Eudragit RS-100. Pharm Nanotechnol. 2019;7(1):72-85. [PMC free article: PMC6691851] [PubMed: 30892168]

3.

Desai RJ, Sarpatwari A, Dejene S, Khan NF, Lii J, Rogers JR, Dutcher SK, Raofi S, Bohn J, Connolly JG, Fischer MA, Kesselheim AS, Gagne JJ. Comparative effectiveness of generic and brand-name medication use: A database study of US health insurance claims. PLoS Med. 2019 Mar;16(3):e1002763. [PMC free article: PMC6415809] [PubMed: 30865626]

4.

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. Cochrane Database Syst Rev. 2018 Sep 24;9(9):CD011798. [PMC free article: PMC6513625] [PubMed: 30246878]

5.

Drugs and Lactation Database (LactMed®) [Internet]. National Institute of Child Health and Human Development; Bethesda (MD): Jan 18, 2021. Glipizide. [PubMed: 29999913]

6.

Skillman TG, Feldman JM. The pharmacology of sulfonylureas. Am J Med. 1981 Feb;70(2):361-72. [PubMed: 6781341]

7.

Melander A, Wåhlin-Boll E. Clinical pharmacology of glipizide. Am J Med. 1983 Nov 30;75(5B):41-5. [PubMed: 6424440]

8.

Lebovitz HE. Glipizide: a second-generation sulfonylurea hypoglycemic agent. Pharmacology, pharmacokinetics and clinical use. Pharmacotherapy. 1985 Mar-Apr;5(2):63-77. [PubMed: 3923454]

9.

Cheng JWM, Badreldin HA, Patel DK, Bhatt SH. Antidiabetic agents and cardiovascular outcomes in patients with heart diseases. Curr Med Res Opin. 2017 Jun;33(6):985-992. [PubMed: 28097882]

10.

Vos RC, van Avendonk MJ, Jansen H, Goudswaard AN, van den Donk M, Gorter K, Kerssen A, Rutten GE. Insulin monotherapy compared with the addition of oral glucose-lowering agents to insulin for people with type 2 diabetes already on insulin therapy and inadequate glycaemic control. Cochrane Database Syst Rev. 2016 Sep 18;9(9):CD006992. [PMC free article: PMC6457595] [PubMed: 27640062]

11.

Laires P, Kurtyka K, Witt EA, Qiu Y, Yu S, Iglay K. Factors associated with physicians' decision to discontinue or down-titrate sulfonylureas for type 2 diabetes patients. Expert Rev Pharmacoecon Outcomes Res. 2019 Feb;19(1):71-79. [PubMed: 30130985]

12.

Gunaratne K, Austin E, Wu PE. Unintentional sulfonylurea toxicity due to a drug-drug interaction: a case report. BMC Res Notes. 2018 May 21;11(1):331. [PMC free article: PMC5963053] [PubMed: 29784014]

13.

Nasri H, Rafieian-Kopaei M. Diabetes mellitus and renal failure: Prevention and management. J Res Med Sci. 2015 Nov;20(11):1112-20. [PMC free article: PMC4755100] [PubMed: 26941817]

14.

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 J Endocrinol Metab. 2015 Sep-Oct;19(5):577-96. [PMC free article: PMC4566336] [PubMed: 26425465]

15.

Douros A, Dell'Aniello S, Yu OHY, Filion KB, Azoulay L, Suissa S. Sulfonylureas as second line drugs in type 2 diabetes and the risk of cardiovascular and hypoglycaemic events: population based cohort study. BMJ. 2018 Jul 18;362:k2693. [PMC free article: PMC6050517] [PubMed: 30021781]

16.

Klein-Schwartz W, Stassinos GL, Isbister GK. Treatment of sulfonylurea and insulin overdose. Br J Clin Pharmacol. 2016 Mar;81(3):496-504. [PMC free article: PMC4767194] [PubMed: 26551662]

Disclosure: Ricardo Correa declares no relevant financial relationships with ineligible companies.

Disclosure: Bryan Quintanilla Rodriguez declares no relevant financial relationships with ineligible companies.

Disclosure: Thomas Nappe declares no relevant financial relationships with ineligible companies.