Continuing Education Activity

Glyburide is a medication used in the management of type 2 diabetes mellitus. It is in the sulfonylurea class of drugs. This activity outlines the indications, action, and contraindications for glyburide as a valuable agent in managing type 2 diabetes mellitus. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the interprofessional team in the treatment of patients with chronic hyperglycemia and related conditions.

Objectives:

• Identify the mechanism of action of glyburide.
• Describe the adverse effects of glyburide.
• Review the appropriate monitoring for patients using glyburide.
• Summarize interprofessional team strategies for improving care coordination and communication to advance the safe use of glyburide and improve outcomes.

Indications

Glyburide, also referred to as glibenclamide, is a second-generation sulfonylurea approved by the Food and Drug Administration (FDA) for the treatment of type 2 diabetes mellitus. The medication is available as a generic formulation. It is an adjunct therapy along with diet and exercise for the management of diabetes.[1] Treatment with glyburide has been and continues to lower blood glucose levels successfully and is also available in combination therapy with metformin. Typical doses for glyburide are relatively minute compared to first-generation sulfonylureas, and dosing is usually a once-daily morning dose.[1] According to the American Diabetes Association (ADA) Standards of Medical Care in Diabetes 2022 update, sulfonylureas such as glyburide are considered one of multiple options for adjunct therapy, especially for patients limited by access to medications or costs. [2][3] The patient population that this recommendation focuses on is non-ASCVD, non-CKD patients with type 2 diabetes mellitus that have not reached their HbA1C target after three months.[3] However, recommendations for first-line therapy has been updated based on patient comorbidities, patient-specific treatment factors, and management needs.[2]

For many years, glyburide has been studied off-label for the treatment of neonatal syndromic hyperglycemia for patients with Kir6.2 or SUR1 mutations.[4] Although no dosage forms are yet available for children with these potassium channel defects, studies included a newly-designed suspension with orphan drug status to evaluate its efficacy with glyburide tablets.[5] Results from the research reflected significant decreases in HbA1C, further warranting its off-label uses.[5]

Due to its overlap in the mechanism of action, recent studies have even begun to highlight low doses of glyburide as a possible agent for reducing intracranial pressure and cerebral edema.[6]

Mechanism of Action

Glyburide, along with others in its class of sulfonylureas, exerts its mechanism of action based on increasing insulin secretion from beta cells in the pancreas.[7] Specifically, sulfonylureas bind to the SUR1 receptors in the membranes of the beta cells of potassium ATP-dependent channels.[7][8] These agents act by blocking these channels, and insulin is released after the cell becomes depolarized.[9] At times, sulfonylureas tend to bind to SUR2 receptors, located on cells in cardiac tissue and the endothelium.[8] After the initial insulin secretion, sulfonylureas can also decrease the clearance of insulin in the liver, furthermore contributing to increased insulin levels in the plasma.[10] Glyburide, along with glipizide, is classified as second-generation sulfonylureas due to increased potency and difference in elimination, allowing their use in patients with renal and hepatic dysfunction.

Administration

Glyburide is orally administered in typical initial dosages of 2.5 mg to 5 mg, with a maximum of 40 mg daily – the maximum dosage is rarely used, as many patients with type 2 diabetes mellitus do not require dosages higher than 10 mg per day.[1] Clinical effects are also not significant beyond 10 to 15 mg of total daily doses.[1][10] Most sulfonylureas should be taken by mouth about 30 minutes before food intake, as both food intake and hyperglycemia may reduce sulfonylurea absorption and its associated antidiabetic effect.[1] Patients should take lower doses of glyburide (less than or equal to 10 mg) with breakfast or as soon as the patient consumes the breakfast meal, with higher daily doses (greater than 10 mg) usually divided between breakfast and evening meals.[1]

Adverse Effects

Hypoglycemia and weight gain are the most frequently encountered side effects of glyburide. Although glyburide is one of the most popular sulfonylureas prescribed, a systematic review conducted by the ADA supports evidence that glyburide correlates with a significantly higher risk of hypoglycemic episodes than other insulin secretagogues sulfonylureas by 80% and 44%, respectively.[11] However, these episodes are most often seen with higher initial glyburide dosing and in patients that have been recently diagnosed – especially in those 65 years of age and older.[1] For this reason, it is crucial to consider patient-specific factors and susceptibility to hypoglycemic episodes when considering prescribing glyburide for a sulfonylurea-naïve patient. 

Due to the risk of severe prolonged hypoglycemia with long-acting sulfonylureas (and subsequent risk for falls), glyburide is listed on the 2019 American Geriatrics Society Beers Criteria as a potentially inappropriate medication in older adults (i.e., those aged 65 years and older).[12]

Possible weight gain can also be a distressing side effect for patients taking glyburide, as with all sulfonylureas. Although the ADA’s systematic review states that weight gain was not a major outcome for glyburide compared with other insulin secretagogues if weight gain occurs, co-administration with metformin is a weight-neutral biguanide agent, can aid with the issue.[1][11]

A cohort study on patients with diabetes mellitus type 2 compared all-cause and cardiovascular mortality for patients on either glyburide or metformin for blood glucose management.[13] The study found that glyburide monotherapy, when compared to metformin, was associated with higher percentages of all-cause (6.3% and 1.6%, respectively) and cardiovascular (4.1% and 0.4%, respectively) deaths, in addition to increases in plasma creatinine. Other nationwide studies, retrospective cohort studies, and other recent studies have confirmed metformin as having lower all-cause mortality rates and higher survival rates compared to glyburide and other drugs of its class as well.[13] 

Adverse effects that are less likely to occur with glyburide and other sulfonylureas include skin rashes, nausea, and sensitivity to light on rare occasions.[10]

Contraindications

There have been multiple studies concerning glyburide use in pregnant patients with gestational diabetes mellitus. Although glyburide is considered a Category C drug by the FDA, expert bodies have begun introducing glyburide as a possible alternative to insulin for antidiabetic therapy. Glyburide does cross the placenta in utero and gets metabolized by placental microsomes, so the fetus has exposure to the medication. Concerning lactation, glyburide, along with its second-generation counterpart glipizide, is compatible with breastfeeding and does not cross into breastmilk to affect breastfed children.[8]

Glyburide therapy should not be re-initiated if the patient has a history of allergic reactions to the medication. However, patients who have had previous allergic reactions to drugs of the same class may not necessarily react to glyburide.[1]

Also, it is essential to use caution with glyburide in hospitalized patients, who are malnourished, misuse alcohol, have renal and cardiac dysfunctions, or with gastrointestinal disease.[10]

Monitoring

As rates for hypoglycemia can be higher with glyburide than other oral antidiabetic agents, close monitoring for signs and symptoms of declining blood glucose levels is required. Hypoglycemia can be life-threatening, and it is crucial to ensure taking proper measures if it occurs in any patient. It is also necessary to monitor glyburide patients even further if they are in circumstances that provoke the onset of hypoglycemia: this includes exercise, lack of eating, and accidental overdosages.[10] Knowledge of the signs and symptoms of hypoglycemia is vital when starting a patient on glyburide and self-monitoring of blood glucose and regularly scheduled testing of blood glucose and HbA1C as recommended by the ADA.

Glyburide and other sulfonylureas may also cause liver dysfunction, potentially resulting in cholestatic jaundice, hepatitis, and liver failure, although this is rare.[10] In patients with liver dysfunction, monitoring of liver function tests may be necessary.

Toxicity

Glyburide toxicity is most likely to result from severe hypoglycemia from an excessive dosage, whether accidentally or intentionally.[10][13] Drug-drug interactions with glyburide and other sulfonylureas due to duplicate metabolism through the CYP2C9 enzyme can also potentiate hypoglycemia.[13] It is essential to monitor for potentially harmful drug-drug interactions with concurrent therapy with salicylates, sulfonamides, drugs containing fibric acid, and warfarin.[10] Additional medications that may inhibit or induce CYP2C9 include azole antifungals, carbamazepine, phenobarbital, rifampin, St. Johns wort, and dexamethasone. The most beneficial way to mitigate sulfonylurea and glyburide toxicity is to elevate the patient's blood glucose back to its normalized range, depending on the setting.[13]

Enhancing Healthcare Team Outcomes

Members of the interprofessional healthcare team, such as physicians, pharmacists, nurses, and nurse practitioners, must work together to ensure that the best possible treatment outcomes occur in type 2 diabetes patients. Consistent monitoring of blood glucose and HbA1C is vital in determining treatment success with glyburide. It is also crucial for all interprofessional healthcare providers to recognize the signs, symptoms, and frequency of hypoglycemia if it occurs while the patient is on glyburide and report back to the senior clinician managing the patient. The best clinician judgment is necessary at the first signs of hypoglycemia to determine if therapy should continue or not. If patients with diabetes mellitus type 2 are not at their goal HbA1C or blood glucose targets, glyburide dosages may be increased every 2 to 4 weeks until meeting the desired objective.[10] Upon initiating glyburide, starting at a low dosage would be considered the safest precautionary measure regarding hypoglycemia and possible weight gain.

Nursing is also integral to glyburide therapy management for reporting possible hypoglycemia and educating patients of the signs of hypoglycemia, which should be reported to the rest of the team immediately if present. At the same time, the pharmacist, nurse practitioner, and primary care provider should inform the patient regarding a positive lifestyle; this means the discontinuation of smoking, eating a healthy diet, joining an exercise program, and maintaining a healthy body weight. There is ample evidence indicating that a lower body weight leads to better control of diabetes.[14] [Level 5] Pharmacists should verify appropriate dosing and perform medication reconciliation, as glyburide does have several significant drug-drug interactions, which require informing the rest of the healthcare team if present.

In summary, while glyburide therapy can be useful for glycemic control in type 2 diabetes patients, it requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level 5]