Glyburide

Mechanism of Action

Glyburide, along with others in the sulfonylurea class, exerts its mechanism of action based on increasing insulin secretion from beta cells in the pancreas.[6] Specifically, sulfonylureas bind to the SUR1 receptors in the membranes of the beta cells of potassium ATP-dependent channels.[6][7]

These agents block these channels, releasing insulin after the cell depolarizes.[8] At times, sulfonylureas bind to SUR2 receptors on cells in cardiac tissue and the endothelium.[7] 

After the initial insulin secretion, sulfonylureas can also decrease insulin clearance in the liver, increasing plasma insulin levels.[9] Glyburide, along with glipizide, is classified as a second-generation sulfonylurea due to its increased potency and difference in elimination, allowing their use in patients with renal and hepatic dysfunction.

Pharmacokinetics

Glyburide is metabolized in the liver via the CYP450 system; it is a CYP2C9 substrate. The drug has a half-life of 10 hours and is excreted in the bile (50%) and urine (50%).

Administration

Glyburide is available in 1.25 mg, 2.5 mg, and 5 mg tablets.

Dosage for type 2 diabetes: 1.25 mg to 20 mg orally, once or divided twice daily.

Formulation note: non-micronized and micronized glyburide formulations are not bioequivalent. Dosing must be re-titrated when switching between formulations.

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 do not require dosages higher than 10 mg per day.[1] Clinical effects are also insignificant beyond dosages of 10 to 15 mg daily.[1][9] 

To optimize absorption and maximize the antidiabetic effect of sulfonylureas, including glyburide, it is recommended to take them orally approximately 30 minutes before meals, as food intake and hyperglycemia may potentially decrease their absorption.[1] Patients should take lower doses of glyburide (≤10 mg) with breakfast or as soon as the patient consumes the breakfast meal, with higher daily doses (>10 mg) usually divided between breakfast and evening meals.[1]

Renal dosing: CrCl <60; avoid use. Avoid use in patients on dialysis.

Hepatic dosing: Start dosing at 1.25 mg in patients with hepatic impairment.

Pregnancy: Multiple studies have examined glyburide use in pregnant patients with gestational diabetes. Although the FDA considers glyburide a Category C drug, expert bodies have started to introduce introducing glyburide as a possible alternative to insulin for antidiabetic therapy. Glyburide crosses the placenta in utero and is metabolized by placental microsomes, exposing the fetus to the medication. 

Lactation: Concerning lactation, both glyburide and its second-generation counterpart, glipizide, are compatible with breastfeeding as they do not transfer into breast milk or pose no known risk of harm to breastfed infants.[7]

Adverse Effects

Adverse Drug Reactions

Hypoglycemia and weight gain are the most frequently encountered adverse effects of glyburide. Although glyburide is one of the most popular sulfonylureas prescribed, a systematic review conducted by the ADA found evidence suggesting that glyburide correlates with a significantly higher risk of hypoglycemic episodes than other insulin secretagogues sulfonylureas by 80% and 44%, respectively.[10] However, these episodes are most often seen with higher initial glyburide dosing and in patients recently diagnosed, especially those 65 years and older.[1] For this reason, clinicians must consider patient-specific factors and susceptibility to hypoglycemic episodes when considering a glyburide prescription 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 those aged 65 and older.[11] 

The ADA Standards of Medical Care in Diabetes 2023 update also considers long-acting sulfonylureas, such as glyburide, as agents to avoid in older adults due to the risk of hypoglycemia and advises against the drug's use in this population. Treatment with glyburide in this at-risk patient population, especially those with more advanced age and complex medical conditions, is considered "overtreatment" per the ADA. Therefore, treatment de-intensification should be considered via dose reduction, discontinuation, or utilization of lower-risk agents, as long as individualized glycemic targets are continually achieved.[12]

Possible weight gain can also be a distressing adverse effect for patients taking glyburide, as with all sulfonylureas. According to the ADA's systematic review, glyburide is less significantly associated with weight gain than other insulin secretagogues. However, if weight gain does occur, coadministration with metformin, a weight-neutral biguanide agent, can be considered to address this issue.[1][10]

A cohort study on patients with type 2 diabetes compared all-cause and cardiovascular mortality for patients on either glyburide or metformin for blood glucose management.[13] The study found that glyburide monotherapy, 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 than glyburide and other drugs of its class.[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.[9]

Drug-Drug Interactions

Concurrent use of glyburide with bosentan is contraindicated.

Monitoring for potentially harmful drug-drug interactions is crucial when patients receive concurrent therapy with salicylates, sulfonamides, drugs containing fibric acid, and warfarin.[9] 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 level back to its normalized range, depending on the setting.[13]

Contraindications

Glyburide has no boxed warnings.

Contraindications

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

Also, prescribers must use caution with glyburide in hospitalized patients, who are malnourished, misuse alcohol, have renal and cardiac dysfunctions, or with gastrointestinal disease.[9]

Monitoring

As glyburide rates for hypoglycemia can be higher 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 take proper measures if the condition occurs in any patient. Monitoring glyburide is also necessary for patients in circumstances that provoke the onset of hypoglycemia, including exercise, lack of eating, and accidental overdosage.[9] 

To ensure patient safety, it is crucial to be aware of the signs and symptoms of hypoglycemia when initiating glyburide therapy. Patients should be educated on self-monitoring of blood glucose levels and adhere to regularly scheduled blood glucose and HbA1C testing as the ADA recommends.

Glyburide and other sulfonylureas may also cause liver dysfunction, potentially resulting in cholestatic jaundice, hepatitis, and liver failure, although this is rare.[9] In patients with liver dysfunction, monitoring of liver function tests may be necessary.

Toxicity

Glyburide toxicity is primarily associated with the risk of severe hypoglycemia due to an excessive dosage, whether it occurs accidentally or intentionally.[9][13] Due to duplicate metabolism involving the CYP2C9 enzyme, drug-drug interactions between glyburide and other sulfonylureas can also potentiate hypoglycemia.[13] 

Enhancing Healthcare Team Outcomes

The interprofessional healthcare team, including clinicians and pharmacists, must work together to ensure that the best possible treatment outcomes occur in patients with type 2 diabetes. Consistent monitoring of blood glucose and HbA1C levels is vital in determining treatment success with glyburide. Interprofessional healthcare providers play a crucial role in recognizing the signs and symptoms of hypoglycemia and the frequency of hypoglycemic events while the patient is on glyburide.

Strong clinician judgment is necessary at the first signs of hypoglycemia to determine the appropriateness of continuing therapy. If patients with type 2 diabetes are not at their goal HbA1C or blood glucose target levels, glyburide dosages may be increased every 2 to 4 weeks until meeting the desired objective.[9] After initiating glyburide, starting at a low dosage would be considered the safest precaution to mitigate the risk of hypoglycemia and possible weight gain.

Nursing plays a crucial role in glyburide therapy management by reporting potential hypoglycemia and educating patients about its signs, which should be promptly communicated to the rest of the healthcare team. Simultaneously, the pharmacist, nurse practitioner, and primary care provider should educate the patient about the importance of positive lifestyle modifications, including smoking cessation, adopting a healthy diet, participating in an exercise program, and maintaining healthy body weight, as ample evidence supports the benefits of lower body weight in achieving better diabetes control.[14] [Level 5]

Pharmacists play a critical role in glyburide therapy by verifying appropriate dosing, conducting medication reconciliation, and identifying significant drug-drug interactions, which should be communicated to the rest of the healthcare team for comprehensive patient care.

In summary, the effective use of glyburide therapy for glycemic control in patients with type 2 diabetes necessitates an interprofessional team approach involving physicians, specialists, specialty-trained nurses, and pharmacists. This collaborative effort, characterized by open communication and shared decision-making, is essential to achieve optimal patient outcomes and ensure the success of glyburide treatment. [Level 5]