Sulfonylureas


Article Author:
Ryan Costello


Article Editor:
Abhijit Shivkumar


Editors In Chief:
Stephen Leslie
Karim Hamawy


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
5/10/2019 6:04:06 PM

Indications

This class of medications represents a group of anti-hyperglycemic agents mainly used in the treatment of type 2 diabetes mellitus. Sulfonylureas, commonly divided into first and second generations, can be utilized as adjuvant therapy with metformin in patients not at target hemoglobin A1c after 3 months on biguanides. If a patient’s hemoglobin A1c initially is greater than 9.0%, providers can consider combination therapy with metformin and a sulfonylurea or other anti-hyperglycemic agent. Additionally, sulfonylurea monotherapy can be considered in patients intolerant to metformin or in those who have a contraindication to this medication. Sulfonylureas can be used in combination with any other class of oral diabetic medications besides meglitinides. Infants with permanent neonatal diabetes also tend to respond well to sulfonylurea treatment. Examples of first-generation sulfonylureas include chlorpropamide, tolazamide, and tolbutamide, while second-generation sulfonylureas include glipizide, gliclazide, and glyburide. Glimepiride occasionally is referred to as a third-generation medication, though it commonly is classified as second-generation. Furthermore, chlorpropamide, glyburide, and glimepiride have a prolonged duration of action when compared to short-acting medications such as gliclazide and tolbutamide. Due to their low cost, wide availability, and effectiveness, sulfonylureas have remained a frequently prescribed medication despite potential hypoglycemic risks.[1][2][3][4][5][6][7][8][1]

Mechanism of Action

Sulfonylureas increase the release of insulin through the stimulation of pancreatic beta cells. By binding to a subunit of potassium ATP-dependent channels are known as the sulfonylurea receptor, this class of medications impedes the cellular release of potassium leading to cell depolarization. As a result, an inflow of calcium into the cell occurs and causes an increase in insulin exocytosis. Sulfonylureas, consequently, are a more potent medication in the earlier stages of type 2 diabetes when a patient has an increased pancreatic beta cell function. In addition, various types of the sulfonylurea subunit exist including SUR1, which is the receptor located on the beta cells of the pancreas as well as the brain, and SUR2, which is located on cardiac, skeletal, and smooth muscles. Individual medications within the sulfonylurea class have a varied affinity for these receptors which can potentially explain some of the side effects of sulfonylureas, particularly concerning the cardiovascular risks of these insulin secretagogues. Other effects of sulfonylureas include increasing the growth and sensitivity of insulin receptors on other tissues like adipocytes and triggering hepatic gluconeogenesis.[9][3][10][11][6]

Administration

All sulfonylureas are taken orally and bind mainly to albumin after absorption occurs in the intestines. To improve efficacy, medications in this class should be taken about 30 minutes before meals. Low starting doses with an increase in dosage every other week until effective blood glucose control has been achieved remains the cornerstone of sulfonylurea therapy. Commonly avoided, higher doses of these insulin secretagogues result in an increased risk of hypoglycemia and rarely enhance management of consistently elevated blood sugars.[6]

Adverse Effects

Hypoglycemia remains the most common side effect reported with the administration of sulfonylureas, though it occurs more frequently with long-acting medications. With an annual first episode risk of about 1.8% for a low blood sugar episode, this diagnosis more typically occurs after periods of fasting or exercise. Particularly in the elderly population, hypoglycemia may go unrecognized, and these patients may experience difficulty communicating their symptoms to others. When compared to other sulfonylureas in the second generation, glyburide has been shown to possess a higher hypoglycemic risk. Furthermore, a potential weight gain of around 2.06 kilograms can be expected while taking sulfonylureas. The cardiovascular safety profile of this class of medications has remained uncertain, though sulfonylureas do appear to increase the risk of acute myocardial infarction and stroke with about 1.2 more cardiovascular disease-related events per 1000 person-years when compared to metformin. Utilization of sulfonylureas rarely can cause dermatologic side effects including photosensitivity and erythroderma. Moreover, chlorpropamide can lead to facial flushing after the consumption of alcohol as well as hyponatremia; both of these effects are unique to this first generation sulfonylurea.[12][13][5][14][6][15]

Contraindications

Cross-reactivity of sulfonamides has been highly debated in patients with a sulfa allergy. One model suggests careful monitoring if sulfonylureas are prescribed in a sulfa-allergic patient with alternative therapy being considered. However, this class of medications may be best avoided in sulfa-allergic patients who experienced prior severe allergic reactions. For patients with gestational diabetes, glyburide can be considered for use in pregnancy, as fetal adverse effect profiles have been shown to be similar to that of insulin. Despite these findings, fetuses could potentially experience hypoglycemia as some of this medication could enter fetal circulation in theory. Additionally, the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults lists glyburide as a medication that should generally be avoided in geriatric patients.[16][17][18]

Monitoring

In patients who have a diagnosis of renal failure, the effects of sulfonylureas may become more prolonged; therefore, a creatinine level should be checked regularly. Genetic mutations that encode for potassium ATP-dependent channels as well as the failure of pancreatic beta cells can also influence the effectiveness of sulfonylureas and should be considered in patients whose glycemic control is not improved while taking these medications. Due to the potential side effect of weight gain, regular weights should be obtained at clinical visits. In addition, a hemoglobin A1c should be regularly monitored up to four times a year, depending on glycemic control with a goal of less than 7.0%. Monotherapy with sulfonylureas has been shown to decrease hemoglobin A1c values by approximately 1.5%.[19][6][20]

Toxicity

With the vast majority of exposures classified as unintentional, sulfonylurea overdoses involved children 6 years or younger in approximately half of all single-substance incidents. Toxicity due to sulfonylureas commonly includes an episode of hypoglycemia, which may present up to 12 hours after the inciting event and last for multiple days. Possible risk factors for unintentional toxicities in diabetic patients on chronic sulfonylurea therapy consist of advanced age, poor nutrition, beta blocker or insulin use, and the use of long-acting sulfonylureas such as glyburide, glimepiride, and chlorpropamide. A hypoglycemic patient can initially appear asymptomatic but may later develop tachycardia, drowsiness, agitation, and confusion. These symptoms can lead to seizures, coma, hypotension, and even death if the blood sugar continues to decrease or if it goes untreated. The initial management of low blood glucose secondary to sulfonylurea administration consists of intravenous dextrose or oral glucose tablets with a likely transition to a continuous intravenous infusion of a rapidly metabolized sugar. Activated charcoal can also be considered with substantial ingestions that may be observed with suicide attempts. Recurrent hypoglycemia can ensue through the utilization of intravenous dextrose via the release of insulin after the administration of dextrose leads to hyperglycemia. Consequently, hourly blood glucose monitoring should be performed in suspected sulfonylurea toxicity cases and should be considered more frequently in patients with active symptoms of hypoglycemia. In patients who remain hypoglycemic despite treatment with supplemental intravenous carbohydrates, octreotide has been effective in the prevention of additional insulin secretion and the resulting hypoglycemia potentiated by dextrose. This somatostatin analog has essentially replaced the use of diazoxide and glucagon in the treatment of sulfonylurea-induced hypoglycemia. In a patient without symptoms, an observation period of at least 8 hours with hourly blood sugar monitoring should ensue before considering discharge from a healthcare facility. If timely treatment is initiated, favorable outcomes from sulfonylurea overdoses typically result.[21][7]

Enhancing Healthcare Team Outcomes

The management of type 2 diabetes is with a multidisciplinary team that includes a diabetic educator, a primary care provider, and possibly an endocrinologist. Sulfonylureas are typically considered for management of hyperglycemia after a trial of biguanide therapy or if a patient is intolerant to metformin.  Hypoglycemia is a known side effect of this class of medications and patients' blood sugars should be regualrly monitored if they are on a regimen involving a sulfonylurea. Patients taking sulfonylureas also should have their renal function and body weight monitored regularly. (Level V)


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Sulfonylureas - Questions

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A 42-year-old male presents to the clinic for a three-month follow-up of type 2 diabetes mellitus. His HbA1c today is 8.1% while it was 8.8% three months ago. His current medication regimen includes metformin and repaglinide. You are considering making changes to his medication regimen. He does not have any past medical history of pancreatitis, medullary thyroid cancer, recurrent UTIs, amputations, congestive heart failure, and has normal kidney function. Which of the following would be an inappropriate change to his medication regimen?



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A 72-year-old non-insulin dependent female reports to your office stating her blood sugar levels have been running in the high 40s and she is concerned about her diabetic regimen. What receptor does the medication most likely causing this side effect work on?



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A 70-year-old male presents to the clinic for a follow-up appointment for type 2 diabetes. The patient has brought a blood sugar log that shows his blood sugars have occasionally been as low as 40mg/dl when he awakes in the morning. He adds that at this blood sugar level, he prefers to chew a candy. His HbA1c two months ago was 7.2, and his current medication regimen for diabetes includes metformin, glyburide, liraglutide, and dapagliflozin. What is the most appropriate adjustment in his current diabetic regimen?



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A 64-year-old male presents to the clinic complaining of frequent awakenings at night due to the severe restlessness. He also adds that whenever he wakes up from sleep, he suffers from severe headache. His past medical history is significant for hypertension, hyperlipidemia, coronary artery disease, and type 2 diabetes. Currently, he is taking aspirin, lisinopril, atorvastatin, and glyburide. Based on the clinical presentation, which of the following medications is most likely contributing to these side effects?



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A 52-year-old female patient is seen in the clinic for a follow-up of type 2 diabetes mellitus. The patient states that since her last visit three months ago she has gained 8 pounds weight. She is concerned about this change in her weight as she is already morbidly obese. Her medication regimen for diabetes includes metformin, exenatide, glimepiride, and insulin glargine. Which of the following medications are the most likely to be contributing to this side effect?



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An 18-year-old male presents to the clinic for the follow-up of previously diagnosed diabetes mellitus. The patient states that in his previous hospitalization he was found to have elevated blood sugar, nausea, vomiting, and abdominal pain. At that point, his His HbA1c was found to be 13.2. He also had a positive GAD-65 and islet cell antibody. The patient says he was discharged from the hospital on 25U of insulin glargine and 5U insulin aspart to be taken with meals plus a sliding scale. He says he recently saw multiple commercials for other medications for diabetes including semaglutide, glimepiride, and empagliflozin and wants to know if he can have a prescription for one of these medications. Which of the following recommendations will you make to the patient?



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A 52-year-old male presents to the clinic for a three-month follow-up of his type 2 diabetes mellitus. He was recently started on a medication that binds to a subunit of potassium ATP-dependent channels to stimulate pancreatic beta cells to produce insulin due to being intolerant to metformin. Monotherapy of this medication has been shown to decrease a patient's hemoglobin A1c value by an average of what percentage?



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You are on your endocrinology rotation and are reviewing charts for patients with afternoon appointments. Which of the following patients may be a candidate for diabetic medications that bind to a subunit of potassium ATP-dependent channels to stimulate the pancreatic beta cells?



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A 36-year-old male presents to clinic today to discuss his diabetic regimen. He says he has suffered from weight gain and has had a number of hypoglycemic episodes since starting a new medication for diabetes. On which of the following cell types of the pancreas does the drug most likely causing this side effect act?



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A 73-year-old male presents to the emergency department (ED) for altered mental status. The caregiver explains that the patient had a decreased appetite the day before and was difficult to arouse this morning. He has a past medical history significant for hypertension well-controlled on losartan and type 2 diabetes mellitus for which he takes both metformin and glimepiride. The patient was tachycardic, slightly hypotensive, and altered on exam. Laboratory data revealed a blood sugar of 36. Intravenous dextrose was pushed in the ED, and his blood sugar remained low at 42 mg/dL. How should the patient be managed at this time?



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A 30-year-old non-obese female presents to clinic for follow-up visit concerning her type 2 diabetes management. She currently takes metformin 1000 mg BID and her most recent hemoglobin A1c after three months on this therapy was 8.2%. She is concerned about affordability of medications as she does not have medical insurance. Considering her financial limitations, you try to prescribe the least costly medication for her. What is the mechanism of action of the medication you will prescribe?



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A 43-year-old female is seen in the clinic as a new patient for type 2 diabetes mellitus. Patient states she cannot remember the medications she takes but knows that one of her medications was recently increased from 500 mg twice a day to 1000 mg twice a day. She also adds that her previous physician explained to her that diabetic medication could potentially cause low blood sugars, so she should check her blood sugars regularly. She denies taking any injectable medications. In addition to an HbA1c, what other labs should be checked in this patient during this visit?



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A 46-year-old type 2 diabetic male presents to the clinic for a three-month follow-up. The patient reports he recently noticed that whenever he drinks alcohol, he experiences facial flushing. He also added that recently his diabetic drug regimen was also changed. On this recent visit, his labs also revealed mild hyponatremia. What is the most likely medication that is causing this adverse effect profile?



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A 72-year-old male presents to the clinic for a 3-month check-up of a type 2 diabetes mellitus. He was recently started on metformin. On his last visit, his Hb A1c was 8.6% while today his HbA1c is 8.0%. Based on the results the provider is planning of adding a second agent. Which of the following agents should specifically be avoided in this patient?



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Sulfonylureas - References

References

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