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Side effect of sulfonylureas: Sulfonylureas – Side Effects & Precautions

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Sulfonylureas – Side Effects & Precautions

This class of drugs can be an important part of a type 2 diabetes treatment plan.

Sulfonylureas are a group of medicines used to treat type 2 diabetes.

With type 2 diabetes, the body doesn’t use the hormone insulin properly, leading to elevated levels of blood sugar (glucose).

The first sulfonylureas were developed in the 1950s.

The drugs work by increasing the release of insulin from the pancreas.

Sulfonylureas are only one part of a treatment plan for type 2 diabetes, which should also include diet and exercise to help control blood sugar levels.

Taking sulfonylureas, along with adopting a healthy lifestyle, can reduce your risk of developing serious or life-threatening complications of diabetes, which may include heart disease, stroke, nerve damage, kidney problems, or eye problems.

Common Sulfonylureas

Some commonly prescribed sulfonylureas include:

Sulfonylureas are often taken in combination with other medicines, especially the drug metformin.

Side Effects of Sulfonylureas

Side effects of sulfonylureas may include:

Sulfonylurea Precautions

Sulfonylureas shouldn’t be taken by people with type 1 diabetes or diabetic ketoacidosis (a dangerous condition that can occur if high blood sugar is left untreated).

People with liver or kidney problems may not be able to take sulfonylureas. Talk to your doctor if this is a concern.

Some sulfonylureas may make your skin more sensitive to sunlight. Avoid unnecessary exposure to the sun, and wear sunscreen and protective clothing while outdoors.

Sulfonylureas typically cause changes in your blood sugar levels. You should know the symptoms of high and low blood sugar, and what to do if you experience them.

Some oral diabetes drugs may increase your risk of serious heart problems.

Not treating your diabetes can damage your heart and other organs. Talk to your doctor about these risks.

Your doctor will probably want to check your blood sugar and urine sugar levels often while you’re taking a sulfonylurea. Keep all appointments with your doctor’s office and laboratory.

Consider wearing a diabetic ID bracelet to be sure you get proper treatment in case of an emergency.

Let your healthcare provider know you’re taking a sulfonylurea before having any type of medical procedure, including a dental procedure.

Tell your doctor about all prescription, non-prescription, illegal, recreational, herbal, nutritional, or dietary drugs you’re taking before starting on a sulfonylurea.

Sulfonylureas and Alcohol

Alcohol may worsen certain side effects of sulfonylureas.

Limit or avoid drinking alcohol while taking these medicines.

Sulfonylureas and Pregnancy

Tell your doctor if you’re pregnant or might become pregnant while taking a sulfonylurea.

It’s not known whether these drugs are safe to use during pregnancy.

Also, talk to your healthcare provider before taking sulfonylureas if you’re breastfeeding.

Sulfonylureas – StatPearls – NCBI Bookshelf

Continuing Education Activity

Sulfonylureas represent a class of medications utilized in the treatment of type 2 diabetes mellitus. This activity outlines the indications, mechanism of action, administration, adverse effects, contraindications, monitoring, and toxicity of sulfonylureas. The importance of utilizing a multi-disciplinary approach to managing patients taking sulfonylureas will also be highlighted.

Objectives:

  • Describe the mechanism of action of sulfonylureas.

  • Explain the potential adverse effects of sulfonylureas.

  • Review sulfonylurea overdoses and the treatment options available.

  • Summarize the importance of utilizing an interprofessional team approach to caring for diabetic patients taking sulfonylureas.

Access free multiple choice questions on this topic.

Indications

Sulfonylureas are the oldest class of oral antidiabetic medication dating back to the 1950s.[1] All sulfonylureas contain a phenyl-sulfonyl-urea structure, which exerts the hypoglycemic effect.[2] Patients with type 2 diabetes mellitus use sulfonylureas as monotherapy or in combination with other oral or injectable medications.[3][4][5] Sulfonylureas are divided into first-generation and second-generation. The first-generation sulfonylureas include chlorpropamide and tolbutamide.[6] Chlorpropamide is no longer available in the United States. The second-generation sulfonylureas include glyburide (also known as glibenclamide), glipizide, glimepiride, and gliclazide. Gliclazide is not available in the United States.[7] Glimepiride came to market in 1995, and it is the newest sulfonylurea.[8] Some references list glimepiride as a third-generation sulfonylurea because its chemical structure has a larger substitution moiety than the other second-generation sulfonylureas.[9]

Sulfonylureas are comparable in efficacy and decrease the glycated hemoglobin A1C (HbA1c) by 1% to 1.25%.[10][11][12][13] Second-generation sulfonylureas are among the most used anti-diabetic medications because they are inexpensive.[4] Providers rarely prescribe first-generation sulfonylureas nowadays.[14] Sulfonylureas are not preferred for elderly patients and those with renal or hepatic impairment.[4] Patients with type 2 diabetes can take sulfonylureas in combination with any other oral antidiabetic medication except the meglitinides (nateglinide and repaglinide).[5]

Similar to sulfonylureas, meglitinides stimulate the pancreatic beta cells to secrete insulin.[15] Clinicians often prescribe sulfonylurea as an add-on to metformin.[16] This combination targets different mechanisms of action and improves glucose control; sulfonylureas stimulate insulin secretion while metformin increases insulin sensitivity. An advantage to this combination is the potential for a neutral effect on the patient’s body weight since sulfonylureas cause weight gain while metformin causes weight loss.[16] A Canadian study showed the combination of acarbose and sulfonylurea to have beneficial effects on HbA1c levels. The combination of sulfonylureas with thiazolidinediones improves glycemic control. 

Mechanism of Action

Sulfonylureas bind to and inhibit the ATP-sensitive potassium channels (K) on the pancreatic beta cells. As a result, potassium efflux decreases, and the beta-cell membrane depolarizes. Membrane depolarization causes calcium channels to open, leading to calcium influx and increased intracellular calcium, which stimulates insulin secretion from the pancreatic beta cells.[17][2] Sulfonylureas cause insulin release regardless of blood glucose levels.[18] K is made of two proteins, Kir6.2 that forms the pore of the K channels, and a sulfonylurea receptor (SUR).[19] SUR1 and SUR2 are subtypes of SUR.[20]

The SUR1 is mostly present in the brain and on the beta cells in the pancreas. SUR2 is present in the cardiac muscle (as isoform SUR2A) and the smooth muscle (as isoform SUR2B). Sulfonylureas differ in their affinity to the SUR subtype receptors and their efficacy in closing the K channels. Unlike the other sulfonylureas, glimepiride has a lower affinity to the cardiac muscles and is not associated with cardiovascular safety concerns.[18] Sulfonylureas also lower the serum glucose levels by decreasing insulin metabolism in the liver, decreasing glucagon secretion, and increasing sensitivity to insulin in peripheral tissues.2.[24]

Glipizide is available in an IR and an extended-release (ER) oral tablet.[3] Glipizide IR has an intermediate duration of action, and glipizide ER has a long duration of action.[5] The starting dose is 5 mg per day for both formulations. The maximum daily dose of glipizide IR is 40 mg per day, while the maximum dose for glipizide ER is 20 mg per day.[3] Food delays the absorption of glipizide IR by 30 minutes, which leads to a delay in onset of action and less control of blood glucose. Therefore, administer the scheduled dose of glipizide IR 30 minutes before a meal; this allows enough time for insulin release and glucose control in response to food ingestion.[25] Administer glipizide ER with a meal. The American Diabetes Association (ADA) guideline recommends starting glipizide at a conservative dose in patients with chronic kidney disease (CKD) to avoid hypoglycemia.[26]

Glimepiride is available as an IR oral tablet. Start glimepiride at 1 to 2 mg per day and a maximum daily dose of 8 mg.2.[26][27]

Gliclazide is available as an IR oral tablet and a modified release (MR) oral tablet. Administer immediate release gliclazide two times daily, 30 minutes before a meal.[28] Gliclazide IR is available as an 80 mg tablet, and the maximum daily dose is 320 mg.[29] Gliclazide MR is available in 30 mg and 60 mg tablets.[30] Administer gliclazide MR once daily with a meal with a maximum dose of 120 mg per day.[30][31]

If a patient is fasting, reduce or hold the sulfonylurea dose and ensure self-monitoring of glucose levels.[32]

Adverse Effects

Sulfonylureas stimulate insulin secretion regardless of the serum glucose levels.[33] Therefore, hypoglycemia is the most common side effect and a major concern associated with sulfonylureas.[2] Hypoglycemia occurs when blood glucose levels drop below 70 mg/dL.[34] Patients may experience sweating, shakiness, irritability, confusion, tachycardia, and a feeling of hunger. Hypoglycemia may be severe, especially after a missed meal, exercise, or taking sulfonylureas at a high dose.[35][36][4][37] Glipizide, glimepiride, and gliclazide are associated with a lower incidence of hypoglycemia compared to glyburide.[4][38] Because sulfonylureas bind to plasma proteins with high affinity, the risk of hypoglycemia increases when certain medications displace sulfonylureas from their plasma protein binding sites. Examples include sulfonamides, gemfibrozil, and warfarin.[39]

Weight gain is common with sulfonylureas.[40] The ADA guideline recommends considering the patient’s weight when selecting an antidiabetic drug.[41] Avoid prescribing sulfonylureas to obese patients.[40]

Other common side effects include nausea, diarrhea, dizziness, and headache.[7] Chlorpropamide and tolbutamide cause facial flushing with alcohol.[42]

The University Group Diabetes Program (UGDP) trial showed an increased risk of mortality with tolbutamide.[43] As a result, the Food and Drug Administration (FDA) required a boxed warning about the increased risk of cardiovascular events with all sulfonylureas and that manufacturers must prove the cardiovascular safety of all new antidiabetic medications.[44]

Glimepiride is not associated with an increased cardiovascular risk.[43] The Cardiovascular and Renal Microvascular Outcome Study with Linagliptin (CARMELINA) showed the dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin, to have neutral cardiovascular safety effects.[45] The Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients with Type 2 Diabetes (CAROLINA) showed similar cardiovascular outcomes between glimepiride and linagliptin.[46]

The ADA guideline recommends metformin as a first-line agent for all patients with type 2 diabetes unless contraindicated.[26] Studies have shown other antidiabetic drug classes to be as effective as sulfonylureas in lowering HbA1c. [1] Oral antidiabetic agents, except meglitinides (i.e., nateglinide and repaglinide), pose less risk of hypoglycemia than sulfonylureas.[47] Some of the newer antidiabetic drug classes have shown to have either neutral cardiovascular effects or cardiovascular benefits.[44] Therefore, in the absence of financial restrictions and given the availability of safer alternatives, patients should not receive sulfonylureas as second-line agents.[1] If a sulfonylurea is necessary for an elderly patient, the ADA guideline recommends using glipizide or glimepiride over glyburide since they are shorter acting and associated with less risk of hypoglycemia.[48]

Contraindications

The Beers Criteria for potentially inappropriate medication use in older adults includes chlorpropamide and glyburide.[49] Older adults may experience prolonged hypoglycemia with these long-acting agents. Chlorpropamide can also cause the syndrome of inappropriate antidiuretic hormone secretion. The 2012 American Geriatric Society Beers Criteria highly recommends and with strong evidence to avoid chlorpropamide and glyburide in older adults. 

There is a debate whether hypersensitivity to sulfonamides is a contraindication to prescribing sulfonylureas.[50] A literature review suggested that patients with allergies to sulfonamides may not need to avoid sulfonylureas.[51] However, given the small number of patients reviewed, there is limited data to confirm or refute the need to avoid sulfonylureas in patients with sulfa allergy. The medication package insert provides the FDA-approved product information, including contraindications.[52] Providers should review this information carefully. The court may determine a provider to be negligent if they prescribe a contraindicated medication that causes harm to a patient.[52]

Oral antidiabetic agents, including sulfonylureas, are not FDA-approved for use in pregnancy and lactation.[53] However, according to the National Institute for Health and Clinical Excellence (NICE) guidance, glyburide is safe in pregnancy and lactation.[54] The Endocrine Society supports the NICE guidance in recommending glyburide for gestational diabetes in selected patients.[53]

The ADA guideline recommends avoiding glyburide in patients with CKD.[26]

Monitoring

The ADA guideline recommends monitoring HbA1c levels at least quarterly after therapy change or if patients do not meet glycemic goals.[55] Providers can monitor HbA1c levels less frequently but at least twice a year in patients who meet their glycemic goal.2.[59]

Instruct patients to perform self-glucose monitoring when they develop symptoms of hypoglycemia.[1] Patients should share this information with their health care provider to guide therapy adjustment. 

Toxicity

Sulfonylureas have a narrow therapeutic index.[35] Hypoglycemia is the most common toxicity associated with intentional or accidental overdose of sulfonylureas and may take up to 12 hours to occur.[35][60] Some symptoms of hypoglycemia are shakiness, irritability, tachycardia, confusion, and hunger. [55] In severe cases, hypoglycemia may lead to loss of consciousness, seizure, coma, or death. In children ages 1 to 4 years old, hypoglycemia occurred with the accidental ingestion of one of the following: chlorpropamide 250 mg, glipizide 5 mg, or glyburide 2.5 mg. [61]

Educate patients that the hypoglycemia alert value is ≤ 70 mg/dL (3.9 mmol/L).[62]  The ADA guideline recommends 15 to 20 grams of pure oral glucose as the treatment of choice for hypoglycemia.[55] Pure glucose provides a better response than food containing carbohydrates. Fat content may delay response to the carbohydrate-containing food, and protein may worsen the hypoglycemic episodes by stimulating insulin release without increasing blood glucose levels.[63]

The “Rule of 15” or “15-15” rule applies to treatment with glucose. The patient should receive 15 grams of glucose, recheck blood glucose levels 15 minutes later, and repeat the process as needed until hypoglycemia resolves.[64] Sources of oral glucose include, but are not limited to, glucose tablets, juice, or soft drink.[35] Depending on the duration of action of the sulfonylurea responsible for the overdose, hypoglycemia may reoccur.[62] Educate patients to eat a meal or a snack once their serum glucose is normal or trending up to prevent a recurrent hypoglycemic episode.[62][55]

In hospitalized patients, intravenous (IV) dextrose is the first-line therapy for severe hypoglycemia from sulfonylureas.[35] Patients may require a continuous IV infusion of dextrose to prevent recurrent hypoglycemia, especially with long-acting sulfonylureas.[65] Check blood glucose levels every 15 minutes.[66]

Glucagon stimulates glucose production in the liver and is useful for patients who refuse or cannot take oral glucose. [62] Glucagon is available in different formulations for various routes of administration.[67] The powder for injection requires reconstitution before intramuscular or subcutaneous administration. Newer formulations of glucagon that patients may favor do not require reconstitution. The FDA approved glucagon nasal powder in July 2019, which is a convenient portable dry spray. In September 2019, the FDA approved a solution for subcutaneous injection available in a prefilled syringe and an autoinjector. Educate all patients and their caregivers on proper glucagon administration techniques.[62]

Octreotide is a somatostatin analog that results in an effect opposite to that of sulfonylureas. By binding to the somatostatin-2 receptors on the pancreatic beta cells, octreotide inhibits calcium influx, thus blocking insulin secretion.[35] Since IV dextrose corrects hypoglycemia but may trigger insulin secretion and a recurrence of hypoglycemia, administering octreotide blocks the undesired insulin secretion in response to IV dextrose. Evidence supports the use of octreotide for hypoglycemia induced by sulfonylureas when dextrose alone does not normalize the blood glucose.[60] There is a debate regarding the best time to administer octreotide. Some experts recommend reserving octreotide to patients who experience recurrent hypoglycemia, while others recommend a proactive approach of initiating octreotide after the first hypoglycemic episode.[35]

Monitor all patients for 12 hours after hypoglycemia treatment to recognize and treat recurrent episodes.[35]

Enhancing Healthcare Team Outcomes

Diabetes mellitus is a chronic condition that can negatively affect various organ systems.[68] Diabetes is a major public health problem that has been on the rise.[69][70] Patients taking antidiabetic medications, including sulfonylureas, assess their HbA1c at least twice a year if they have been stable within therapeutic goals. Assess HbA1c at least three times a year if diabetes is uncontrolled.[55] [Level 5]

Available data supports an interprofessional team approach in diabetes care. An interprofessional healthcare team model for diabetes care may include clinicians (MDs, DOs, NPs, PAs), nurses, diabetes educators, dietitians, and pharmacists. Providers from different professions complement each other to improve patient outcomes and decrease healthcare costs.[71]

A clinician-pharmacist collaborative practice is beneficial to patients with diabetes.[72] This practice promotes better diabetes control with a reduction in HbA1c, reducing low-density lipoprotein (LDL) levels, improved screening for microalbuminuria, and an increased number of annual eye and foot exams. Pharmacists can also play a major role in interviewing patients to obtain an accurate medication history, identifying medication non-adherence, and adjusting medication regimens.[73]

Evidence supports implementing nurse champion models, including nurses, certified diabetes educators, and clinical mentors for diabetes care.[71] A nurse champion model results in a win-win situation for hospitals and patients. Hospitals save money by decreasing readmission rates and medication errors. Patients experience improved quality of life, reduction in HbA1c, decreased hospital readmissions, and greater weight loss. Overall, this collaborative effort leads to a higher standard of care for patients with diabetes. 

Dietitians serve as an invaluable resource for patients with diabetes. The evidence-based practice guideline by the Academy of Nutrition and Dietetics strongly supports dietitians in providing medical nutrition therapy to improve patient outcomes.[74]

The healthcare team should follow a patient-centered approach and tailor diabetes therapy to the patient’s needs.[75] The therapeutic plan should include the management of other risk factors or diabetes complications. The healthcare team should encourage physical activity and a healthy lifestyle, including smoking cessation and weight management, and treat hypertension and dyslipidemia to decrease cardiovascular risk. The healthcare team should identify and address barriers to medication adherence. [Level 2] For example, if the patient is diagnosed with depression, then treating depression effectively may improve medication adherence for chronic conditions like diabetes.[76]

The healthcare team should realize that food insecurity might complicate diabetes. Patients who do not have access to nutritious, healthy food may experience hyperglycemia, and patients who are unable to obtain food may experience hypoglycemia.[75] Whenever possible, the healthcare team should seek resources available in the community to help patients overcome food insecurity. [Level 5]

As mentioned before, hypoglycemia is a common adverse effect associated with sulfonylureas. Severe hypoglycemia may lead to serious consequences, including seizure, coma, or death. To minimize the risk of hypoglycemic events, the healthcare team should identify patients at risk of hypoglycemia and consider less stringent HbA1c goals.[55] [Level 3] In addition, reassess the target HbA1c levels over time as the goals might change based on the patient’s age and comorbidities. [Level 5] Inquire about episodes of hypoglycemia during each patient encounter. Remind patients and their caregivers to react to a serum glucose level of less than or equal to 70 mg/dL by consuming glucose. Remind them about the “15-15” rule. [Level 2] During each visit, assess their glucagon injection technique. Ensure that everyone involved in the patient’s care knows where glucagon is and remind them to replace the product before the expiration date.[55] [Level 5]

While newer and potentially safer alternatives are now available, sulfonylureas can be a useful adjunct in diabetes management, especially when the cost of therapy is an issue. Successful therapy requires a collaborative interprofessional effort to maximize the therapeutic efficacy of sulfonylureas while minimizing potential adverse events. [Level 5]

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Sulfonylureas – StatPearls – NCBI Bookshelf

Continuing Education Activity

Sulfonylureas represent a class of medications utilized in the treatment of type 2 diabetes mellitus. This activity outlines the indications, mechanism of action, administration, adverse effects, contraindications, monitoring, and toxicity of sulfonylureas. The importance of utilizing a multi-disciplinary approach to managing patients taking sulfonylureas will also be highlighted.

Objectives:

  • Describe the mechanism of action of sulfonylureas.

  • Explain the potential adverse effects of sulfonylureas.

  • Review sulfonylurea overdoses and the treatment options available.

  • Summarize the importance of utilizing an interprofessional team approach to caring for diabetic patients taking sulfonylureas.

Access free multiple choice questions on this topic.

Indications

Sulfonylureas are the oldest class of oral antidiabetic medication dating back to the 1950s.[1] All sulfonylureas contain a phenyl-sulfonyl-urea structure, which exerts the hypoglycemic effect.[2] Patients with type 2 diabetes mellitus use sulfonylureas as monotherapy or in combination with other oral or injectable medications.[3][4][5] Sulfonylureas are divided into first-generation and second-generation. The first-generation sulfonylureas include chlorpropamide and tolbutamide.[6] Chlorpropamide is no longer available in the United States. The second-generation sulfonylureas include glyburide (also known as glibenclamide), glipizide, glimepiride, and gliclazide. Gliclazide is not available in the United States.[7] Glimepiride came to market in 1995, and it is the newest sulfonylurea.[8] Some references list glimepiride as a third-generation sulfonylurea because its chemical structure has a larger substitution moiety than the other second-generation sulfonylureas.[9]

Sulfonylureas are comparable in efficacy and decrease the glycated hemoglobin A1C (HbA1c) by 1% to 1.25%.[10][11][12][13] Second-generation sulfonylureas are among the most used anti-diabetic medications because they are inexpensive.[4] Providers rarely prescribe first-generation sulfonylureas nowadays.[14] Sulfonylureas are not preferred for elderly patients and those with renal or hepatic impairment.[4] Patients with type 2 diabetes can take sulfonylureas in combination with any other oral antidiabetic medication except the meglitinides (nateglinide and repaglinide).[5]

Similar to sulfonylureas, meglitinides stimulate the pancreatic beta cells to secrete insulin.[15] Clinicians often prescribe sulfonylurea as an add-on to metformin.[16] This combination targets different mechanisms of action and improves glucose control; sulfonylureas stimulate insulin secretion while metformin increases insulin sensitivity. An advantage to this combination is the potential for a neutral effect on the patient’s body weight since sulfonylureas cause weight gain while metformin causes weight loss.[16] A Canadian study showed the combination of acarbose and sulfonylurea to have beneficial effects on HbA1c levels. The combination of sulfonylureas with thiazolidinediones improves glycemic control. 

Mechanism of Action

Sulfonylureas bind to and inhibit the ATP-sensitive potassium channels (K) on the pancreatic beta cells. As a result, potassium efflux decreases, and the beta-cell membrane depolarizes. Membrane depolarization causes calcium channels to open, leading to calcium influx and increased intracellular calcium, which stimulates insulin secretion from the pancreatic beta cells.[17][2] Sulfonylureas cause insulin release regardless of blood glucose levels.[18] K is made of two proteins, Kir6.2 that forms the pore of the K channels, and a sulfonylurea receptor (SUR).[19] SUR1 and SUR2 are subtypes of SUR.[20]

The SUR1 is mostly present in the brain and on the beta cells in the pancreas. SUR2 is present in the cardiac muscle (as isoform SUR2A) and the smooth muscle (as isoform SUR2B).2.[24]

Glipizide is available in an IR and an extended-release (ER) oral tablet.[3] Glipizide IR has an intermediate duration of action, and glipizide ER has a long duration of action.[5] The starting dose is 5 mg per day for both formulations. The maximum daily dose of glipizide IR is 40 mg per day, while the maximum dose for glipizide ER is 20 mg per day.[3] Food delays the absorption of glipizide IR by 30 minutes, which leads to a delay in onset of action and less control of blood glucose. Therefore, administer the scheduled dose of glipizide IR 30 minutes before a meal; this allows enough time for insulin release and glucose control in response to food ingestion.[25] Administer glipizide ER with a meal. The American Diabetes Association (ADA) guideline recommends starting glipizide at a conservative dose in patients with chronic kidney disease (CKD) to avoid hypoglycemia.[26]

Glimepiride is available as an IR oral tablet. Start glimepiride at 1 to 2 mg per day and a maximum daily dose of 8 mg.2.[26][27]

Gliclazide is available as an IR oral tablet and a modified release (MR) oral tablet. Administer immediate release gliclazide two times daily, 30 minutes before a meal.[28] Gliclazide IR is available as an 80 mg tablet, and the maximum daily dose is 320 mg.[29] Gliclazide MR is available in 30 mg and 60 mg tablets.[30] Administer gliclazide MR once daily with a meal with a maximum dose of 120 mg per day.[30][31]

If a patient is fasting, reduce or hold the sulfonylurea dose and ensure self-monitoring of glucose levels.[32]

Adverse Effects

Sulfonylureas stimulate insulin secretion regardless of the serum glucose levels.[33] Therefore, hypoglycemia is the most common side effect and a major concern associated with sulfonylureas.[2] Hypoglycemia occurs when blood glucose levels drop below 70 mg/dL.[34] Patients may experience sweating, shakiness, irritability, confusion, tachycardia, and a feeling of hunger. Hypoglycemia may be severe, especially after a missed meal, exercise, or taking sulfonylureas at a high dose.[35][36][4][37] Glipizide, glimepiride, and gliclazide are associated with a lower incidence of hypoglycemia compared to glyburide.[4][38] Because sulfonylureas bind to plasma proteins with high affinity, the risk of hypoglycemia increases when certain medications displace sulfonylureas from their plasma protein binding sites. Examples include sulfonamides, gemfibrozil, and warfarin.[39]

Weight gain is common with sulfonylureas.[40] The ADA guideline recommends considering the patient’s weight when selecting an antidiabetic drug.[41] Avoid prescribing sulfonylureas to obese patients.[40]

Other common side effects include nausea, diarrhea, dizziness, and headache.[7] Chlorpropamide and tolbutamide cause facial flushing with alcohol.[42]

The University Group Diabetes Program (UGDP) trial showed an increased risk of mortality with tolbutamide.[43] As a result, the Food and Drug Administration (FDA) required a boxed warning about the increased risk of cardiovascular events with all sulfonylureas and that manufacturers must prove the cardiovascular safety of all new antidiabetic medications.[44]

Glimepiride is not associated with an increased cardiovascular risk.[43] The Cardiovascular and Renal Microvascular Outcome Study with Linagliptin (CARMELINA) showed the dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin, to have neutral cardiovascular safety effects.[45] The Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients with Type 2 Diabetes (CAROLINA) showed similar cardiovascular outcomes between glimepiride and linagliptin.[46]

The ADA guideline recommends metformin as a first-line agent for all patients with type 2 diabetes unless contraindicated.[26] Studies have shown other antidiabetic drug classes to be as effective as sulfonylureas in lowering HbA1c. [1] Oral antidiabetic agents, except meglitinides (i.e., nateglinide and repaglinide), pose less risk of hypoglycemia than sulfonylureas.[47] Some of the newer antidiabetic drug classes have shown to have either neutral cardiovascular effects or cardiovascular benefits.[44] Therefore, in the absence of financial restrictions and given the availability of safer alternatives, patients should not receive sulfonylureas as second-line agents.[1] If a sulfonylurea is necessary for an elderly patient, the ADA guideline recommends using glipizide or glimepiride over glyburide since they are shorter acting and associated with less risk of hypoglycemia.[48]

Contraindications

The Beers Criteria for potentially inappropriate medication use in older adults includes chlorpropamide and glyburide.[49] Older adults may experience prolonged hypoglycemia with these long-acting agents. Chlorpropamide can also cause the syndrome of inappropriate antidiuretic hormone secretion. The 2012 American Geriatric Society Beers Criteria highly recommends and with strong evidence to avoid chlorpropamide and glyburide in older adults. 

There is a debate whether hypersensitivity to sulfonamides is a contraindication to prescribing sulfonylureas.[50] A literature review suggested that patients with allergies to sulfonamides may not need to avoid sulfonylureas.[51] However, given the small number of patients reviewed, there is limited data to confirm or refute the need to avoid sulfonylureas in patients with sulfa allergy. The medication package insert provides the FDA-approved product information, including contraindications.[52] Providers should review this information carefully. The court may determine a provider to be negligent if they prescribe a contraindicated medication that causes harm to a patient.[52]

Oral antidiabetic agents, including sulfonylureas, are not FDA-approved for use in pregnancy and lactation.[53] However, according to the National Institute for Health and Clinical Excellence (NICE) guidance, glyburide is safe in pregnancy and lactation.[54] The Endocrine Society supports the NICE guidance in recommending glyburide for gestational diabetes in selected patients.[53]

The ADA guideline recommends avoiding glyburide in patients with CKD.[26]

Monitoring

The ADA guideline recommends monitoring HbA1c levels at least quarterly after therapy change or if patients do not meet glycemic goals.[55] Providers can monitor HbA1c levels less frequently but at least twice a year in patients who meet their glycemic goal.2.[59]

Instruct patients to perform self-glucose monitoring when they develop symptoms of hypoglycemia.[1] Patients should share this information with their health care provider to guide therapy adjustment. 

Toxicity

Sulfonylureas have a narrow therapeutic index.[35] Hypoglycemia is the most common toxicity associated with intentional or accidental overdose of sulfonylureas and may take up to 12 hours to occur.[35][60] Some symptoms of hypoglycemia are shakiness, irritability, tachycardia, confusion, and hunger. [55] In severe cases, hypoglycemia may lead to loss of consciousness, seizure, coma, or death. In children ages 1 to 4 years old, hypoglycemia occurred with the accidental ingestion of one of the following: chlorpropamide 250 mg, glipizide 5 mg, or glyburide 2.5 mg. [61]

Educate patients that the hypoglycemia alert value is ≤ 70 mg/dL (3.9 mmol/L).[62]  The ADA guideline recommends 15 to 20 grams of pure oral glucose as the treatment of choice for hypoglycemia.[55] Pure glucose provides a better response than food containing carbohydrates. Fat content may delay response to the carbohydrate-containing food, and protein may worsen the hypoglycemic episodes by stimulating insulin release without increasing blood glucose levels.[63]

The “Rule of 15” or “15-15” rule applies to treatment with glucose. The patient should receive 15 grams of glucose, recheck blood glucose levels 15 minutes later, and repeat the process as needed until hypoglycemia resolves.[64] Sources of oral glucose include, but are not limited to, glucose tablets, juice, or soft drink.[35] Depending on the duration of action of the sulfonylurea responsible for the overdose, hypoglycemia may reoccur.[62] Educate patients to eat a meal or a snack once their serum glucose is normal or trending up to prevent a recurrent hypoglycemic episode.[62][55]

In hospitalized patients, intravenous (IV) dextrose is the first-line therapy for severe hypoglycemia from sulfonylureas.[35] Patients may require a continuous IV infusion of dextrose to prevent recurrent hypoglycemia, especially with long-acting sulfonylureas.[65] Check blood glucose levels every 15 minutes.[66]

Glucagon stimulates glucose production in the liver and is useful for patients who refuse or cannot take oral glucose. [62] Glucagon is available in different formulations for various routes of administration.[67] The powder for injection requires reconstitution before intramuscular or subcutaneous administration. Newer formulations of glucagon that patients may favor do not require reconstitution. The FDA approved glucagon nasal powder in July 2019, which is a convenient portable dry spray. In September 2019, the FDA approved a solution for subcutaneous injection available in a prefilled syringe and an autoinjector. Educate all patients and their caregivers on proper glucagon administration techniques.[62]

Octreotide is a somatostatin analog that results in an effect opposite to that of sulfonylureas. By binding to the somatostatin-2 receptors on the pancreatic beta cells, octreotide inhibits calcium influx, thus blocking insulin secretion.[35] Since IV dextrose corrects hypoglycemia but may trigger insulin secretion and a recurrence of hypoglycemia, administering octreotide blocks the undesired insulin secretion in response to IV dextrose. Evidence supports the use of octreotide for hypoglycemia induced by sulfonylureas when dextrose alone does not normalize the blood glucose.[60] There is a debate regarding the best time to administer octreotide. Some experts recommend reserving octreotide to patients who experience recurrent hypoglycemia, while others recommend a proactive approach of initiating octreotide after the first hypoglycemic episode.[35]

Monitor all patients for 12 hours after hypoglycemia treatment to recognize and treat recurrent episodes.[35]

Enhancing Healthcare Team Outcomes

Diabetes mellitus is a chronic condition that can negatively affect various organ systems.[68] Diabetes is a major public health problem that has been on the rise.[69][70] Patients taking antidiabetic medications, including sulfonylureas, assess their HbA1c at least twice a year if they have been stable within therapeutic goals. Assess HbA1c at least three times a year if diabetes is uncontrolled.[55] [Level 5]

Available data supports an interprofessional team approach in diabetes care. An interprofessional healthcare team model for diabetes care may include clinicians (MDs, DOs, NPs, PAs), nurses, diabetes educators, dietitians, and pharmacists. Providers from different professions complement each other to improve patient outcomes and decrease healthcare costs.[71]

A clinician-pharmacist collaborative practice is beneficial to patients with diabetes.[72] This practice promotes better diabetes control with a reduction in HbA1c, reducing low-density lipoprotein (LDL) levels, improved screening for microalbuminuria, and an increased number of annual eye and foot exams. Pharmacists can also play a major role in interviewing patients to obtain an accurate medication history, identifying medication non-adherence, and adjusting medication regimens.[73]

Evidence supports implementing nurse champion models, including nurses, certified diabetes educators, and clinical mentors for diabetes care.[71] A nurse champion model results in a win-win situation for hospitals and patients. Hospitals save money by decreasing readmission rates and medication errors. Patients experience improved quality of life, reduction in HbA1c, decreased hospital readmissions, and greater weight loss. Overall, this collaborative effort leads to a higher standard of care for patients with diabetes. 

Dietitians serve as an invaluable resource for patients with diabetes. The evidence-based practice guideline by the Academy of Nutrition and Dietetics strongly supports dietitians in providing medical nutrition therapy to improve patient outcomes.[74]

The healthcare team should follow a patient-centered approach and tailor diabetes therapy to the patient’s needs.[75] The therapeutic plan should include the management of other risk factors or diabetes complications. The healthcare team should encourage physical activity and a healthy lifestyle, including smoking cessation and weight management, and treat hypertension and dyslipidemia to decrease cardiovascular risk. The healthcare team should identify and address barriers to medication adherence. [Level 2] For example, if the patient is diagnosed with depression, then treating depression effectively may improve medication adherence for chronic conditions like diabetes.[76]

The healthcare team should realize that food insecurity might complicate diabetes. Patients who do not have access to nutritious, healthy food may experience hyperglycemia, and patients who are unable to obtain food may experience hypoglycemia.[75] Whenever possible, the healthcare team should seek resources available in the community to help patients overcome food insecurity. [Level 5]

As mentioned before, hypoglycemia is a common adverse effect associated with sulfonylureas. Severe hypoglycemia may lead to serious consequences, including seizure, coma, or death. To minimize the risk of hypoglycemic events, the healthcare team should identify patients at risk of hypoglycemia and consider less stringent HbA1c goals.[55] [Level 3] In addition, reassess the target HbA1c levels over time as the goals might change based on the patient’s age and comorbidities. [Level 5] Inquire about episodes of hypoglycemia during each patient encounter. Remind patients and their caregivers to react to a serum glucose level of less than or equal to 70 mg/dL by consuming glucose. Remind them about the “15-15” rule. [Level 2] During each visit, assess their glucagon injection technique. Ensure that everyone involved in the patient’s care knows where glucagon is and remind them to replace the product before the expiration date.[55] [Level 5]

While newer and potentially safer alternatives are now available, sulfonylureas can be a useful adjunct in diabetes management, especially when the cost of therapy is an issue. Successful therapy requires a collaborative interprofessional effort to maximize the therapeutic efficacy of sulfonylureas while minimizing potential adverse events. [Level 5]

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Uses, common brands, and safety information

Glipizide, glimepiride, and glyburide are examples of sulfonylureas, which stimulate the pancreas to release more insulin to lower blood glucose levels in people with Type 2 diabetes

Sulfonylureas list | What are sulfonylureas? | How they work | Uses | Types | Who can take sulfonylureas? | Safety | Side effects | Costs

In the 1930s, it was discovered that a synthetic sulfur compound used to treat typhoid fever caused patients’ blood sugar to fall significantly, a condition known as hypoglycemia. It was later confirmed that the sulfur compound caused the release of insulin from the pancreas, resulting in low blood glucose levels in typhoid patients. Insulin is a naturally occurring hormone that helps the body regulate blood glucose levels and provides cells with energy.

Diabetes mellitus is a condition in which the body’s ability to produce insulin is impaired, resulting in high blood glucose levels (hyperglycemia). In Type 2 diabetes, the pancreas may still make insulin, but it may not be in sufficient amounts to control the level of blood glucose in the body. Researchers found that when Type 2 diabetes patients were given the sulfur compound, a member of a class of drugs known as sulfonylureas (SUs), it stimulated the pancreas to produce more insulin to help reduce the high blood glucose levels to more normal levels.

In the 1950s the first SU, tolbutamide, was approved for use in Type 2 diabetes care followed by the introduction of several more drugs in the sulfonylurea class. Today, SUs are widely used since they are generally safe, effective, and inexpensive. This table lists commonly used SUs followed by information on how they work, what conditions they treat, safety, and cost.

Other sulfonylureas

Sulfonylurea combinations

What are sulfonylureas?

SUs are a class of drugs widely used in the management of Type 2 diabetes. They have been available in the U.S. for more than 60 years, beginning with the approval of Orinase (tolbutamide) by the U.S. Food and Drug Administration (FDA) in 1957. In 1984, a group of more potent second-generation SUs—Glynase (glyburide) and Glucotrol (glipizide)—were introduced. In 1995, the FDA approved a third-generation SU, Amaryl (glimepiride). 

SUs are generally thought to be safe and effective and are among the cheaper antidiabetic drugs available. The incidence of hypoglycemia, or low blood glucose, is a common side effect and may limit their use to some degree in favor of newer, different classes of antidiabetic drugs. 

How do sulfonylureas work?

In most patients with Type 2 diabetes, the pancreas still produces insulin, however, it does not make enough insulin or the body does not use it effectively which causes blood glucose levels to rise. SUs increase the release of insulin by stimulating the pancreatic beta cells. SUs are most effective in the earlier stages of Type 2 diabetes when there is still plenty of active beta cells in the pancreas. The effects of sulfonylureas may also help reduce blood glucose levels by improving the ability of insulin receptors on the body’s cells to use the insulin that is present.

What are sulfonylureas used for?

SUs are approved as an adjunct to diet and exercise to improve blood glucose control in adults with Type 2 diabetes.

RELATED: What are carbohydrates?

Types of sulfonylureas

SUs are generally classified into three groups, or “generations.”

First-generation sulfonylureas

The first SUs approved, which include Orinase (tolbutamide) and Tolinase (tolazamide), are known as first-generation SUs. While they are effective in lowering blood glucose levels, they do have some significant drawbacks including rare but significant liver toxicity. First-generation SU use has been largely replaced by second-generation agents.

Second-generation sulfonylureas

Second-generation SUs include Glucotrol (glipizide) and Glynase (glyburide). These have shown an advantage because they are more potent and can be given as a once-daily dose. Second-generation SUs are less likely to result in drug-drug interactions that lead to hypoglycemia, or low blood glucose levels, that may occur with the first-generation SUs.

Third-generation sulfonylurea

A third-generation SU introduced in 1995, called Amaryl (glimepiride), is even less likely to cause low blood glucose levels than other generations of SUs. Glimepiride may also cause the release of more insulin from the pancreas than some of the older agents.

Who can take sulfonylureas?

Adults

SUs are approved as an adjunct to diet and exercise to improve glycemic control in adults with Type 2 diabetes.

Children

The efficacy and safety of SUs have not been fully evaluated in pediatric patients with Type 2 diabetes and their use is not recommended in children or adolescents.

Seniors

Although there have not been overall differences seen in the effectiveness and safety of SUs in older patients, older patients are more susceptible to problems of low blood glucose (hypoglycemia). Because hypoglycemia is often more difficult to recognize in seniors, starting and maintenance dosing should be conservative to avoid low blood glucose levels. Older patients are more likely to have reduced kidney function, which may put them at an increased risk of experiencing low blood glucose levels. The American Diabetes Association recommends SUs should not be prescribed to older adults who live alone, have unreliable food intake, or lack a support system.

Are sulfonylureas safe?

Hypoglycemia

Sulfonylureas are generally well tolerated. The most common adverse effect of SUs is hypoglycemia, which is when blood glucose levels have fallen low enough, usually below 70mg/dL, that action is necessary to bring blood glucose levels back to a normal range. Hypoglycemia may last for several hours and severe hypoglycemia may even require medical treatment.

The signs and symptoms of hypoglycemia may include:

  • Irregular or fast heartbeat
  • Fatigue
  • Pale skin
  • Shakiness
  • Anxiety
  • Sweating
  • Hunger
  • Irritability
  • Tingling or numbness of the lips, tongue, or cheek

Worsening hypoglycemia signs and symptoms may include:

  • Confusion, abnormal behavior, or both, such as the inability to complete routine tasks
  • Visual disturbances, such as blurred vision
  • Seizures
  • Loss of consciousness

Hypoglycemia in older patients may be more frequent and dangerous. As those with Type 2 diabetes age, their ability to recognize the symptoms of hypoglycemia may decrease and they may experience very low blood glucose levels without knowing it and fail to get immediate help.

Even though all SUs may cause hypoglycemia, the risk of hypoglycemia is higher when taking the longer-acting SUs such as Glucotrol XL (glipizide extended-release). Hypoglycemia typically occurs as a result of taking an excessive dose, after exercising, or if a meal is missed.

The best way to prevent hypoglycemia is to start SU therapy at the lowest recommended dose. Then the healthcare professional can increase the dose at intervals of two to four weeks until the desired blood glucose levels are reached. It is important to self-monitor blood glucose levels routinely to reduce the chances of experiencing a hypoglycemic event.

Weight gain

SUs are very commonly associated with weight gain. While the exact reason is unknown, it is commonly thought that an increase in between-meal snacking to avoid hypoglycemia may be one contributing factor. The degree of weight gain may also be related to the “generation” of SU prescribed, as Glynase (glyburide) is associated with greater weight gain than Amaryl (glimepiride) or Glucotrol (glipizide). Fortunately, weight gain is preventable when the SU is combined with another diabetes medication called metformin.

Cardiovascular events

Weight gain, fluid retention, and hypoglycemia are all cardiovascular risk factors. Some studies have warned that SUs may be associated with cardiovascular events, including increased mortality, and may also be associated with poorer outcomes following a heart attack (myocardial infarction). Although only one drug in the SU class (tolbutamide) was implicated, care must be taken since this warning may also apply to other SUs.

RELATED: Can hypoglycemia occur without diabetes?

Recalls

There are no current SU recalls as of April 2021. 

Restrictions

Patients with sulfa allergies or any other known hypersensitivity or allergies to the ingredients should avoid SUs.

Diabetic ketoacidosis should be treated with insulin and not a sulfonylurea.

Sulfonylureas do not treat Type 1 diabetes mellitus.

RELATED: Type 1 vs. Type 2 diabetes mellitus

Can you take sulfonylureas while pregnant or breastfeeding?

First-generation sulfonylureas are not recommended for use during pregnancy as there are concerns regarding fetal hypoglycemia and birth defects. High blood glucose levels during pregnancy are associated with an increased number of birth defects leading many experts to recommend insulin to maintain blood glucose levels. There are studies supporting the use of Glynase (glyburide) combined with metformin for the management of pregnant women with Type 2 diabetes as well as for women who develop diabetes during pregnancy (gestational diabetes).

Studies have determined that the transmission of second-generation SUs, such as Glynase (glyburide) and Glucotrol (glipizide), through breast milk to infants is minimal. The benefits provided by these medications seem to outweigh the small risk of the low presence of the drugs in breast milk. However, breastfed infants of lactating women using SUs should be monitored for symptoms of hypoglycemia.

Are sulfonylureas controlled substances?

No, sulfonylureas are not controlled substances.

Common sulfonylurea side effects

The following are potential common side effects when taking SUs. This is not an exhaustive list and you should always talk to your healthcare professional and seek medical advice about what side effects to expect and how to address them.

  • Nausea
  • Hypoglycemia (low blood glucose levels)
  • Dizziness
  • Nervousness
  • Tremor
  • Flatulence
  • Headache
  • Drowsiness
  • Rash
  • Pruritus (itching)
  • Photosensitivity (increased sensitivity to sunlight)

How much do sulfonylureas cost?

SUs have a wide price range depending on the specific drug, quantity, and dosage. Since most SUs are available in generic form, they are much less expensive than the brand-name counterpart. For example, glipizide ER 10 mg a day costs about $28 a month. The brand-name version, Glucotrol XL, costs about $116 a month. A SingleCare card could reduce certain prescription costs up to 80% at participating pharmacies.

Modern Sulfonylureas: Dangerous or Wrongly Accused?

Except for insulin, sulfonylureas and biguanides are the best studied and most widely used glucose-lowering agents. However, neither class of drugs has had an easy life because of concern about safety. Phenformin, a biguanide, was associated with lactic acidosis and withdrawn from use (1) after causing increased mortality in the University Group Diabetes Program (UGDP) (2). The UGDP also found a sulfonylurea, tolbutamide, to be associated with increased mortality (3). Since then, a newer biguanide, metformin, has risen to its current place as the leading oral therapy for diabetes based on its relative lack of hazard from lactic acidosis and evidence, especially from a subgroup of participants in the UK Prospective Diabetes Study (UKPDS), that it can reduce cardiovascular risk and mortality (4,5). Even though the main randomized comparison in the UKPDS (sulfonylurea or insulin vs. lifestyle therapy) showed that cholorpropamide, glyburide, or glipizide also can reduce medical risks (5,6), the reputation of all sulfonylureas has remained tarnished. A warning of “increased risk of cardiovascular mortality” remains in their labeling information. Treatment guidelines and publications reporting effects of new drugs in other classes often emphasize the risk of hypoglycemia and weight gain from sulfonylureas. And yet, at least 25% of patients with type 2 diabetes are using sulfonylureas (7,8), presumably because they are very inexpensive, allow once-daily oral dosing, reliably reduce glucose, and rarely cause symptomatic side effects other than hypoglycemia. More than 40 years after the UGDP, their risks versus benefits are still debated (9–11). Statistical assessments of data pooled from randomized studies and clinical databases continue to be published, with conflicting conclusions (12,13).

This issue of Diabetes Care includes a thoughtful contribution to this discussion by Azoulay and Suissa (14). These experienced epidemiologists describe the potential pitfalls in designing and interpreting analyses of observational (real world) data on treatment with sulfonylureas or other agents. They identify three difficulties. The first is “exposure misclassification,” a failure to identify the time each patient is actually taking the drug in question. A second is “time-lag bias,” in which the analysis does not account for the effect of studying patients at earlier versus later stages of diabetes. The third is “selection bias,” resulting from exclusion of certain patients because of changes of regimen or clinical events during the period of observation. After assessing 20 observational studies of patients with type 2 diabetes who were using sulfonylureas, they judged that only 6 were free of these kinds of bias. They found cardiovascular risk to be increased during treatment with a sulfonylurea (relative risk 1.53, 95% CI 1.43–1.65) in studies with an identified potential bias, metformin as comparator, and mortality as the outcome. Relative risk was not increased (1.06, 95% CI 0.92–1.23) in studies with no major bias, a comparator other than metformin, and all cardiovascular events as the outcome. Presumably these differences contribute to the inconsistency of the literature.

The authors further commented on difficulties posed by properties of the treatment to which sulfonylureas are compared. All the studies judged free of bias compared use of a sulfonylurea with metformin, except one that compared sulfonylurea plus metformin with metformin alone. The bias-free studies directly comparing sulfonylureas with metformin showed more frequent deaths or cardiovascular events during treatment with a sulfonylurea (relative risk ranged from 1.16 to 1.55, with lower boundaries of the 95% CI above 1.00). A possible interpretation of this finding is that sulfonylureas increase cardiovascular risk. An alternative is that metformin is beneficial, while sulfonylureas have a neutral effect. The cardiovascular benefit of metformin in the UKPDS supports the second interpretation. The bias-free study that included metformin in both arms showed no difference in risk, also suggesting a neutral effect of the sulfonylurea. Because metformin, with its favorable cardiovascular effects, is the preferred first-line oral agent, a sulfonylurea would most helpfully be compared not with metformin but with alternative second-line therapies.

To summarize, the main findings of Azoulay and Suissa (14) suggest that some of the harm attributed to sulfonylureas may be related to unintended bias in the design or interpretation of studies rather than an effect of this class of agents. Their description of several categories of bias is illuminating and could improve the design of future analyses of observational data. However, some related questions deserve further comment.

One problem lies in the assumption that all sulfonylureas are alike. Sulfonylureas differ in at least two ways that are relevant to cardiovascular risk. One concerns an effect on vascular KATP channels that interferes with ischemic preconditioning and may increase the risk of cardiac events. This undesired effect occurs with tolbutamide and glyburide but not with gliclazide, glipizide, or glimepiride (15). Whether this difference alters cardiovascular outcomes is not well established, but some evidence suggests it does. A well-conducted, prospective observational study evaluated risks associated with sulfonylureas versus other therapies used by patients admitted to hospitals throughout France for myocardial infarction (16). A multivariable analysis showed that sulfonylureas (as a class) were associated with lower rather than higher mortality from the event (odds ratio 0.50, 95% CI 0.27–0.94, P = 0.03). When individual sulfonylureas were compared, the risk of early mortality was 85% lower for patients who were taking gliclazide or glimepiride than for those taking glyburide (odds ratio 0.15, 95% CI 0.04–0.56, P < 0.005). There is also evidence that glyburide causes more hypoglycemia than other currently used agents. A dramatic example is an analysis of emergency department admissions for hypoglycemia in Germany that showed >80% fewer events with glimepiride than glyburide (0.86 vs. 5.6 events per 1,000 patient-years) (17).

Another issue not emphasized by Azoulay and Suissa (14) is selection bias related to the clinician’s judgement in choosing a treatment well suited to an individual patient. Treatment allocation bias creates an imbalance that is difficult to neutralize by statistical methods, including calculation of a propensity score, especially in databases lacking detailed information on concurrent illnesses. It is a persistent limitation of observational studies and can be entirely avoided only by random allocation of treatment.

For these reasons, both well-designed observational studies focused on the newer sulfonylureas and randomization comparisons are needed. Notably, it would be good to know whether cardiovascular risk differs when a dipeptidyl peptidase 4 inhibitor is used as second-line therapy instead of a sulfonylurea. This new newer and more expensive class of oral agents is proposed to be safer than sulfonylureas (18) and appears to have little effect on cardiovascular outcomes generally but (at least in the case of saxagliptin) may increase heart failure. The randomized CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA) is directly addressing this question (19). Also, in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE), treatment with glimepiride or alternative agents is randomly allocated (20).

Meanwhile, metaphorically, the jury is still deliberating as to whether all sulfonylureas are unsafe based on worrisome evidence from studies of tolbutamide and glyburide (Table 1). Gliclazide, glipizide, and glimepiride are reliably effective in lowering glucose, but are they too dangerous to use? As suggested by Azoulay and Suissa (14), more skillful analysis of observational data are possible, and some randomized trial experience is soon to be reported. If new evidence supports a not guilty verdict, the modern sulfonylureas should regain respect and continue to be an important option for controlling glucose.

Table 1

Arguments for and against the modern sulfonylureas

Article Information

Funding. Support for this work was from the Rose Hastings and Russell Standley Memorial Trusts.

Duality of Interest. M.C.R. has received research grant support through Oregon Health & Science University from AstraZeneca, Eli Lilly, and Novo Nordisk and honoraria for consulting or speaking from AstraZeneca, Biodel, Elcelyx, Eli Lilly, GlaxoSmithKline, Sanofi, Theracos, and Valeritas. These dualities of interest have been reviewed and managed by Oregon Health & Science University. No other potential conflicts of interest relevant to this article were reported.

  • © 2017 by the American Diabetes Association.

Sulphonylurea Class Drugs – Suitability, Benefits & Side Effects

Sulphonylureas are a class of oral (tablet) medications that control blood sugar levels in patients with type 2 diabetes by stimulating the production of insulin in the pancreas and increasing the effectiveness of insulin in the body

They are generally taken once or twice a day, with or shortly before a meal, and can be taken on their own or prescribed for use alongside other diabetes drugs such as metformin

Drugs in this class

The following drugs are all in the sulphonylureas class (trade name first, generic name in brackets):

  • Amaryl (Glimepiride)
  • Daonil (Gilbenclamide)
  • Diamicron (Gilclazide)
  • Diamicron MR (Gilclazide)
  • Glibenese (Glipizide)
  • Minodiab (Glipizide)
  • Tolbutamide (Tolbutamide)

How do sulphonylureas work?

Sulphonylureas are insulin secretagogues, which means they work by causing the body to secrete insulin.

Another class of diabetes drugs which works in this way is the prandial glucose regulators class.

Sulphonylureas bind to a channel of proteins in the pancreas (ATP-sensitive potassium channel).

This triggers a sequence of events within the cells that leads to an increase in the amount of insulin that is produced by pancreatic beta cells

Who are sulphonylureas suitable for?

Sulphonylureas are suitable for people with type 2 diabetes with blood glucose levels that are higher than the recommended levels (an HbA1c above 6.5%) usually once metformin has been prescribed.

Sulphonylureas are not appropriate for people with significantly diminished ability to produce insulin, such as those with type 1 diabetes or that have had a pancreatectomy.

Benefits

The primary benefit of sulphonylureas is their effect on increasing insulin secretion and therefore helping to reduce blood glucose levels.

Side effects

Sulphonylureas are not recommended for people who are overweight or obese, as their mode of action (increase in insulin production and secretion) means that weight gain can be a relatively common side effect.

Their effect on insulin levels also means users are at increased risk of hypoglycaemia (low blood sugar), although this risk is reduced with newer sulphonylureas such as glimepiride.

In addition, some users may suffer an allergic reaction during the first six weeks to eight weeks of treatment, resulting in itchy red skin/skin rashes. If this happens, you might need to switch to another anti-diabetes drug.

Should I Worry About Diabetes Drugs Side Effects or Interactions?

Diabetes drugs can be a great way to keep your blood sugar levels from getting out of whack. But they can sometimes cause side effects or may not mix well with other medicines you take.

Talk to your doctor about what you need to watch out for. Side effects can range from an upset stomach to a serious condition. And other medicines you take can make your diabetes drug stop working — or even make it work too well.

Know Your Medicines

Different types of diabetes drugs have their own side effects and ways they interact with other medicines.

Biguanides: Metformin (Glucophage, Glucophage XR, Glumetza, Fortamet, Riomet). Metformin is usually the first drug that doctors suggest you try to treat type 2 diabetes. It cuts blood sugar by improving the way your body uses insulin. It also lowers the amount of sugar that the liver makes.

What are the side effects? You may have nausea, gas, bloating, diarrhea, b12 deficiency, and an upset stomach. These problems usually go away in a few weeks, as your body gets used to the medicine. It may also help to take the drug with food.

In rare cases, metformin may cause a serious condition called lactic acidosis. That’s when too much lactic acid builds up. Call your doctor right away if you get any of these symptoms:

Do they clash with other drugs? Some drugs may interfere with some of the enzymes that metformin uses to work. Your doctor may need to monitor your blood sugar or adjust your metformin dose if you take any of these:

Anticholinergic drugs, such as dicyclomine (Bentyl) and oxybutynin (Ditropan, Ditropan XL, Oxytrol), may raise the amount of metformin your body absorbs. This may lead to low blood sugar.

Sulfonylureas: Glipizide (Glucotrol, Glucotrol XL), glimepride (Amaryl), glyburide (DiaBeta, Glynase PresTab). These drugs lower your blood sugar by helping your pancreas make more insulin.

What are the side effects? The most common one is low blood sugar. This can make you feel shaky, sweaty, dizzy, and confused.

Severe low blood sugar can be life-threatening. To prevent it, eat regularly and don’t skip meals.

Other side effects that you might get are weight gain, dark urine, and an upset stomach. Sulfonylureas can also cause skin rashes and reactions to the sun.

Do they clash with other drugs? About 100 drugs can change the way sulfonylureas work. Some can make them work too well, which may lead to dangerously low blood sugar. Others may cause the medication to be less effective. Your doctor may need to keep tabs on your blood sugar or adjust your sulfonylurea dose.

The medicines that may affect how sulfonylureas work include:

  • Azole antifungals, including fluconazole and  ketoconazole 
  • Some antibiotics, such as chloramphenicol, ciprofloxacin, clarithromycin (Biaxin), isoniazid (Nydrazid), rifampin, and sulfasalazine (Azulfidine, Azulfidine Entabs, Gantrisin Pediatric, Sulfazine, Sulfazine EC, co-trimoxazole, Zonegran)
  • Cholesterol-lowering drugs, such as clofibrate and gemfibrozil
  • Tricyclic antidepressants
  • h3 blockers
  • Gout medications, such as probenecid 
  • Some high blood pressure medicines, including ACE inhibitors and bosentan
  • Beta-blockers
  • Corticosteroids
  • Calcium channel blockers
  • Oral contraceptives
  • Thiazide diuretics
  • Thyroid medicines

Meglitinides: nateglinide (Starlix), repaglinide (Prandin). They help your pancreas make more insulin. Although these drugs work faster, they don’t last as long in the body.

What are the side effects? These medications can lead to low blood sugar and weight gain.

Do they clash with other drugs? Some drugs can affect how your body processes meglitinides. This may cause your blood sugar to become too low or too high. Your doctor may need to keep an eye on your blood sugar levels, adjust your dose, or change your medicine.

The drugs that might not mix well with meglitinides include:

Thiazolidinediones (TZDs): Pioglitazone (Actos), rosiglitazone (Avandia). These drugs boost the way insulin works in the body.

What are the side effects? It may cause you to hang on to fluids in your body, which can lead to swelling. TZDs can also make you gain weight and raise your levels of LDL “bad” cholesterol. They are also linked with serious side effects, such as bone fractures and heart failure as well as being associated with an increase risk of bladder cancer in women.

Do they clash with other drugs? Some drugs block the enzyme that processes TZDs. Your doctor may want to prescribe another medicine if you take one of these medications:

Other medicines, when combined with a TZD, may raise your chance of having heart problems:

  • NSAIDs
  • Sulfonylureas
  • Nitrates

Alpha-glucosidase inhibitors: Acarbose (Precose,) miglitol (Glyset). You take alpha-glucosidase inhibitors with the first bite of each meal. They slow the breakdown of carbohydrates.

What are the side effects? Because these medicines affect your digestion, you may have gas, diarrhea, and stomach pain. They also may cause an increase in blood markers of a stressed liver.

Do they clash with other drugs? Alpha-glucosidase inhibitors may not work as well if you also take digestive enzymes and activated charcoal supplements.

Alpha-glucosidase inhibitors can also make it harder for the body to absorb digoxin. They may also change the way warfarin works. Talk to your doctor if you take either of these drugs.

DPP-4 inhibitors: alogliptin (Nesina),  linagliptin (Tradjenta), saxagliptin (Onglyza), Sitagliptin (Januvia). These medicines help your pancreas release more insulin after meals. They also lower the amount of sugar you make.

What are the side effects? You could get a sore throat, stuffy nose, upset stomach, and diarrhea. You may also run the risk of acute pancreatitis liver failure, possible worsening heart failure and joint pain

Do they clash with other drugs? Some drugs may affect how much DPP-4 inhibitors are absorbed in the body. Your doctor will want to track your blood sugar levels carefully and watch for potential side effects if you take these medicines:

ACE inhibitors combined with DPP-4 may raise your chance of swelling.

SGLT2 inhibitors: Canagliflozin (Invokana), dapagliflozin (Farxiga), empagliflozin (Jardiance),  ertugliflozin (Steglatro).

They work in the kidneys and remove extra sugar from your blood through urine.

What are the side effects? These drugs raise your chances of having urinary tract and yeast infections. They may also cause low blood sugar. On the positive side, they may reduce the risk of kidney disease for those with diabetes and can reduce the risk of being hospitalized or dying from heart failure.

Do they clash with other drugs? SGLT2 inhibitors don’t interact with many drugs. Rifampin may make the drug less effective. SGLT2 inhibitors may also raise the amount of digoxin in the body.

Insulin therapy: insulin aspart (Novolog), insulin detemir (Levemir), insulin glargine (Lantus), Insulin glulisine (Apidra), insulin isophane (Humulin, Novolin N), insulin lispro (Humalog),.
If other medicines aren’t doing enough, you may need insulin therapy. You’ll need to inject insulin using a needle and syringe or a pen injector.

What are the side effects? The most common side effect is low blood sugar. You may also have a wide variety of symptoms, such as headaches, rashes, dizziness, anxiety, cough, and dry mouth. Talk to your doctor. Some may go away as your body gets used to the medicine.

Do they clash with other drugs? Some drugs affect the way that insulin works in the body. This may cause your blood sugar to become too low or high. Your doctor may need to monitor your blood sugar level, adjust your dose, or change your medicine if you take some of these:

  • Diabetes medicines
  • Salicylic acid
  • Certain antidepressants, such as fluoxetine and monoamine oxidase inhibitors
  • Some antibiotics, including isoniazid and sulfonamide
  • Fibrates
  • Some high blood pressure medicines, such as ACE inhibitors and angiotensin II receptor blocking agents
  • Certain cholesterol-lowering drugs, including fibrates and niacin
  • Propoxyphene, pentoxifylline and somatostatin analogs
  • Corticosteroids
  • Oral contraceptives
  • Estrogens
  • Diuretics
  • Phenothiazines
  • Danazol (Danocrine)
  • Protease inhibitors
  • Glucagon (GlucaGen)
  • Thyroid medicine

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Combination therapy with metformin and sulfonylurea for adults with type 2 diabetes

Review Question

We wanted to investigate the effects of the combination of the antidiabetic drugs metformin with a sulfonylurea versus other antidiabetic interventions in people with type 2 diabetes.

Relevance

Many people with type 2 diabetes are treated with several types of hypoglycemic drugs such as “sulfonylurea” (eg glibenclamide or glyburide, glipizide and gliclazide). These drugs lower blood glucose levels by stimulating the release of insulin in the body, thereby increasing blood insulin levels. Another antidiabetic agent, metformin, lowers blood glucose levels by improving the body’s ability to stimulate insulin to perform better (insulin sensitivity).The combination of metformin with a sulfonylurea is widely used. We wanted to investigate the effect of the combination of metformin with a sulfonylurea on important patient outcomes, such as complications of diabetes (eg, kidney and eye disease, heart attacks, strokes), death from any cause, health-related quality of life, and drug side effects.

Research characteristics

We found 32 randomized controlled trials (clinical trials in which people were randomly assigned to one of two or more treatment groups) in which a total of 28,746 people with type 2 diabetes were identified to either receive metformin with a sulfonylurea or comparator medicine.The comparator groups were represented by the following types of antidiabetic drugs in addition to metformin: five studies – analogs of glucagon-like peptide 1, nine studies – dipeptidyl peptidase 4 inhibitors, 11 studies – thiazolidinediones, three studies – glinides, and four studies – inhibitors of sodium-glucose co-transporter 2.

Study participants were treated for one to four years. There were large differences between the people taking part in the studies, especially with regard to age, duration of diabetes and the presence of diabetic complications at the beginning of the study.

This evidence is current as of March 2018.

Key Findings

Data on patient-relevant outcomes were scarce and data were scarce for all comparisons of metformin plus sulfonylurea versus other antidiabetic agents. The available data do not show clear differences between the combination of metformin with a sulfonylurea and other combinations of metformin with antidiabetic drugs or with metformin alone for most of the patient outcomes.There were more cases of low blood sugar (hypoglycemic episodes) on combination therapy with metformin and sulfonylurea compared to all other combinations of metformin with other antidiabetic agents.

We found no studies reporting health-related quality of life. We found nine studies in progress and two more unpublished studies awaiting evaluation. Together, these studies will include about 16,631 participants. Once published, these studies may have a significant impact on the results of our review.

Certainty of evidence

All included studies had deficiencies in how they were conducted or how the study authors reported results. For individual comparisons of antidiabetic drugs, the number of participants was often small, resulting in a high risk of inadvertent error (game of chance).

The role of glimepiride in the optimization of antihyperglycemic therapy in patients with type 2 diabetes mellitus

Currently, the main goal of the treatment of type 2 diabetes mellitus (DM) is not only and even not so much the preservation of the patient’s life and the elimination of symptoms of decompensation of the disease, but the achievement of optimal parameters of carbohydrate metabolism and the prevention of late complications – cardiovascular pathology, diabetic neuropathy, retinopathy, etc. nephropathy.If several decades ago, acute complications (diabetic ketoacidosis, hyperosmolar coma) posed a real threat to a patient with diabetes, now, in the vast majority of cases, cardiovascular accidents are the cause of death of these patients. Therefore, the treatment of such patients should be aimed at normalizing glycemic levels and preventing late complications.

In the pathogenesis of type 2 diabetes, two main mechanisms play a leading role – insulin resistance and a decrease in the secretory activity of pancreatic b-cells.At the initial stages of the development of the disease, even before its manifestation, insulin resistance prevails, which develops against the background of a sedentary lifestyle, poor nutrition and obesity. A decrease in the sensitivity of peripheral tissues to insulin is accompanied by the development of compensatory hyperinsulinemia. At this stage of the disease, the most rational measures are lifestyle modification (nutrition, physical activity) and drugs that affect insulin resistance. However, type 2 diabetes is a constantly progressive disease.Gradually, the function of pancreatic b-cells decreases, insulin secretion decreases – and hyperglycemia develops. According to numerous studies, in particular UKPDS, at the time of the onset of type 2 diabetes, about half of patients already have severe insulin deficiency. At this stage, pathogenetically justified is the use of drugs that stimulate the production of insulin by the b-cells of the pancreas – sulfonylurea derivatives (SSM). Sulfonylurea preparations are considered to be effective and affordable antihyperglycemic agents.These drugs have been used in clinical endocrinology for over half a century. The history of oral glucose-lowering therapy begins in the 50s of the last century, when the first sulfonylurea derivatives – carbutamide, tolbutamide, chlorpropamide – were introduced into widespread practice. These drugs, which had a pronounced hypoglycemic effect, also had a number of side effects. An attempt to improve the safety profile of this class of oral hypoglycemic agents led to the emergence of the second generation of sulfonylurea derivatives – glibenclamide, glipizide, gliclazide.Since 1995, a third-generation sulfonylurea drug has appeared on the pharmaceutical market, which not only has a better safety profile, but also opens up new horizons in the treatment of type 2 diabetes. Glimepiride differs significantly from other members of its class. It has a gentle stimulating effect on pancreatic b-cells and an extra-pancreatic effect.

When choosing an oral hypoglycemic agent, attention should be paid to several criteria: efficacy, safety (risk of hypoglycemia and cardiotoxicity), effect on weight, extra-pancreatic effect (decrease in insulin resistance), ease of administration (compliance).The undoubted difference between glimepiride and sulfonylurea derivatives of previous generations is its ability to reduce the insulin resistance of peripheral tissues. This is a drug that reliably affects both pathogenetic mechanisms in type 2 diabetes – insulin secretion and insulin resistance. Glimepiride has the lowest PI / HA ratio (the ratio of the average increase in plasma insulin levels and the average decrease in blood glucose 6 hours after taking the drug). This indicator is: for glimepiride – 0.03, gliclazide – 0.07, glipizide – 0.11, glibenclamide – 0.16.

According to the algorithms of the American Diabetes Association and the European Association for the Study of Diabetes and the International Diabetes Federation, the choice of anti-hypoglycemic therapy depends on the current and target level of glycated hemoglobin (HbA1c). Initial treatment for type 2 diabetes usually includes a recommendation for lifestyle changes (as close as possible to the so-called healthy) and the appointment of metformin. In case of ineffectiveness of the prescribed therapy, oral hypoglycemic drugs (OAD) are combined, and injections of an analog / mimetic of glucagon-like peptide or insulin (usually prolonged action) can also be added.In the framework of this algorithm, second- and third-generation sulfonylureas are preferred over the first generation due to the lower risk of hypoglycemia.

Long-acting first-generation sulfonylureas such as chlorpropamide have frequently been associated with hypoglycemia and other side effects, including fluid retention, hyponatremia, and their efficacy was unpredictably altered when combined with a variety of drugs and alcohol. Second-generation PSM (gliclazide, glipizide, glibenclamide), as well as third-generation (glimepiride), on the contrary, are usually safer and less likely to cause hypoglycemia.For example, in a study comparing glipizide with first-generation SCI, hypoglycemia during treatment with glipizide was 23% less common.

Glimepiride was first used in clinical practice in Sweden and was registered by the FDA for use in the United States in 1995. It is currently used in more than 60 countries around the world. It comes in dosages of 1, 2, 3 and 4 mg per tablet. The main advantages of glimepiride in comparison with other PSMs are fast and complete absorption and the ability to use it once a day.The risk of developing hypoglycemia with glimepiride is relatively low. A large, prospective, population-based study reported that the incidence of severe hypoglycemia was 6.5 times lower with this drug than with glyburide. When using glimepiride, a less pronounced increase in body weight was also observed than when using other PSM, with a comparable glucose-lowering effect in patients with type 2 diabetes. However, like other PSIs, there is a risk of hypoglycemia during treatment with glimepiride, and there may be rare side effects from hematological blood parameters.In addition, glimepiride increases the insulin sensitivity of insulin-dependent tissues.

The molecular formula of glimepiride is C24h44N4O5S, the molecular weight is 490.6 g / mol. The International Union of Pure and Applied Chemistry (IUPAC) named it 4-ethyl-3-methyl-N- [2- [4 – [(4-methylcyclohexyl) carbamolsulfamoyl] phenyl] ethyl] -5-oxo-2H-pyrrole-1 -carboxamide. It is practically insoluble in water. PSMs have the same central structure, and their differences are noted in two positions: in the para-position of the benzene ring and in the urea site.On the surface of an insulin-producing beta cell, glimepiride binds to the sulfanilamide receptor, which is linked to the transmembrane ATP-dependent potassium channel. The specific center of its interaction with the sulfanilamide receptor is a 65-kDa protein region, which differs from that with which most other PSMs bind. Binding of PSM to one of the receptor sites blocks binding to any other sites of sulfanilamide receptors, and thus allosteric inhibition of the action of sulfonamides is manifested.That is why the combination of various sulfonamide preparations is devoid of any clinical meaning.

When PSM binds to the receptor, the ATP-dependent potassium channel of the beta cell closes, which blocks the entry of potassium from the extracellular space into the beta cell, which in turn causes depolarization of the cell membrane. In response, voltage-gated calcium channels of the cell membrane open, calcium enters the beta cell, its concentration in the beta cell increases, which stimulates insulin secretion.

Compared to glyburide, glimepiride has 2–3 times less affinity for the beta-cell sulfanilamide receptor, but 2.5–3 times higher frequency of association with the receptor and 8–9 times higher frequency of dissociation with it. As a result, the sulfanilamide receptor is blocked by glimepiride to a lesser extent than other PSMs, which is believed to be the reason for the low risk of hypoglycemia during treatment with glimepiride.

After oral administration, glimepiride is rapidly absorbed, and its bioavailability reaches 100%, and it is practically not affected by food intake.In humans, 99% of glimepiride circulates in the blood in a form associated with plasma proteins, mainly with albumin. It is metabolized in the liver and is not excreted unchanged in the urine, unlike the first generation PSM, which are excreted unchanged, mainly by the kidneys. In the liver, glimepiride is converted by the CYP4502C9 enzyme first to the M1 metabolite. Then cytosolic enzymes convert M1 into its carboxyl derivative – M2. Animal studies show that M1 has 30% of the activity of the parent substance, while M2 is practically devoid of a physiological effect.Most of both metabolites are excreted in the urine (60%), and the remainder is excreted in the feces.

After administration, the maximum concentration of glimepiride is reached after 2-3 hours, and it linearly depends on the dose of the drug in the range of 1-8 mg. The half-life (t1 / 2) with a single dose is 5 hours and increases to 9 hours with repeated administration. But at the same time, the constant intake of the drug is not accompanied by its cumulation. When glimepiride is taken twice a day, there are two peaks in its serum concentration (Cmax), and once a day – one peak.The frequency of administration of glimepiride does not affect the time to reach the maximum concentration of the drug in the blood (Tmax). The Cmax value with a single dose of the drug is higher than with a double dose, although this does not affect the dose of the drug entering the systemic circulation (AUC).

There were no significant differences in Cmax, Tmax, elimination half-life or AUC depending on obesity in type 2 diabetes patients. However, differences were found in the pharmacokinetics of metabolites M1 and M2: higher in type 2 diabetes in obese people, but these differences have no clinical significance.

The predominantly hepatic metabolism of glimepiride allows its use in persons with minor renal impairment; however, since it is a stimulant of insulin secretion, insulin clearance in the presence of impaired renal function will be slowed down, which increases the risk of hypoglycemia.

In patients with creatinine clearance (CrCl) <50% Cmax, t1 / 2, and the mean time of action for glimepiride did not change. The relative total clearance and volume of distribution of glimepiride increased at CrCl <50%, and the changes were proportional to the degree of renal impairment.In most patients with chronic renal failure (CRF), a dose of 1-4 mg glimepiride was sufficient to achieve target glycemic values. It is believed that an increase in the relative clearance of the drug in chronic renal failure is associated with a violation of its binding to proteins - with kidney damage, more glimepiride is in an unbound state. Taking into account the presented results, when using glimepiride in patients with chronic renal failure and creatinine clearance <22 ml / min, treatment should be started with its minimum dose (1 mg), carefully monitoring the effect of the drug.

Due to the fact that the hepatic metabolism of the drug is provided by the CYP4502C9 enzyme, with different variants of the CYP2C9 genotype, specific effects may develop. In particular, in individuals with the CYP2C9 * 1 / * 3 genotype, the violation of glimepiride metabolism is manifested by an increase in AUC, although no changes in Cmax were observed. In these cases, the initial dose of the drug should be low or medium. The antifungal drug fluconazole inhibits the above enzyme and, accordingly, increases the AUC for glimepiride.At the same time, liver diseases do not affect the pharmacokinetics of glimepiride, however, caution should be exercised when using the drug in patients with this pathology.

Glimepiride enhances both the first and second phases of insulin secretion, both in normal blood glucose levels and in hyperglycemia. The maximum activity in reducing the blood glucose level is achieved after 2-3 hours, and the glucose-lowering effect after a single administration can last up to 24 hours. The maximum level of insulin and C-peptide in the blood is observed 2 hours after taking glimepiride, and it enhances the stimulation of insulin secretion caused by an increase in blood glucose after a meal.Both under conditions of euglycemia and hyperglycemia, there is a linear relationship between the concentration of glimepiride in the blood and insulin secretion.

Glimepiride increases the insulin sensitivity of insulin-dependent tissues both in vivo and in vitro . This may be due to the stimulation of the activity of the glucose transport protein GLUT4.

Despite the fact that glimepiride has an affinity for ATP-dependent potassium channels on cardiomyocytes, it does not interfere with the so-called ischemic preconditioning (unlike some other SCIs).The essence of ischemic preconditioning is that short-term myocardial ischemia, which does not cause myocardial infarction, reduces the risk of myocardial infarction during prolonged ischemia. Since PSI suppress the opening of ATP-dependent potassium channels, they can disrupt this adaptive response of the myocardium, which develops with the participation of these channels. This distinctive quality of glimepiride may be due to the fact that, unlike other PSMs, it affects the activity of ATP-dependent potassium channels on the sarcolemma, but not the activity of mitochondrial channels in cardiomyocytes.Despite the fact that the clinical significance of ischemic preconditioning in humans has not been studied, but from the experimental data obtained, it can be assumed that glimepiride has an advantage over other PSM in patients with an increased risk of developing a heart attack.

The efficacy of glimepiride has been studied in many studies based on evidence-based medicine. The dose-response relationship for glimepiride in the dosage range of 1, 4 or 8 mg / day was studied in a randomized study of 304 patients with type 2 diabetes (R.B. Goldberg et al.). With the introduction of all doses of glimepiride, a significant decrease in fasting blood glucose (GL) and 2 hours after a meal (GLP), as well as HbA1c, was observed. In particular, GBV levels decreased by 2.4; 3.8 and 4.1 mmol / L when using 1, 4 and 8 mg of glimepiride, respectively; GLP decreased by 3.5; 5.1 and 5.0 mmol / l, respectively; HbA1c levels decreased by 1.2; 1.8 and 1.9%, respectively.

Rosenstock et al. presented the results of a randomized, double-blind, multicenter study involving 416 patients with type 2 diabetes treated with SCI.Patients were prescribed glimepiride in four dosages: 4 and 8 mg 2 times a day and 8 and 16 mg / day for 14 weeks. In patients receiving placebo, the level of GN increased slightly from 13.0 mmol / L at the beginning of the study to 14.5 mmol / L at the end, and with all glimepiride treatment regimens, on the contrary, decreased by 3.9-5.7 mmol / l. Compared with placebo, glimepiride also reduced GLP levels by 5.6–6.6 mmol / L. At 2 hours after a meal, insulin and C-peptide levels were increased in patients treated with glimepiride.The HbA1c level increased in the placebo group from 7.7% at the beginning of the study to 9.7% at the end (p <0.001), while in the glimepiride group it decreased from 8.0 to 7.5% (p <0.001). There were no significant differences in hypoglycemic reactions between daily doses of 8 and 16 mg of glimepiride or between the options for administration once a day or twice a day.

Similar data were obtained by Sonnenberg et al. in a 15-week crossover study of 106 patients with type 2 diabetes who were prescribed glimepiride and whose starting dose (3 mg twice daily or 6 mg once daily for 4 weeks) was selected at random.Patients were transferred every 4 weeks from one treatment option to another. The average daily glycemic level decreased comparable both with the appointment of the drug 2 times a day, and 1 time a day. Plasma insulin and C-peptide levels increased significantly at the peak of postprandial glycemia, but not on an empty stomach.

Glimepiride is the only FDA approved SCM for combination therapy with insulin and has been studied in a number of studies. In one multicenter study conducted in overweight patients with type 2 diabetes, aged 45–70 years with poorly controlled SCI monotherapy, it was shown that the combination of glimepiride with one evening injection of 70/30 mixed insulin (NPH + simple insulin) provided the same effective control over blood glucose levels as a more complex administration regimen with multiple injections without the use of oral medications.

Kabadi et al. suggest that glimepiride reduces the need for insulin to a greater extent than other PSMs (tolazamide, glyburide, or glipizide). Fritsche et al. conducted a controlled randomized study of 695 patients with type 2 diabetes, which examined the efficacy and safety of taking 3 mg glimepiride in combination with morning or evening administration of insulin glargine or evening administration of NPH insulin. The insulin dose was titrated according to a special scheme, in which the target GN level was ≤ 5.5 mmol / L.The HbA1c level decreased by 1.24% in the group of patients receiving glargine in the morning, by 0.96% in those receiving glargine in the evening, and by 0.84% ​​in those receiving NPH in the evening. HbA1c scores were better with morning than evening glargine injections (p = 0.008) or evening NPH insulin injections (p = 0.001). By the end of the study, the level of GN improved from baseline equally in all groups. Nocturnal hypoglycemia was observed less frequently with both morning (17%) and evening injections of insulin glargine (23%) compared with evening injections of NPH insulin (38%) (p <0.001).Thus, in patients with type 2 diabetes, the risk of developing nocturnal hypoglycemia is lower when glimepiride is prescribed in combination with glargine than with NPH insulin.

The absence of weight gain is an important indicator of the quality of drug treatment for patients with type 2 diabetes, since the main pathogenetic factor of type 2 diabetes – insulin resistance – causes obesity. In this respect, glimepiride has a significant advantage over other PSMs, insulin and pioglitazone, since, unlike them, it does not cause weight gain against the background of effective glycemic control.

In a study by S. Martin et al. over 12 months, the effect of glimepiride and glyburide on body weight was compared in 520 outpatients with type 2 diabetes. It turned out that at the end of the study, the average body weight loss and decrease in body mass index relative to baseline values ​​were higher in the glimepiride group (–2.0 ± 4 kg / –0.7 ± 1.4 kg / m2) than in the glyburide (–0.58 ± 3.70 kg / –0.2 ± 1.3 kg / m2) (p <0001).

Despite the fact that the published data on the safety and tolerability of glimepiride do not exceed 2-3 years, they are numerous and include more than 5 thousand.patients with type 2 diabetes. In placebo-controlled studies, most of the adverse events associated with glimepiride occurred in less than 2% of patients with type 2 diabetes, and these were hypoglycemia, dizziness, asthenia, headache, rash and nausea, and such reactions from the gastrointestinal of the intestinal tract, such as vomiting, abdominal pain and diarrhea, occurred in less than 1% of patients. These studies indicate that adverse events associated with glimepiride are not more common, and in some cases even less common than with other PSMs.

The most important clinical adverse effect of glimepiride, like other SCIs, is hypoglycemia. Holstein et al. compared the incidence of severe hypoglycemia (eliminated by intravenous glucose injections or glucagon) in patients treated with glimepiride or glyburide. The results of this study showed that the total incidence of hypoglycemia with glimepiride was 6.5 times lower than with glyburide.

Reducing the risk of hypoglycemia is also especially important for people who play sports or exercise regularly.Massi-Benedetti et al. showed that physical activity in type 2 diabetes patients receiving glimepiride causes a statistically significant decrease in C-peptide and insulin levels compared with patients receiving glyburide. This observation suggests that during treatment with glimepiride, the physiological ability to suppress the secretion of endogenous insulin is retained, which can explain the decrease in the incidence of hypoglycemia during and after exercise in patients receiving glimepiride.

The risk of developing hypoglycemia is also influenced by such factors as old age, concomitant diseases of the kidneys and / or cardiovascular system. Combination therapy with glimepiride with other oral hypoglycemic drugs may increase the risk of hypoglycemia.

Other undesirable serious effects of glimepiride include rare hematologic side effects such as leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, and pancytopenia.With the use of PSM, including glimepiride, the development of a syndrome of inadequate secretion of antidiuretic hormone has been reported, believed to be due to an increase in the action of antidiuretic hormone and / or stimulation of its secretion.

Thus, glimepiride, the third generation PSM, is a highly effective antihyperglycemic drug for the treatment of type 2 diabetes, which can be used as monotherapy (once a day) or in combination with other antihyperglycemic drugs of the non-sulfanilamide group, including insulin.Glimepiride effectively reduces GN, GLP and HbA1c levels and has a good safety profile.

Glimepiride does not affect body weight and poses a lower risk of hypoglycemia in type 2 diabetes than other insulin secretion stimulants. The data obtained suggest that glimepiride may be safer than other PSMs in patients with cardiovascular diseases, since it does not block ischemic preconditioning. This is a very important circumstance, given that a large number of patients with type 2 diabetes suffer from ischemic heart disease.

Summarizing the above studies, the following conclusions can be drawn regarding monotherapy with glimepiride in comparison with placebo: glimepiride effectively lowers blood glucose levels both on an empty stomach and after a meal, and regardless of the frequency of taking the drug – once or twice a day; glimepiride increases insulin secretion in response to food intake and has little or no effect on fasting insulinemia; treatment with glimepiride makes it possible to achieve the target HbA1c values ​​recommended by international organizations in a significant proportion of patients with type 2 diabetes.

Glimepiride formulations have significant advantages in terms of good glycemic retention due to a dual mechanism and in terms of preventing insular depletion.

Treatment of type 2 diabetes, which should be lifelong, is financially burdensome for the average Ukrainian, due to the fact that, unlike insulin preparations, only certain categories of patients receive oral hypoglycemic drugs from the state budget.The optimal solution to this problem is the use of generics. However, given the crucial role of drugs in this group in the treatment of type 2 diabetes, the approach to the choice of generics should be as balanced as possible. To date, only the use of generics with proven bioequivalence, made from a high quality substance, can provide therapeutic equivalence to the original drug. Patients quite often switch to generic drugs, but one should take into account the fact that there is a difference between generic drugs.The reason is that even legislatively, fluctuations in bioequivalence indicators (primarily the concentration of an active substance in plasma during a day) can range from +25% to –20%.

The practice of the USA is very interesting and indicative in this case. The US Regulatory Authority, the Food and Drug Administration (FDA), publishes the Electronic Orange Book. Approved Drag Products with Therapeutic Equivalence Evaluations, which lists licensed drugs with therapeutic equivalence codes.The system of letter codes allows you to quickly determine the therapeutic equivalence of a certain generic drug to a reference (most often, an original drug). The two main categories to which generic drugs can be classified are designated by codes A and B. Code A is assigned to drugs with bioequivalence and therapeutic equivalence, as well as reference drugs. Code B denotes drugs that the FDA currently considers therapeutically nonequivalent to the reference.Of course, the drugs of choice when there is a question of affordability compared to original drugs are equivalent generics (code A).

Today Amapiride, produced by the world’s largest generic company Teva (Israel), is the only generic glimepiride in Ukraine, the bioequivalence of which has been studied on the basis of the largest Canadian research center Algorithme Pharm. According to the results of the study, the difference in bioequivalence indicators of the original drug and Amapiride is only 1%.

The uncontrolled use of various other generics of glimepiride, which are produced in enterprises that are not certified according to GMP criteria, can lead to significant fluctuations in glycemia throughout the day, associated with deviations in the concentration of the active substance, both upward and downward. Indeed, the content of the active substance, its profile of solubility, accumulation and other indicators vary significantly from batch to batch.

As you can see, the closest effect to the original drug can be provided only by a generic drug with the closest possible bioequivalence indicators.

Unlike most generics of glimepiride approved for use in Ukraine, Amapiride is registered and successfully used in more than 25 countries around the world, including the USA, Canada, England, Italy, Spain, Germany, France, Switzerland, etc. testifies to its high quality and efficiency.

The use of Amapiride in clinical practice makes it possible to achieve the most similar therapeutic effect to the original drug in patients with type 2 diabetes.

Bibliography

1. Dreval A.V. Diabetes mellitus treatment. – M .: EKSMO, 2010.

2. Davis S.N. The role of glimepiride in the effective management of type 2 diabetes. // J. Diabetes Complications. – 2004. – Vol. 18, No. 6. – P. 367-376.

3. Nathan D.M., Buse J.B., Davidson M.B. et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes // Diabetes Care.- 2009. – Vol. 32, No. 1. – P. 193-203.

4. Massi-Benedetti M. Glimepiride in type 2 diabetes mellitus: a review of the worldwide therapeutic experience // Clin. Ther. – 2003. – Vol. 25, No. 3. – P. 799-816.

5. Matsuki M., Matsuda M., Kohara K. et al. Pharmacokinetics and pharmacodynamics of glimepiride in type 2 diabetic patients: compared effects of once– versus twice – daily dosing // Endocr. J. – 2007. – Vol. 54, No. 4. – P. 571-576.

6. Holstein A., Plaschke A., Egberts E.H. Lower incidence of severe hypoglycaemia in patients with type 2 diabetes treated with glimepiride versus glibenclamide // Diabetes Metab. Res. Rev. – 2001. – Vol. 17, No. 6. – P. 467-473.

7. Overkamp D, Volk A, Maerker E et al. Acute effect of glimepiride on insulin-stimulated glucose metabolism in glucose-tolerant insulin-resistant offspring of patients with type 2 diabetes // Diabetes Care. – 2002. – Vol. 25, No. 11. – P. 2065-2073.

8. NCBI Pubchem Compound Database.National Center for Biotechnology Information. Glimepiride. 2009. Avai-lable from: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=476&loc=ec_rcs. [Cited June 21, 2009].

9. Shukla U.A., Chi E.M., Lehr K.H. Glimepiride pharmacokinetics in obese versus non-obese diabetic patients // Ann. Pharmacother. – 2004. – Vol. 38, No. 1. – P. 30-35.

10. Niemi M., Cascorbi I., Timm R. et al. Glyburide and glimepiride pharmacokinetics in subjects with different CYP2C9 genotypes // Clin.Pharmacol. Ther. – 2002. – Vol. 72. – P. 326-332.

11. Korytkowski M., Thomas A., Reid L. et al. Glimepiride improves both first and second phases of insulin secretion in type 2 diabetes // Diabetes Care. – 2002. – Vol. 25, No. 9. – P. 1607-1611.

12. Rosenstock J., Samols E., Muchmore D.B., Schneider J. Glimepiride, a new once-daily sulfonylurea. A double-blind placebo-controlled study of NIDDM patients. Glimepiride Study Group // Diabetes Care. – 1996. – Vol. 19, no. 11. – P.1194-1199.

13. Haupt A., Kausch C., Dahl D. et al. Effect of glimepiride on insulin-stimulated glycogen synthesis in cultured human skeletal muscle cells: a comparison to glibenclamide // Diabetes Care. – 2002. – Vol. 25, No. 12. – P. 2129-2132.

14. McCluskey D., Touger M.S., Melis R., Schleusener D.S. Results of a randomized, double-blind, placebo-controlled study administering glimepiride to patients with type 2 diabetes mellitus inadequately controlled with rosiglitazone monotherapy // Clin.Ther. – 2004. – Vol. 26, No. 11. – P. 1783-1190.

15. Umpierrez G., Issa M., Vlajnic A. Glimepiride versus pioglitazone combination therapy in subjects with type 2 diabetes inadequately controlled on metformin monotherapy: results of a randomized clinical trial // Curr. Med. Res. Opin. – 2006. – Vol. 22, No. 4. – P. 751-759.

16. Garber A.J. Benefits of combination therapy of insulin and oral hypoglycemic agents // Arch. Intern. Med. – 2003. – Vol. 163, no. 15 – P. 1781-1782.

17.Kabadi M.U., Kabadi U.M. Efficacy of sulfonylureas with insulin in type 2 diabetes mellitus // Ann. Pharmacother. – 2003. – Vol. 37, no. 11. – P. 1572-1576.

18. Fritsche A., Schweitzer M. A., Haring H. U. Glimepiride combined with morning insulin glargine, bedtime neutral protamine hagedorn insulin, or bedtime insulin glargine in patients with type 2 diabetes. A randomized, controlled trial // Ann. Intern. Med. – 2003. – Vol. 138, No. 12. – P. 952-959.

19. Martin S., Kolb H., Beuth J.et al. Change in patients’ body weight after 12 months of treatment with glimepiride or glibenclamide in type 2 diabetes: a multicentre retrospective cohort study // Diabetologia. – 2003. – Vol. 46, no. 12. – P. 1611-1617.

20. Massi-Benedetti M., Herz M., Pfeiffer C. The effects of acute exercise on metabolic control in type II diabetic patients treated with glimepiride or glibenclamide // Horm. Metab. Res. – 1996. – Vol. 28, No. 9. – P. 451-455.

21. Caulfield M., O’Brien K.Cardiovascular safety of oral antidiabetic agents: the insulin secretagogues // Clin. Diabetes. – 2002. – Vol. 20, No. 2. – P. 81-84.

instructions for use, dosages, composition, analogs, side effects / Pillintrip

Given the experience of using gliclazide, one should remember about the possibility of developing the following side effects.

Hypoglycemia

Like other drugs of the sulfonylurea group, Diabeton ® MB can cause hypoglycemia in case of irregular meals and especially if meals are skipped.Possible symptoms of hypoglycemia: headache, severe hunger, nausea, vomiting, increased fatigue, sleep disturbance, irritability, agitation, decreased concentration, delayed reaction, depression, confusion, impaired vision and speech, aphasia, tremor, paresis, loss of self-control , feeling of helplessness, impaired perception, dizziness, weakness, convulsions, bradycardia, delirium, shallow breathing, drowsiness, loss of consciousness with the possible development of coma, up to death.

Adrenergic reactions may also occur: increased sweating, clammy skin, anxiety, tachycardia, increased blood pressure, palpitations, arrhythmia and angina pectoris.

As a rule, the symptoms of hypoglycemia are relieved by the intake of carbohydrates (sugar). Taking sweeteners is ineffective. Against the background of other sulfonylurea derivatives, recurrences of hypoglycemia were noted after successful relief.

In severe or prolonged hypoglycemia, emergency medical care is indicated, possibly with hospitalization, even if there is an effect of carbohydrate intake.

Other side effects

From the gastrointestinal tract: abdominal pain, nausea, vomiting, diarrhea, constipation. Taking the drug with breakfast helps to avoid or minimize these symptoms.

The following side effects are less common.

Skin and subcutaneous tissue disorders: rash, itching, urticaria, Quincke’s edema, erythema, maculopapular rash, bullous reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis).

From the circulatory and lymphatic system: hematological disorders (anemia, leukopenia, thrombocytopenia, granulocytopenia) are rare. As a rule, these phenomena are reversible in the event of discontinuation of therapy.

From the liver and biliary tract: increased activity of liver enzymes (AST, ALT, ALP), hepatitis (isolated cases). If cholestatic jaundice develops, therapy should be discontinued.

These phenomena are usually reversible if therapy is discontinued.

On the part of the organ of vision: transient visual disturbances caused by changes in blood glucose concentration may occur, especially at the beginning of therapy.

Side effects inherent in sulfonylurea derivatives: As with other sulfonylurea derivatives, the following side effects were noted: erythrocytopenia, agranulocytosis, hemolytic anemia, pancytopenia, allergic vasculitis, hyponatremia. There was an increase in the activity of liver enzymes, impaired liver function (for example, with the development of cholestasis and jaundice) and hepatitis; manifestations decreased over time after the withdrawal of sulfonylurea drugs, but in some cases led to life-threatening liver failure.

Adverse Effects Reported in Clinical Trials

In study ADVANCE , there was a slight difference in the incidence of various serious adverse events between the two patient groups. No new safety data were received. A small number of patients had severe hypoglycemia, but the overall incidence of hypoglycemia was low. The incidence of hypoglycemia in the intensive glycemic control group was higher than in the standard glycemic control group.Most episodes of hypoglycemia in the intensive glycemic control group were observed with concomitant insulin therapy.

Classification of sulfonylureas, mechanism of action and side effects / medicine | Thpanorama

Sulfonylureas are oral hypoglycemic agents used in the treatment of type 2 diabetes mellitus that act by increasing the release of insulin from the beta cells of the pancreas. These were the first antidiabetic drugs that were discovered, developed and clinically indicated in the world.

The effect of these derivatives was discovered by Janbon when tested with the novel sulfonamide in typhoid fever patients. He noticed that many developed hypoglycemia and suggested that Lubatier, who had studied insulin, try the drug. This proved the hypoglycemic effect of this compound in diabetic patients ..

This sulfonamide – or sulfonylurea – originally studied in 1942 led to the development of numerous structural changes offered an important range of therapeutic options….

index

  • 1 Classification
    • 1.1 First generation
    • 1.2 Second generation
  • 2 Mechanism of action
  • 3 Adverse effects
    • 3.1 Contraindications
    • 3.2 Drugs 908 Interactions

    First generation

    From acylsulfonylureas with discrete changes in its radical 1, the first generation sulfonylureas were formed.

    sweetener

    The first drug in this group for sale. It is currently not used due to its adverse effects.

    Chlorpropamide

    This is the only member of this first generation that has continued to be used and commercialized since the 1950s ..

    Tolazamide

    They can still be found in some developing countries due to their low cost and simple dosages

    acetohexamine

    It has been discontinued due to its high risk of hypoglycemia.

    Second generation

    More recently, more noticeable chemical changes were introduced in the radical 2 of acylsulfonylureas with the appearance of second generation hypoglycemenates. the most popular drugs in the group of oral hypoglycemic agents ..

    gliclazide

    Perhaps the least commercially used of this group.Manufacturers have decided on other compounds.

    glipizide

    Mass production of this drug was preferred over its sister gliclazide and is still frequently used in patients with type 2 diabetes.

    glibornuride

    Its use has become popular in Europe, where it is still indicated in the treatment of type 2 diabetes mellitus.

    glychidon

    It has a double effect: it stimulates the production of insulin and promotes the penetration of sugar into the cell.Sold in Africa and Europe.

    glimepiride

    It is currently one of the best-selling sulfonylureas in the world, accompanied by a huge advertising mechanism ..

    There is controversy regarding glimepiride, as some authors consider it a first third generation sulfonylurea, as it has more substituents in radicals 1 and 2 than other second-generation sulfonylureas ..

    Mechanism of action

    All sulfonylureas have a common mechanism of action: they bind to ATP-dependent potassium channels in the membrane of pancreatic beta cells, which causes them to close.

    As a result of depolarization, calcium channels open, which increases the fusion of insulin transporter granules with the cell membrane and, finally, increases insulin secretion.

    As in the case of glycidone, sulfonylureas have been shown to sensitize beta cells to glucose, limiting glucose production in the liver, lipolysis and insulin clearance in the liver ..

    By promoting the penetration of glucose into beta cells and other cells in the body, blood sugar levels are reduced and laboratory tests can detect normal or low glycemic levels….

    Finally, sulfonylureas are thought to reduce the secretion of glucagon, an insulin antagonist hormone responsible for increasing liver glucose production, thereby lowering blood glucose levels.

    Adverse Effects

    Sulfonylureas are generally well tolerated and safe. These drugs have few side effects, the most important of which is hypoglycemia.

    Some members of this group of drugs have very long half-lives and active metabolites that can cause hypoglycemia, especially if the patient skips a meal.One must be very careful when it is indicated in patients with renal or hepatic impairment.

    Tolbutamine, which is not currently used, is associated with a significant risk of death from cardiovascular causes.

    Chlorpropamide caused cholestatic jaundice and dilutional hyponatremia; when accompanied by alcohol consumption, it can cause nausea, vomiting, aplastic anemia, neutropenia, thrombocytopenia, and skin lesions.

    Contraindications

    – They should not be given to patients with type 1 diabetes, children, patients with ketoacidosis or hyperosmolarity, myocardial infarction, or acute cerebrovascular disease….

    – Avoid its use in pregnant women or while breastfeeding.

    – Patients with renal or hepatic impairment should be monitored while taking this type of medication and, if possible, these medications should be replaced with safer medications.

    – They are contraindicated in patients with sulfate allergy.

    Drug interactions

    Most of the first generation sulfonylureas already in use, such as tolbutamide and chlorpropamide, which are transported by serum albumin, can be displaced by other compounds that are linked in the same way, such as aspirin, warfarin, phenylbutazone and others long-acting.

    Some sulfonylureas are metabolized in the liver through subunits of the cytochrome P450 enzyme, so some drugs that activate these enzymes can increase the clearance of sulfonylureas, as in the case of rifampicin, an antibiotic rarely used for diseases such as tuberculosis.

    Other compounds have antagonistic action on any oral hypoglycemic agents such as steroids, thiazides, nicotinic acid, phenobarbital, some antipsychotics or antidepressants and oral contraceptives….

    Sulfonylureas are not effective in the absence of insulin, as in long-term patients with type 1 diabetes or those whose pancreas has been surgically removed.

    Currently, sulfonylureas can be combined with other oral hypologysants such as metformin and sitagliptin to achieve better glycemic control, always accompanied by adequate diet and good exercise.

    ref.

    1. (American Diabetes Association 2015).What are my options? . Living with diabetes. Oral medications. Recovered from diabetes.org
    2. Ghosh, Sujoy and Collier, Andrew (2012). Diabetes management. Churchill’s Pocket Guide , Second Edition, Section 3, 83-125.
    3. Cortez Hernandez, Alfredo (1999). Oral hypoglycemic agents. Diabetes mellitus . Disclaimer, Chapter VI, 91-117.
    4. Bazit, Abdul; Riaz, Musarrat and Fawwad, Asher (2012).Glimepiride: Evidence, Trends and Observations. Vascular Health and Risk Management . 8: 463-472.
    5. Sola, Danielle and cols (2015). Sulfonylureas and their use in clinical practice. Archives of Medical Science , 11 (4), 840-848.
    6. Wikipedia (s.F.). Sulfonylureas. Retrieved from en.wikipedia.org

    90,000 Side Effects – Aspergillosis Patient and Caregiver Support from the National Aspergillosis Center NHS, UK

    Each drug or treatment carries a risk of side effects, which are known in the medical literature as “adverse events”.The risk is often higher for people who take many different medications together (“polypharmacy”) or who take medications such as prednisone for a long time. Your doctor will help you decide which combination of treatment options is safest for you.

    Always read the patient information leaflet (found at the bottom Antifungal page ) that comes with your treatment to see what side effects you can expect. If you have misplaced this leaflet, you can find the remedy using e-medication booklet .

    You will find out the name of some of the side effects (headache, nausea, fatigue). Others may sound pretty exotic, but they are usually difficult words for something simple. You can ask your doctor or pharmacist what they mean. For example: itching means itching, anuresis means not being able to cry, and xerostomia means dry mouth.

    Clinical trials measure the incidence of various side effects and this is reported in a standard way:

    • Very common: More than 1 in 10 people are affected
    • General: 1 in 10 to 1 in 100 people
    • Uncommon: 1 in 100 to 1 in 1000 people
    • Rare: 1 in 1000 to 1 in 10,000 people
    • Very rare: less than 1 in 10,000 people are affected

    However, in the real world, drugs may behave slightly differently than in clinical trials, so it is very important to report any unpleasant side effects using MHRA Yellow Card Scheme (UK ) or FDA Voluntary Reporting Form (UNITED STATES OF AMERICA).

    How to minimize side effects:

    • Follow the instructions in the Patient Information Leaflet that came with your medicine, in particular when to take the medicine or take it on a full or empty stomach.
    • Try to take prednisone in the morning to reduce the risk of insomnia, and with meals to reduce stomach irritation and heartburn.
    • Your doctor may prescribe another type of medication to reduce side effects, such as PPIs (proton pump inhibitors) to treat heartburn.

    Many supplements or complementary therapies claim to have no side effects because they are “all natural,” but this is not true. Anything that has an effect can have a side effect. For example, St. John’s wort is an herbal remedy that may help mild depression, but there is a small risk of developing cataracts.