Medications> Glucose-lowering>

INDICATIONS

• Type 2 diabetes mellitus

• Chlorpropamide: central diabetes insipidus

MECHANISM

• Sulfonylureas and meglitinides (repaglinide and nateglinide) stimulate first-phase insulin secretion from functioning beta cells in the pancreas.
• Both classes of drugs bind to and cause closure of potassium-ATP channels on pancreatic beta cell membranes. This results in membrane depolarization, calcium influx, and insulin exocytosis.
• Sulfonylureas bind to a different membrane site than meglitinides, but the intracellular effects are the same.

USUAL ADULT DOSING

• Chlorpropamide: 100 mg - 500 mg once daily. Maximum total daily dose (TDD) 750 mg daily.
• Tolbutamide: 250 mg - 3 g daily, once or in divided doses. Maximum TDD 3 g.
• Glipizide: 5 mg - 40 mg daily. If TDD > 15 mg, divide into at least 2 doses. Maximum TDD 40 mg.
• Glipizide XL: 5 mg - 10 mg once daily. Maximum 20 mg daily.
• Glyburide: 1.25 mg - 20 mg once daily or in 2 divided doses. Maximum TDD 20 mg.
• Glyburide micronized: 0.75 mg - 12 mg once daily or in 2 divided doses. Maximum TDD 12 mg.
• Glimepiride: 1 mg - 4 mg once daily. Maximum TDD 8 mg daily.
• Repaglinide: 0.5 mg - 4 mg with each meal. Maximum TDD 16 mg.
• Nateglinide: 60 mg - 120 mg to be given 1 to 30 minutes before meals. Maximum 180 mg three times per day.
• Reduce dose or entirely eliminate sulfonylurea once insulin therapy is started.  

FORMS

*Prices represent cost per unit specified and are representative of "Average Wholesale Price" (AWP). AWP Prices were obtained and gathered by Lakshmi Vasist Pharm D using the Red Book, manufacturer's information, and the McKesson database.

^Dosage is indicated in mg unless otherwise noted.

DOSING IN SPECIAL POPULATIONS

• Patients with renal insufficiency are at increased risk for hypoglycemia due to the predominant renal excretion of the sulfonylureas, and prolongation of drug effects in this setting.
• For the sulfonylureas, usual dosing for GFR > 80 mL/min . For GFR 50-80 mL/min, a 50% dose reduction is recommended. For GFR < 50 mL/min, it is recommended to avoid these drugs entirely or to use very conservative dosing (25% dose reduction) due to increased risk for hypoglycemia.
• If a sulfonylurea must be used in renal insufficiency, glipizide (inactive metabolites) or glimepiride (substantial fecal excretion) are preferred. Avoid glyburide due to accumulation of partially active metabolites which may lead to profound hypoglycemia.
• The meglitinides are generally well tolerated in all stages of renal insufficiency.

• Conservative dosing is recommended (i.e. start at 50% of the usual starting dose). This is due to the increased risk for hypoglycemia, as most of these drugs are metabolized by the liver.

• Glyburide is the only sulfonylurea to be rated as FDA Category B
• All of the other sulfonylureas are rated as FDA Category C
• Both meglitinides are rated as FDA Category C

• Thomson Lactation Ratings: infant risk cannot be ruled out

ADVERSE DRUG REACTIONS

• Contraindicated in diabetic ketoacidosis
• Not to be used for therapy in type 1 diabetes mellitus
• Patients should avoid excessive alcohol use (increased risk for hypoglycemia)

• Hypoglycemia, more common in those with renal insufficiency, hepatic impairment, and in the elderly
• Exercising without prior caloric intake also increases risk for hypoglycemia
• Weight gain
• Chlorpropamide-alcohol flushing: Up to 15% of people taking chlorpropamide note a distinct facial flush upon alcohol ingestion 

• Nausea, vomiting, diarrhea, flatulence, abdominal pain
• Hyponatremia with chlorpropamide
• Elevated liver transaminases

• Hypersensitivity skin reactions

DRUG INTERACTIONS

• Agents that enhance sulfonylurea action: NSAIDs, warfarin, salicylates, sulfonamides, allopurinol, probenecid, guanethidine, MAOIs, chloramphenicol, alcohol, beta blockers
• Agents that decrease sulfonylurea action: glucocorticoids, diuretics, niacin, levothyroxine, estrogens, progestins, phenytoin, diazoxide, isoniazid, rifampin, phenothiazines, sympathomimetics

PHARMACOKINETIC

COMMENTS

• Overall HbA1c reduction with the sulfonylureas is about 1-2% after at least 3 months.
• Overall HbA1c reduction with the meglitinides is about 1-1.5%; repaglinide (Prandin) is more potent that nateglinide (Starlix). These agents are quite effective in patients who have isolated postprandial hyperglycemia but not necessarily impaired fasting fasting glucose.
• Side effects include weight gain and hypoglycemia due to increased insulin secretion.
• Second generation sulfonylureas are preferred over first generation sulfonylureas (chlorpropamide and tolbutamide), as the latter tend to have more drug interactions and adverse effects.
• Each year, about 5-10% of diabetic patients on sulfonylureas need to be switched over to insulin due to secondary failure of sulfonylurea therapy.

REFERENCES

RELATED MODULES

• Elderly and Diabetes
• Introduction to Diabetes
• Nutrition for Type 2 Diabetes
• Type 2 Diabetes: Sequencing Therapies