In 1970, the University Group Diabetes Program (UGDP) in the United States reported that the number of deaths due to cardiovascular disease in diabetic patients treated with tolbutamide was excessive compared with either insulin-treated patients or those receiving placebos. Owing to design flaws, this study and its conclusions were not generally accepted. In the United Kingdom, the UKPDS did not find an untoward cardiovascular effect of sulfonylurea usage in their large, long-term study. The sulfonylureas continue to be widely prescribed, and six are available in the United States.
Tolbutamide is well absorbed but rapidly metabolized in the liver. Its duration of effect is relatively short (6–10 hours), with an elimination half-life of 4–5 hours, and it is best administered in divided doses (eg, 500 mg before each meal). Some patients only need one or two tablets daily. The maximum dosage is 3000 mg daily. Because of its short half-life and inactivation by the liver, it is relatively safe in the elderly and in patients with renal impairment. Prolonged hypoglycemia has been reported rarely, mostly in patients receiving certain antibacterial sulfonamides (sulfisoxazole), phenylbutazone for arthralgias, or the oral azole antifungal medications to treat candidiasis. These drugs inhibit the metabolism of tolbutamide in the liver and increase its circulating levels.
Chlorpropamide has a half-life of 32 hours and is slowly metabolized in the liver to products that retain some biologic activity; approximately 20–30% is excreted unchanged in the urine. The average maintenance dosage is 250 mg daily, given as a single dose in the morning. Prolonged hypoglycemic reactions are more common in elderly patients, and the drug is contraindicated in this group. Other adverse effects include a hyperemic flush after alcohol ingestion in genetically predisposed patients and hyponatremia due to its effect on vasopressin secretion and action.
Tolazamide is comparable to chlorpropamide in potency but has a shorter duration of action. Tolazamide is more slowly absorbed than the other sulfonylureas, and its effect on blood glucose does not appear for several hours. Its half-life is about 7 hours. Tolazamide is metabolized to several compounds that retain hypoglycemic effects. If more than 500 mg/d are required, the dosage should be divided and given twice daily.
Acetohexamide is no longer available in the United States. Its half-life is only about 1 hour but its more active metabolite, hydroxyhexamide, has a half-life of 4–6 hours; thus the drug duration of action is 8–24 hours. Where available, its dosage is 0.25–1.5 g/d as single dose or in two divided doses.
Chlorpropamide, tolazamide, and acetohexamide are now rarely used in clinical practice.
Glyburide, glipizide, gliclazide, and glimepiride are 100–200 times more potent than tolbutamide. They should be used with caution in patients with cardiovascular disease or in elderly patients, in whom hypoglycemia would be especially dangerous.
Glyburide is metabolized in the liver into products with very low hypoglycemic activity. The usual starting dosage is 2.5 mg/d or less, and the average maintenance dosage is 5–10 mg/d given as a single morning dose; maintenance dosages higher than 20 mg/d are not recommended. A formulation of “micronized” glyburide (Glynase PresTab) is available in a variety of tablet sizes. However, there is some question as to its bioequivalence with non-micronized formulations, and the FDA recommends careful monitoring to re-titrate dosage when switching from standard glyburide doses or from other sulfonylurea drugs.