Second-Generation Sulfonylureas

SECOND-GENERATION SULFONYLUREAS

The second-generation sulfonylureas are prescribed more frequently in the USA than are the first-generation agents because they have fewer adverse effects and drug interactions. These potent sulfonylu-rea compounds—glyburide, glipizide, and glimepiride—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 verylow 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 nonmicron-ized formulations, and the FDA recommends careful monitoring to re-titrate dosage when switching from standard glyburide doses or from other sulfonylurea drugs.

Glyburide has few adverse effects other than its potential for causing hypoglycemia. Flushing has rarely been reported after ethanol ingestion, and the compound slightly enhances free water clearance. Glyburide is contraindicated in the presence of hepatic impairment and in patients with renal insufficiency.

Glipizide has the shortest half-life (2–4 hours) of the morepotent agents. For maximum effect in reducing postprandial hyper-glycemia, this agent should be ingested 30 minutes before breakfast because absorption is delayed when the drug is taken with food. The recommended starting dosage is 5 mg/d, with up to 15 mg/d given as a single dose. When higher daily dosages are required, they should be divided and given before meals. The maximum total daily dosage recommended by the manufacturer is 40 mg/d, although some studies indicate that the maximum therapeutic effect is achieved by 15–20 mg of the drug. An extended-release preparation (Glucotrol XL) provides 24-hour action after a once-daily morning dose (maximum of 20 mg/d). However, this formulation appears to have sacrificed its lower propensity for severe hypoglycemia com-pared with longer-acting glyburide without showing any demon-strable therapeutic advantages over the latter (which can be obtained as a generic drug).

Because of its shorter half-life, the regular formulation of glip-izide is much less likely than glyburide to produce serious hypo-glycemia. At least 90% of glipizide is metabolized in the liver to inactive products, and 10% is excreted unchanged in the urine. Glipizide therapy is therefore contraindicated in patients with significant hepatic or renal impairment, who would be at high risk for hypoglycemia.

Glimepiride is approved for once-daily use as monotherapy orin combination with insulin. Glimepiride achieves blood glucose lowering with the lowest dose of any sulfonylurea compound. A single daily dose of 1 mg has been shown to be effective, and the recommended maximal daily dose is 8 mg. Glimepiride has a long duration of effect with a half-life of 5 hours, allowing once-daily dosing and thereby improving compliance. It is completely metab-olized by the liver to metabolites with weak or no activity.