Glimepiride, Glipizide, Glyburide—Which Sulfonylurea When?

Sulfonylureas have been utilized for the treatment of type 2 diabetes mellitus (T2DM) since the 1950s. Their oral dosage form and long history of clinical experience make them a mainstay in the treatment of T2DM. Three sulfonylureas are available in the United States—glimepiride, glipizide, and glyburide—and all 3 are roughly clinically interchangeable in terms of hemoglobin A_1c (HbA_1c) lowering. Given their generic status, all 3 are relatively inexpensive.

Do any factors differentiate the sulfonylureas, or are these agents truly interchangeable?

Patient Case

LV is a 72-year-old woman with a history of hypertension and T2DM. She is taking lisinopril, 10 mg daily, for her hypertension and simvastatin, 20 mg daily, for her T2DM. Treatment with metformin had failed, causing severe nausea and diarrhea, delaying alternative treatments while she works on improving her diet and increasing her exercise level. Despite these efforts, her HbA_1c has continued to rise and is now 7.8%.

At this visit, her vital signs include the following: heart rate, 75 beats/min; blood pressure, 134/72 mm Hg; and respiratory rate, 15 breaths/min. Her weight is 55 kg, and her height is 176 cm (body mass index, 7.8 kg/m²). In addition to her HbA_1c of 7.8%, other pertinent laboratory test results include a serum creatinine level of 1.2 mg/dL and a creatinine clearance of 43 mL/min.

LV prefers an oral diabetes agent that is inexpensive, and after you discuss the management plan with her, she agrees to begin taking a sulfonylurea. Which sulfonylurea should she be started on?

The Evidence

Glimepiride, glipizide, and glyburide all lead to reductions in HbA_1c on the order of 1% to 2%. Glimepiride is purported to have the highest incidence of hypoglycemia of the 3 agents, although this may be due in part to glimepiride having the longest half-life of the 3 sulfonylureas, allowing for once-daily dosing at all doses. Because of their shorter half-life, glyburide and glipizide require twice-daily administration as their doses are increased. All 3 agents undergo hepatic metabolism, with only glyburide having active metabolites—a key difference among the sulfonylureas.

The metabolites of glyburide are weakly active, and this weak level of activity does not contribute substantially to the overall HbA_1c lowering effects in most patients with diabetes. However, because these metabolites are cleared renally, patients with reduced kidney function will experience accumulation, which can lead to increased therapeutic effects and increase the risk of hypoglycemia.

The relative lack of advantages of glyburide compared with the other agents, combined with its increased risk of adverse effects, creates a risk-to-benefit ratio that does not favor its use. Given that the risks are increased only in patients with poor kidney function, one could simply adjust the choice of agents to select from, but owing to the lack of advantages of glyburide, it makes more sense to remove it as a choice. There is not a scenario in which glyburide is the preferred agent, but there are certain scenarios in which it is clearly the least-preferred agent.

Clinical Application

Given the lack of advantages of glyburide and its increased potential for harm relative to the other sulfonylureas in patients with reduced kidney function, such as LV, she would best be started on either glipizide or glimepiride. She should monitor her blood glucose levels daily, and she should return to the office in 1 month for follow-up and have her HbA_1c checked again at 3 months.

Eric A. Dietrich, PharmD, BCPS, is a graduate of the University of Florida College of Pharmacy and completed a 2-year fellowship in family medicine where he was in charge of an anticoagulation clinic. He works for the College of Pharmacy and the College of Medicine at the University of Florida in Gainesville.

Kyle Davis, PharmD, BCPS, is a graduate of the University of Florida College of Pharmacy in Gainesville and completed a 2-year residency in internal medicine at Indiana University in Indianapolis. He is an internal medicine specialist at Ochsner Medical Center in Jefferson, Louisiana.