Sulfonylureas

Introduction

Sulfonylureas (SFUs) work primarily by chronically stimulating pancreatic insulin secretion, which in turn reduces hepatic glucose output and increases peripheral glucose disposal. Four first-generation SFU compounds have been available in the United States for the treatment of Type 2 diabetes (T2D) for >20 years. They are:

• Acetohexamide
• Chlorpropamide
• Tolazamide
• Tolbutamide.

Two second-generation SFU compounds, glipizide and glyburide, were introduced in the United States in 1984 and another (glimepiride) more recently. Thus the second-generation compounds are:

• Glimepiride
• Glipizide
• Glyburide.

The efficacy of the first- and second-generation SFUs is similar, although second-generation agents are better formulated and have some advantages. Second-generation SFUs:

• Are more potent on a per-milligram basis
• Tend to produce fewer side effects
• Interact less frequently with other drugs.

Improved formulations of glipizide (Glucotrol XL) and glyburide (Glynase PresTab) are also available. In addition, the pharmacokinetics of some of these second-generation agents allow for more effective once-a-day dosing, which enhances compliance.

Side Effects of SFUs

Most of the side effects associated with SFU therapy are mild, infrequent and occur less often with the second-generation agents; they include:

• Weight gain
• Hypoglycemia
• Mild GI upset
• Skin reactions:
  • Rashes
  • Purpura
  • Pruritus.

Hyponatremia, fluid retention and an Antabuse-like reaction to alcohol have also been reported with the use of chlorpropamide. The major complication of SFU therapy is severe hypoglycemia, which has been more of a problem with chlorpropamide than with any other agent because of its long half-life and duration of action. Hypoglycemia is also more common in individuals who consume large amounts of alcohol and/or skip meals, and in the elderly. Other reactions are rare and include hematologic reactions (leukopenia, thrombocytopenia and hemolytic anemia) and cholestasis (with and without jaundice).

Prescribing SFUs

In general, SFU therapy should be initiated at the lowest possible dose, especially in the elderly (Table 8-1). It is begun once daily, before breakfast, and increased progressively every 1 to 2 weeks until the desired therapeutic glycemic response is achieved or the maximum dose is reached. The dosing regimen is changed to twice daily when the daily dose approaches ≥50% of the maximum recommended dose. Dosing adjustments can also be made based on self-monitoring of blood glucose (SMBG) data. For example, if the patient’s SMBG results show elevated FBG values, the evening dose should be titrated upward. If, on the other hand, the evening fasting blood glucose (FBGs) are elevated, the morning dose can be raised.

Clinicians should focus on achieving satisfactory glycemic control based on glucose and glycosylated hemoglobin (A1C) levels and not concentrate solely on the patient’s symptoms, which could lead to premature dosage discontinuation or dose reduction. In patients with glucose toxicity and markedly elevated glucose values (i.e., >200-300 mg/dL), it may be necessary to use insulin temporarily to achieve glycemic control. Once glycemic control has been achieved for several days to weeks, the patient may be an appropriate candidate for oral-agent therapy alone. Patients who do not achieve appropriate glycemic control in response to one or more oral agents should be promptly switched to or have insulin therapy added to the existing oral regimen.

In general, SFUs should not be considered routinely as monotherapy for newly diagnosed obese patients with T2D or in diabetic individuals in whom nonpharmacologic therapy has failed. Such patients usually have circulating hyperinsulinemia that can be further exacerbated if SFUs are used. SFUs also lead to weight gain and can cause hypoglycemia. There is also some evidence to suggest that the early use of SFUs may lead to premature β-cell exhaustion. In addition, concerns persist about the possible adverse effects of some SFUs on cardiac function.

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Second-Generation SFUs

Glimepiride

Glimepiride (Amaryl) therapy has been shown to improve overall glucose control without producing clinically meaningful increases in fasting insulin and C-peptide levels. It is the only SFU with an Food and Drug Administration (FDA)-approved indication for combination therapy with insulin. Studies have shown that glimepiride causes little or no weight gain or hypoglycemia.

The usual maintenance dosage is 1 mg to 4 mg once daily. The maximum recommended dosage is 8 mg once daily. After reaching a dose of 2 mg, further increases should be no more than 2 mg at 1- to 2-week intervals based on the patient’s blood glucose response.

Glipizide

Glipizide (Glucotrol, Glucotrol XL) is a second-generation SFU that is metabolized by the liver mainly to inactive products, thereby reducing the risk of hypoglycemia. Glucotrol XL utilizes a controlled delivery system, and when compared with the immediate-release Glucotrol, the risk of hypoglycemia and the glucose and insulin responses to meals are similar although compliance is improved. Glipizide is particularly suited for the elderly or any patient with mild renal or liver dysfunction. Recommended dosing is normally 1 to 2 times daily for immediate-release glipizide. The long-acting extended-release formulation (Glucotrol XL) maintains therapeutic plasma levels effectively for 24 hours, and once-daily dosing is adequate in the majority of patients.

Glyburide

Glyburide (DiaBeta, Micronase, Glynase PresTab) is metabolized by the liver to mostly inert products that are excreted in the urine and bile. However, some of the by-products do have hypoglycemic activity and caution is advised, especially in patients with evidence of liver or kidney dysfunction. The duration of action is 16 to 24 hours, and recommended dosing is 1 to 2 times daily. A micronized particle formulation facilitates more rapid absorption (Glynase PresTab).