New drugs: exenatide, pramlintide acetate, and micafungin sodium

Antidiabetic Agents Two new agents with unique mechanisms of action increase the options for improving glycemic control in patients with diabetes mellitus. Exenatide (Byetta—Amylin; Lilly) is a synthetic form of a protein found in the saliva of the Gila monster, a large lizard that is native to Mexico and the southwestern United States. It mimics the action of incretins such as glucagon-like peptide-1 (GLP-1), and the amino acid sequence of exenatide (sometimes designated as an incretin-mimetic agent) partially overlaps that of human GLP-1. Exenatide is thought to bind with and activate GLP-1 receptors, resulting in a reduction in fasting and postprandial glucose concentrations in patients with type 2 diabetes. It improves glycemic control through several mechanisms, including increased insulin synthesis and secretion in the presence of elevated glucose concentrations, restoration of the “first-phase insulin response,” reduced serum glucagon concentrations during periods of hyperglycemia, slowed gastric emptying, and reduced food intake. Exenatide is indicated for subcutaneous administration as adjunctive therapy to improve glycemic control in patients with type 2 diabetes mellitus who are taking metformin (e.g., Glucophage), a sulfonylurea (e.g., glyburide), or a combination of metformin and a sulfonylurea but have not achieved adequate glycemic control. The primary endpoint in the clinical trials in which the new drug was evaluated was mean change from baseline glycosylated hemoglobin (A1C) at 30 weeks. In each of the studies a statistically significant reduction from baseline A1C was observed in the groups of patients treated with exenatide as compared with patients for whom placebo was added to their previous regimen. The percentage of patients achieving an A1C of 7% or less was in the general range of 30% to 40% in the studies, compared with approximately 10% in the groups receiving placebo. The use of exenatide resulted in a reduction of both fasting and postprandial plasma glucose concentrations in a dosedependent manner, and a reduction in baseline body weight was experienced with the higher dosage (10 mcg twice a day) of the new drug. The concurrent use of exenatide with antidiabetic agents other than metformin and/or a sulfonylurea has not yet been evaluated. It is not a substitute for insulin and should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Its use as monotherapy is currently being evaluated but is not a labeled indication at the present time. The addition of exenatide to a metformin regimen has not been associated with an increased incidence of hypoglycemia. However, when the new agent is added to a regimen that includes a sulfonylurea, the incidence of hypoglycemia is increased and a reduction in dosage of the sulfonylurea should be considered. The most frequently experienced adverse events reported in the clinical studies of exenatide include nausea (44%), vomiting (13%), diarrhea (13%), feeling jittery (9%), dizziness (9%), headache (9%), and dyspepsia (6%). Nausea is experienced most often when therapy is initiated, is usually mild to moderate in intensity, and frequency and severity often decrease as therapy is continued. The use of the new drug is not recommended in patients with severe gastrointestinal (GI) disease, including gastroparesis, a complication of diabetes. Exenatide is classified in pregnancy category C and should be used during pregnancy only if the potential benefit justifies the risk to the fetus. Whether the drug is excreted in human milk is unknown, and a decision should be made whether to not use the drug or discontinue nursing. The effectiveness and safety of exenatide in pediatric patients have not been established. Because exenatide slows gastric emptying, it may reduce the extent and rate of absorption of orally administered drugs. It delays and reduces the peak concentration of digoxin but not its area under the serum–concentration time curve (AUC). It also reduces both the peak concentration and AUC of lovastatin (e.g., Mevacor) and acetaminophen (e.g., Tylenol). Exenatide should be used with caution in patients who are taking oral medications that require rapid GI absorption. Medications such as antibiotics and oral contraceptives that depend on threshold concentrations for effectiveness should be administered at least 1 hour before exenatide. As with other therapeutic proteins, a potential exists for the development of antiexenatide antibodies. Almost 40% of the patients in the 30-week studies had low titer antiexenatide antibodies, but the extent of glycemic control was generally similar in these individuals compared with the patients without antibody titers. In a smaller group of patients (6%) who had higher titer antibodies, the glycemic response to the drug appeared attenuated in approximately one half of the patients (i.e., 3% of the total number of N E W D R U G S