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Review of exenatide for the treatment of type 2 diabetes
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The FDA approved exenatide in April 2005 and it was the first incretin mimetic to hit the market.
Exenatide (Byetta, Amylin) is synthetic exendin-4, which binds to and activates the pancreatic glucagon like peptide-1 receptor, resulting in an increase in insulin secretion from beta cells in the presence of hyperglycemia. It also suppresses glucagon secretion, slows gastric emptying and decreases food intake. Its use is limited to patients with type 2 diabetes, as it has no role in the management of type 1 diabetes.
Clinical trials
Exenatide has been studied for up to 82 weeks in patients inadequately controlled on sulfonylureas and/or metformin. Glycosylated hemoglobin was reduced 0.4% to 0.6% in patients on the 5-mcg regimen and 0.8% to 1.3% in patients on the 10-mcg regimen. Changes in fasting plasma glucose were minimal, however, this is to be expected as exenatide has a greater effect on postprandial glucose levels. Body weight also improved in these patients with a 0.9 kg to 1.6 kg weight loss seen in patients using 5-mcg twice daily and 1.6 kg to 5.3 kg in patients using 10-mcg twice daily.
One placebo-controlled study examined the effect of adding exenatide in patients suboptimally controlled on a thiazolidinedione with or without metformin. The addition of exenatide led to a HbA1c decrease of 1%, fasting plasma glucose of 31 mg/dL and body weight of 1.5 kg.
 James R. Taylor |
The addition of exenatide has been compared to the addition of insulin glargine and insulin aspart in two separate studies. When compared to insulin glargine, both agents decreased HbA1c by 1%. Exenatide demonstrated greater efficacy in reducing postprandial glucose concentrations and body weight, however, insulin glargine produced greater effects on preprandial glucose levels and fewer adverse events. In a study comparing the addition of exenatide to insulin aspart, both agents decreased HbA1c as well as fasting serum glucose. Additionally, exenatide led to weight loss and greater improvement in morning and evening postprandial glucose levels.
A long-acting release formulation of exenatide is currently in phase-2 clinical trials. With a half-life of two weeks, exenatide long-acting release could be administered once weekly. Results of a recent study showed that at a dose of 0.8 mg and 2 mg once weekly for 15 weeks resulted in significant improvements in HbA1c and fasting plasma glucose.
Dosing and cost
Exenatide is indicated as adjunctive therapy in combination with metformin, a sulfonylurea or a TZD. It can also be used in triple therapy with metformin and a sulfonylurea or metformin and a TZD. It is not currently indicated for use as monotherapy. It is dosed at 5-mcg subcutaneously twice daily (60 minutes prior to a meal). After one month, if an optimal response is not achieved, the dose may be increased to 10-mcg twice daily. Exenatide is cleared primarily by the kidneys and is not recommended for use in patients with a creatinine clearance <30 mL/min. Dosage adjustments are not necessary for those with creatinine clearance >30 mL/min and hepatic dysfunction is not expected to affect exenatide concentrations. Retail cost is about $175 to $200 for a one-month supply.
Adverse events and interactions
Nausea is the most common adverse event and occurs in 36% to 39% of patients with the 5-mcg dose and 45% to 50% with the 10-mcg dose, although it is usually transient. Exenatide results in a moderate reduction in weight, which does not appear to be related to the adverse gastrointestinal effects. There is a risk of mild to moderate hypoglycemia when exenatide is used with a sulfonylurea, which is most likely due to the effects of the sulfonylurea. Exenatide reportedly results in low levels of antibodies in approximately 40% of patients. About 6% of patients may develop high antibody levels possibly resulting in a diminished response. The FDA has received at least 30 post-marketing reports of acute pancreatitis in patients taking exenatide, some of which are believed to be related to this drugs use.
At present, there are no known clinically significant drug interactions with exenatide. There was a 17% decrease in the plasma Cmax of digoxin when digoxin 0.25 mg/day was administered with exenatide, although total drug exposure (AUC) was unchanged. Lovastatin AUC and Cmax were decreased by 40% and 28%, respectively when administered with exenatide. Exenatide should not be used in patients with type 1 diabetes or diabetic ketoacidosis. There are no other contraindications at this time. Safety has not been studied in pregnant or nursing women, therefore it should be used with caution, if at all, in these patients.
Place in therapy
Exenatide has been shown to significantly reduce HbA1c when used as adjunct therapy. However, these reductions may not be quite as significant as that seen with more traditional therapies. Studies designed to evaluate exenatide as monotherapy vs. traditional agents are underway to help clarify its efficacy in relation to these agents. Exenatide is typically associated with modest weight loss. Another potential advantage is that they may preserve or even reverse the decline in beta-cell function. More long-term data are needed to confirm this, but this would support the use of these agents early in the treatment phase. Potential disadvantages include the cost, need to inject doses, high rates of nausea/vomiting and relative lack of long-term safety and efficacy studies. Impact, if any, on cardiovascular disease is also unknown at this point.
Exenatide’s unique mechanism of action and other potential advantages certainly position it to be a first-line option. However, more long term safety and efficacy studies are needed to clearly define its role. Until such time, exenatide appears to be a viable option to more traditional agents, especially in those unable to take or tolerate other agents.
James R. Taylor, PharmD, CDE, is a Clinical Associate Professor in the Department of Pharmacy Practice at the University of Florida.
For more information:
- Buse JB, Henry RR, Han J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004;27:2628-2635.
- DeFronzo RA, Ratner RE, Han J, et al. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28:1092-1100.
- Heine RJ, VanGaal LF, Johns D, et al. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes. Ann Int Med. 2005;143:559-569.
- Kendall DM, Riddle MC, Rosenstock J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care. 2005;28:1083-1091.
- Kim D, MacConell L, Zhuang D, et al. Effects of once-weekly dosing of a long-acting release formulation of exenatide on glucose control and body weight in subjects with type 2 diabetes. Diabetes Care. 2007;30:1487-1493.
- Nauck MA, Duran S, Kim D, et al. A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study. Diabetologia. 2007;50:259-267.
- Nielsen LL, Young AA, Parkes DG. Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved glycemic control of type 2 diabetes. Regulatory Peptides. 2004;117:77-88.
- Ratner RE, Maggs D, Nielsen LL, et al. Long-term effects of exenatide therapy over 82 weeks on glycaemic control and weight in over-weight metformin-treated patients with type 2 diabetes mellitus. Diabetes Obes Metab 2006; 8:419-428.
- Riddle MC, Henry RR, Poon TH, et al. Exenatide elicits sustained glycemic control and progressive reduction of body weight in patients with type 2 diabetes inadequately controlled by sulphonylureas with or without metformin. Diabetes Metab Res Rev. 2006;22:483-491.
- Zinman B, Hoogwerf BJ, Garcia SD, et al. The effect of adding exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes. Ann Int Medi. 2007;146: 477-485.