Exenatide is used as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. The drug is available as an injection for twice-daily administration (Byetta) and as an extended-release for injectable suspension formulation for once-weekly administration (Bydureon).
Exenatide has been used as monotherapy or in combination with metformin, a sulfonylurea, or a thiazolidinedione; in combination with metformin and a sulfonylurea or a thiazolidinedione; or in combination with insulin glargine with or without metformin and/or a thiazolidinedione. The extended-release formulation of exenatide has been used as monotherapy or in combination with metformin, a sulfonylurea, or a thiazolidinedione or in combination with metformin and a sulfonylurea or a thiazolidinedione. Current guidelines on the treatment of type 2 diabetes mellitus generally recommend the use of GLP-1 receptor agonists such as exenatide as second-line therapy (after first-line metformin therapy) and also as an option for first-line treatment. Because of the uncertain relevance to humans of thyroid C-cell tumors found in rodents given extended-release exenatide, this formulation of the drug is not recommended as first-line therapy for patients with inadequate glycemic control on diet and exercise alone.
(See Risk of Thyroid C-cell Tumors with Extended-release Exenatide under Warnings/Precautions: Warnings, in Cautions.)
Safety and efficacy of exenatide or extended-release exenatide have not been established in patients with a history of pancreatitis; other antidiabetic agents should be considered in such patients.
(See Pancreatitis and Pancreatic Precancerous Changes under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
Exenatide or extended-release exenatide is not a substitute for insulin. The manufacturer states that exenatide or extended-release exenatide should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis because the drug is not effective for these conditions. The safety and efficacy of exenatide in combination with prandial insulin or of extended-release exenatide in combination with insulin have not been established, and such concomitant use is not recommended.
(See Use with Drugs Known to Cause Hypoglycemia under Cautions: Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
Exenatide and extended-release exenatide contain the same active ingredient and should not be used concomitantly.
When given as monotherapy or add-on therapy, twice-daily exenatide improves glycemic control (e.g., as determined by changes in glycosylated hemoglobin [hemoglobin A1c, HbA1c]) more than placebo and similar to that of titrated insulin lispro or insulin aspart 70/30 therapy. In addition, therapy with GLP-1 receptor agonists such as exenatide generally is associated with weight loss compared with that observed with placebo and most other antidiabetic agents (e.g., sulfonylureas, thiazolidinediones, insulin).
Safety and efficacy of exenatide as monotherapy in patients with type 2 diabetes mellitus have been established in a 24-week, randomized, double-blind, placebo-controlled study. In this study, patients with baseline HbA1c concentrations of 6.5-10% (mean: 7.8-7.9%) received exenatide 5 or 10 mcg or placebo subcutaneously twice daily before the morning and evening meals. Patients assigned to receive exenatide 10 mcg twice daily received 5 mcg twice daily for 4 weeks, then 10 mcg twice daily. The primary study end point was the change in HbA1c concentration from baseline to week 24 (or the last value at time of early discontinuance of therapy). At week 24, therapy with exenatide 5 or 10 mcg twice daily resulted in mean reductions of 0.7 or 0.9%, respectively, in HbA1c compared with baseline. HbA1c concentrations below 7% were achieved in 48, 53, or 38% of patients receiving exenatide 5 mcg, exenatide 10 mcg, or placebo, respectively. Patients receiving exenatide also experienced greater weight reduction than those receiving placebo (-2.8, -3.1, or -1.4 kg with twice-daily dosages of exenatide 5 mcg, 10 mcg, or placebo, respectively).
In several studies of 30 weeks' duration in which exenatide (5 or 10 mcg twice daily) was given in combination with maximally effective dosages of metformin hydrochloride, a sulfonylurea (e.g., glipizide, glyburide, glimepiride, tolazamide, chlorpropamide), or metformin hydrochloride in combination with a sulfonylurea, combined therapy with subcutaneous exenatide and these oral antidiabetic agents or regimens resulted in a reduction from baseline in HbA1c and progressive weight loss compared with that achieved with existing oral antidiabetic therapy.
Safety and efficacy of exenatide as add-on therapy to other antidiabetic agents also have been established in other studies. In a 16-week, placebo-controlled study in patients who had not achieved adequate glycemic control with a thiazolidinedione with or without metformin, the addition of subcutaneous exenatide (5 or 10 mcg twice daily) to existing oral antidiabetic therapy resulted in a reduction from baseline in HbA1c at week 16 compared with that achieved with existing oral antidiabetic therapy. In a 30-week, placebo-controlled study in patients with type 2 diabetes mellitus who had inadequate glycemic control on titrated insulin glargine with or without metformin and/or a thiazolidinedione (i.e., pioglitazone), addition of exenatide (5 or 10 mcg twice daily) to existing antidiabetic therapy reduced HbA1c from baseline at week 30 compared with that achieved with existing antidiabetic therapy. In a 26-week randomized, open-label study in patients with type 2 diabetes mellitus receiving metformin therapy (baseline HbA1c 6.5-10%), addition of exenatide (5 mcg twice daily for 4 weeks, then 10 mcg twice daily) was noninferior to addition of titrated, premixed insulin aspart (70% long-acting insulin aspart protamine, 30% rapid-acting insulin aspart) in improving HbA1c (least-squares mean HbA1c reduction of 1 or 1.14% with exenatide or insulin aspart 70/30, respectively). In addition, exenatide therapy was associated with less hypoglycemia than insulin aspart and resulted in weight reduction while insulin aspart 70/30 caused weight gain.
Clinical studies indicate that the once-weekly extended-release formulation of exenatide generally is as effective as conventional regimens of metformin or pioglitazone and more effective than sitagliptin, titrated insulin glargine, insulin detemir, or twice-daily exenatide in improving glycemic control. Improvements in glycemic control have been maintained during long-term therapy (e.g., up to 6 years) with extended-release exenatide. In addition, compared with twice-daily exenatide, once-weekly extended-release exenatide generally has been associated with a similar degree of weight loss and GI adverse effects.
Safety and efficacy of once-weekly subcutaneous extended-release exenatide as monotherapy or in combination with other antidiabetic agents have been established in several randomized, open-label or double-blind clinical studies generally of 24-30 weeks' duration (e.g., DURATION studies) in adults with type 2 diabetes mellitus. In the 6 DURATION studies, once-weekly therapy with subcutaneous extended-release exenatide was compared with subcutaneous insulin glargine, liraglutide, or twice-daily exenatide or with oral antidiabetic agents (metformin, sitagliptin, pioglitazone) in patients who had inadequate glycemic control (mean baseline HbA1c concentrations of 8.3-8.6%) with or without preexisting oral antidiabetic therapy. The primary efficacy end point in these studies was the mean change in HbA1c from baseline to the end of the study; extended-release exenatide reduced HbA1c by 1.3-1.9% compared with reductions of 0.9-1.5% for twice-daily exenatide, 1.2-1.6% for pioglitazone, 0.9-1.2% for sitagliptin, 1.5% for metformin, 1.3% for insulin glargine, and 1.5% for liraglutide. In general, extended-release exenatide was more effective than twice-daily exenatide overall in reducing HbA1c and fasting plasma glucose, while twice-daily exenatide had a greater effect on postprandial hyperglycemia. In addition, the proportion of patients achieving an HbA1c of less than 7% with extended-release exenatide in the DURATION studies generally was similar to that with pioglitazone and greater than that with sitagliptin or insulin glargine.
In the long-term therapy (up to 6 years) portions of the DURATION-1 study, improvements in glycemic control and weight generally were sustained in patients who continued once-weekly therapy with extended-release exenatide and sustained or enhanced in those whose therapy was switched from the twice-daily to the once-weekly formulation. Compared with insulin and most oral antidiabetic agents, therapy with subcutaneous extended-release exenatide resulted in slow but progressive weight loss, which was similar to that associated with twice-daily exenatide and sustained during long-term therapy. Extended-release exenatide therapy was well tolerated in these studies, with no major hypoglycemic episodes reported and a low risk of hypoglycemia compared with insulin and most other oral antidiabetic agent comparators; when hypoglycemic episodes occurred, patients generally were receiving concomitant sulfonylurea therapy.