DURATION-2: EXENATIDE ONCE WEEKLY DEMONSTRATED SUPERIOR GLYCEMIC CONTROL AND WEIGHT REDUCTION COMPARED TO SITAGLIPTIN OR PIOGLITAZONE AFTER 26 WEEKS OF TREATMENT [6-LB]

Bergenstal R, Wysham C, Yan P, MacConell L, Malloy J, Porter L; Minneapolis, MN; Spokane, WA; San Diego, CA

Exenatide is a glucagon-like peptide-1 (GLP-1) analogue that is currently approved in the United States in a formulation that is administered by twice-daily subcutaneous injection.¹ A more convenient once-weekly formulation of exenatide is currently being evaluated in clinical trials. This new formulation was previously shown to produce significantly greater improvement in glycosylated hemoglobin (A_1c) values than twice-daily exenatide, to increase the proportion of patients who achieved a goal A_1c value of less than 7%, to reduce patient-reported hypoglycemic episodes, and to improve patient satisfaction with therapy.^2,3 Subsequent studies have demonstrated sustained glycemic control for up to 2 years with once-weekly exenatide.⁴

In the DURATION-2 study, the results of which were presented at the 2009 American Diabetes Association 69th Scientific Sessions meeting, the investigators compared the efficacy and safety of once-weekly exenatide with sitagliptin (an inhibitor of dipeptidyl peptidase-4 [DPP-4], an enzyme that inactivates the incretins GLP-1 and glucose-dependent insulinotropic polypeptide) and the peroxisome proliferator-activated receptor-γ agonist pioglitazone after 26 weeks. Patients with type 2 diabetes on stable metformin (N = 491) were randomized to double-blind treatment with once-weekly exenatide 2 mg, sitagliptin 100 mg, or pioglitazone 45 mg. At baseline, the patients’ mean A_1c value was 8.5%, the mean fasting plasma glucose was 164 mg/dL, and mean weight was 88 kg. At the end of the 26-week study, the mean reduction in A_1c was significantly greater with exenatide once weekly (1.55%) than with sitagliptin (0.92%; P <.05) or pioglitazone (1.23%; P <.05). A reduction of A_1c to 7% or lower was noted for more patients in the exenatide group (66%) than with sitagliptin (42%; P <.05) or pioglitazone (56%; P <.05). More patients in the exenatide group also achieved an A_1c goal of 6.5% or lower (43%, 18%, and 33% for the exenatide, sitagliptin, and pioglitazone groups, respectively; P <.05 for exenatide vs each of the other 2 groups). Body weight decreased by an average of 2.7 kg for patients in the exenatide group, and by an average of 0.9 kg in the sitagliptin group (P <.05 vs exenatide), but increased by an average of 3.2 kg in the pioglitazone group (P <.05 vs exenatide). At the conclusion of the study, the average body weight for the pioglitazone group was greater than that of the exenatide group by 5.1 kg. Once-weekly exenatide was also associated with greater improvements from baseline than the other treatments' several other clinical outcomes, including fasting plasma glucose, systolic blood pressure, and the albumin:creatinine ratio. Nausea (generally mild and transitory) was noted for 24% of patients with exenatide, 10% with sitagliptin, and 5% with pioglitazone; one patient in each group discontinued prematurely due to nausea.

Exenatide was the first GLP-1 analogue to enter clinical practice. Although several studies have demonstrated that exenatide is effective for the treatment of type 2 diabetes, the requirement for a twice-daily subcutaneous injection may be a barrier for some patients. If it is approved for clinical use, the introduction of a once-weekly formulation of exenatide would represent a more convenient option for patients with type 2 diabetes.

References
1. Exenatide [prescribing information]. San Diego, CA: Amylin Pharmaceuticals, Inc; 2008.
2. Drucker DJ, Buse JB, Taylor K, et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet. 2008;372:1240-1250.
3. Best JH, Boye KS, Rubin RR, et al. Improved treatment satisfaction and weight-related quality of life with exenatide once weekly or twice daily. Diabet Med. 2009;26:722-728.
4. After 1 year, type 2 diabetes patients taking exenatide once weekly sustained improvements in glycemic control and weight. Medical News Today Web site. Available at: http://www.medicalnewstoday.com/articles/110784.php. Accessed October 14, 2009.