Efficacy and tolerability of exenatide monotherapy over 24 weeks in antidiabetic drug-naive patients with type 2 diabetes: A randomized, double-blind, placebo-controlled, parallel-group study

Background: Evaluation of exenatide monotherapy in patients with type 2 diabetes may be of clinical interest based on improvements in glycemic control and weight that have been reported with the use of exenatide in combination with oral antidiabetic agents. Objective: The aim of this study was to evaluate the efficacy and tolerability of exenatide monotherapy in patients with type 2 diabetes naive to antidiabetic agents and whose disease was inadequately controlled with diet and exercise alone. Methods: This 24-week, double-blind, placebo-controlled, parallel-group study was conducted at 23 centers across the United States, Puerto RICO, Romania, Russia, and India. Patients aged >= 18 years with type 2 diabetes were randomly assigned to receive exenatide 5 mu g, exenatide 10 mu g, or placebo administered SC BID. Patients were instructed by investigators to maintain their individualized prestudy diet and exercise regimens throughout the study. Efficacy measures included: glycosylated hemoglobin (HbA(1c)); fasting serum glucose (FSG); 6-point self-monitored blood glucose; percentages of patients achieving HbA(1c) values :! 6.5% and : 7.0%; weight; and homeostasis model of P-cell function (HOMA-B, a clinical measure of pancreatic beta-cell function). Tolerability measures included patient-reported adverse events, hypoglycemia, and blood pressure. Results: A total of 232 patients were included in the intent-to-treat population (130 men, 102 women; 68% white; mean [SDI age, 54 [10] years; duration of type 2 diabetes, 2 [3] years; weight, 86 [16] kg; body mass index, 31 [5] kg/m(2); HbA(1c), 7.8% 10.9%]). At end point, least-squares mean (SE) HbA(1c) reductions (%) from baseline were significantly greater with exenatide 5 and 1.0 mu g than placebo (-0.7 [0.1] and -0.9 [0.1] vs -0.2 [0.1]; P = 0.003 and P < 0.001, respectively), as were FSG reductions (mg/dL) (-17.5 [4.0] and -18.7 [4.0] vs -5.2 [4.0]; P = 0.029 and P = 0.016, respectively). Changes in daily mean postprandial glucose excursions (mg/dL) from baseline to end point were significantly greater with exenatide 5 and 10 mu g than placebo (-21.3 [2.7] and -24.7 [2.7] vs -8.3 [2.5]; both, P < 0.001). With exenatide 5 and 10 mu g, 31% and 35% of patients achieved HbA(1c) : 6.5% at end point versus 19% with placebo (P = NS and P = 0.026, respectively), while 48% and 46% versus 29% achieved HbA(1c) : 7.0% (P = 0.024 and P = 0.036, respectively). Changes in weight (kg) at 24 weeks were greater with exenatide 5 and 10 mu g than placebo (-2.8 [0.3] and -3.1 [0.3] vs -1.4 [0.3]; P = 0.004 and P < 0.001, respectively). HOMA-B values increased from baseline to end point by 32% and 28% in the exenatide 5- and 10-mu g groups, respectively, versus 6% for placebo. Improvements from baseline to end point in HOMA-B were significantly greater with exenatide 5 and 10 mu g than placebo (P 0.002 and P = 0.010, respectively). Significant improvements in mean systolic and diastolic blood pressure (mm Hg) from baseline to end point were also observed with exenatide (systolic, both 5 and 10 mu g, -3.7 [1.2] [P = 0.037]; diastolic, 10 mu g, -2.3 [0.7] [P = 0.046]) versus placebo (systolic, -0.3 [1.2]; diastolic, -0.3 [0.7]). Overall, 25% of patients reported >= 1 treatment-emergent adverse event. Nausea was reported with the greatest incidence (5 mu g, 3%; 10 mu g, 13%; placebo, 0%; P = 0.010 for the combined exenatide group vs placebo). Most (88%) treatment-emergent adverse events were mild or moderate in intensity. Hypoglycemia was reported in 5%, 4%, and 1% of patients in the exenatide 5- and 10-mu g and placebo groups, respectively (P = NS), with no incidents of severe hypoglycemia reported. Conclusions: In these patients with type 2 diabetes naive to treatment with antidiabetic agents, exenatide monotherapy was associated with improved HbA(1c), improved fasting and postprandial glucose control, reduced weight, improved beta-cell function (HOMA-B), and improved blood pressure, and was well tolerated. These results suggest that exenatide monotherapy may provide a viable treatment option beyond diet and exercise and support further study of exenatide monotherapy in antidiabetic drug-naive patients with type 2 diabetes.