title: 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.
abstract: 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 >or=18 years with type 2 diabetes were randomly assigned to receive exenatide 5 microg, exenatide 10 microg, 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 <or=6.5% and <or=7.0%; weight; and homeostasis model of beta-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 [SD] 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% [0.9%]). At end point, least-squares mean (SE) HbA(1c) reductions (%) from baseline were significantly greater with exenatide 5 and 10 microg 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 microg 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 microg, 31% and 35% of patients achieved HbA(1c) <or=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) <or=7.0% (P = 0.024 and P = 0.036, respectively). Changes in weight (kg) at 24 weeks were greater with exenatide 5 and 10 (2)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-microg groups, respectively, versus 6% for placebo. Improvements from baseline to end point in HOMA-B were significantly greater with exenatide 5 and 10 microg 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 microg, -3.7 [1.2] [P = 0.037]; diastolic, 10 microg, -2.3 [0.7] [P = 0.046]) versus placebo (systolic, -0.3 [1.2]; diastolic, -0.3 [0.7]). Overall, 25% of patients reported >or=1 treatment-emergent adverse event. Nausea was reported with the greatest incidence (5 microg, 3%; 10 microg, 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-microg 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.
authors.affiliation: American Health Network, Indianapolis, Indiana, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Moretto
authors.forename: Denái R
authors.initials: DR
authors.lastname: Milton
authors.forename: Terry D
authors.initials: TD
authors.lastname: Ridge
authors.forename: Leigh A
authors.initials: LA
authors.lastname: Macconell
authors.forename: Ted
authors.initials: T
authors.lastname: Okerson
authors.forename: Anne M
authors.initials: AM
authors.lastname: Wolka
authors.forename: Robert G
authors.initials: RG
authors.lastname: Brodows
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose; D001794:Blood Pressure; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D000077270:Exenatide; D005260:Female; D006442:Glycated Hemoglobin; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014688:Venoms / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D001786:Blood Glucose; D000077270:Exenatide; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms