ObjectiveProgressive -cell dysfunction hinders the maintenance of glycaemic control in type 2 diabetes, but comparative data on -cell-protective therapies are lacking in the early stage of type 2 diabetes. Here we evaluated the comparative glycaemic efficacy and impact on -cell function of three antihyperglycaemic agents that have a -cell-protective effect, exenatide, insulin and pioglitazone, in newly diagnosed patients with type 2 diabetes. Design and methodsIn this 48-week, multicentre, parallel-group study, 416 patients newly diagnosed with type 2 diabetes were randomly assigned 1:1:1 to receive exenatide, insulin or pioglitazone. The primary end-point was the change in glycosylated haemoglobin (HbA1c) from baseline. Secondary end-points included effects on weight, blood pressure, lipid profiles and -cell function assessed by homeostasis model assessment, fasting proinsulin:insulin (PI/I), disposition index (DI) and acute insulin response (AIR). ResultsAt week 48, mean [95% confidence interval (CI)] HbA(1c) changes from baseline were -1.8% (-1.55% to -2.05%) with exenatide, -1.7% (-1.52% to -1.96%) with insulin and -1.5% (-1.23% to -1.71%) with pioglitazone. Treatment differences were -0.20% (95% CI -0.46% to 0.06%) for exenatide versus insulin (P=0.185), and -0.37% (95% CI -0.63% to -0.12%) for exenatide versus pioglitazone (P=0.002). Significant improvements from baseline in AIR, PI/I and DI were observed with all treatments, with the greatest improvements in DI, as well as weight, blood pressure and lipid profile, observed with exenatide. ConclusionsAll three agents showed efficacy regarding glycaemic control and metabolic benefits; however, exenatide showed the greatest efficacy. -cell function improved in all treatment groups; hence, early initiation of -cell-protective therapy may halt the decline in -cell function in type 2 diabetes.