The add-on of a prandial (short-acting) GLP-1 RA to basal insulin in subjects with T2DM who fail to control A1C on basal insulin, stems from the physiological principles of post-prandial glucose homeostasis, and it is based on evidence from clinical trials. The 4B and GetGoal DUO 2 studies are the first to establish in head-to-head comparison, the efficacy and safety of short-acting GLP-1 RAs vs prandial insulin, when added-on to basal insulin glargine. In the 4B study (exenatide 2/d vs lispro 3/d) exenatide demonstrated similar efficacy vs lispro in reducing A1C to ~7.2%. However, exenatide reduced also body weight and hypoglycemia incidence as compared to lispro. In GetGoal DUO 2, the head-to-head comparison was between lixisenatide 1/d vs glulisine either 1/d (at the main meal, basal-plus) or 3/d (basal-bolus). Like in 4B, in GetGoal DUO 2 the A1C decreased to similar values with lixisenatide or glulisine 1/d (~7.2%), or glulisine 3/d (~7.0%). Again, as in the 4B, body weight and hypoglycemia incidence were lower with lixisenatide. In both studies a similar percentage of subjects reached the A1C <7.0% on GLP-1 RA or prandial insulin. A higher percentage of subjects reported adverse events on GLP-1 RAs, primarily gastrointestinal related. The studies 4B and GetGoal DUO 2 suggest that after failure of basal insulin in T2DM, the add-on of prandial GLP-1 RA is as effective as prandial insulin in lowering A1C, with added benefits of reducing body weight and risk for hypoglycemia. In addition, the GLP-1 RA + basal insulin is a simpler therapeutic option as compared to basal-plus and basal-bolus regimens.