DURATION-3, an open-label, randomised, controlled study of T2DM patients, compared the once-weekly formulation of the GLP-1 receptor agonist exenatide (EQW) to titrated insulin glargine (IG). Of 467 enrolled participants, 140 EQW and 147 IG patients completed 3 years in their original treatment groups. In both groups the most common reason for discontinuation was subject decision (EQW 11%, IG 16%). In the intent-to-treat population, the LS mean reduction in A1C from baseline at 3 years was significantly greater (P=0.03) in the EQW group (-1.01%, SE 0.07) than IG group (-0.81%, 0.07) despite adherence to a treat-to-target insulin titration algorithm. Bodyweight decreased significantly (P<0.001) within the EQW group (-2.49 kg, 0.28) while patients in the IG group experienced significant (P<0.001) weight gain (+2.01 kg, 0.28). Twice as many EQW patients (68%) achieved reduction in both A1C and bodyweight at 3 years compared to IG patients (34%). Decrease in fasting glucose was significantly (P<0.001) less in the EQW (-31.1 mg/dL, 3.4) than IG (-47.7 mg/dL, 3.4) group. The safety profile of both drugs was consistent with previous reports. Over 3 years gastrointestinal adverse events occurred more often in EQW patients (16% nausea; 6% vomiting; 14% diarrhoea) than IG patients (2%, 3%, 7% respectively), but incidence of nausea and vomiting decreased after 26 weeks in the EQW group. The percentage of patients testing positive for anti-exenatide antibodies decreased from 26 weeks to 3 years (56% vs 19%). The exposure-adjusted rate of hypoglycaemia in the EQW group was 1/3 that of the IG group (0.3 vs 0.9 events/pts/year). In the longest controlled study of a long-acting GLP-1 receptor agonist to-date, patients treated with EQW experienced significantly better sustained glycaemic control and weight loss with lower risk of hypoglycaemia than patients treated with IG.