Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial

Background Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce glycaemia and weight, and improve cardiovascular risk factors via different mechanisms. We aimed to compare the efficacy and safety of co-initiation of the GLP-1 receptor agonist exenatide and the SGLT2 inhibitor dapagliflozin with exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled by metformin. Methods DURATION-8 was a 28 week, multicentre, double-blind, randomised, active-controlled phase 3 trial done at 109 sites in six countries. Adults (aged >= 18 years) with type 2 diabetes and inadequate glycaemic control (HbA(1c) 8-12% [64-108 mmol/mol]) despite stable metformin monotherapy (>= 1500 mg/day) were randomly assigned (1:1:1), via an interactive voice and web-response system, to receive once-weekly exenatide 2 mg by subcutaneous injection plus once-daily dapagliflozin 10 mg oral tablets, exenatide with dapagliflozin-matched oral placebo, or dapagliflozin with exenatide-matched placebo injections. Randomisation was stratified by baseline HbA(1c) (<9.0% vs >= 9.0% [<75 mmol/mol vs >= 75 mmol/mol]). The primary endpoint was change in HbA(1c) from baseline to week 28. Secondary endpoints were the change from baseline in fasting plasma glucose at week 2 and week 28, and 2 h postprandial glucose at week 28; the proportion of patients with an HbA(1c) less than 7,0% (< 53 mmol/mol) at week 28; change in weight at week 28; the proportion of patients with weight loss of 5% or more at week 28; and change in systolic blood pressure at week 28. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02229396. Findings Between Sept 4, 2014, and Oct 15, 2015, we randomly assigned 695 patients to receive exenatide plus dapagliflozin (n=231), exenatide alone (n=231; n=1 untreated), or dapagliflozin alone (n=233). The intention-to-treat population comprised 685 participants (mean HbA(1c) 9,3% [SD 1,1]; 78 mmol/mol [12]), of whom 611 (88%) completed the study. After 28 weeks, the change in baseline HbA(1c) was -2, 0% (95% CI-2, 1 to -1, 8) in the exenatide plus dapagliflozin group, -1, 6% (-1, 8 to -1, 4) in the exenatide group, and -1, 4% (-1, 6 to-1, 2) in the dapagliflozin group. Exenatide plus dapagliflozin significantly reduced HbA 1c from baseline to week 28 compared with exenatide alone (-0, 4% [95% CI-0,6 to-0,1]; p=0.004) or dapagliflozin alone (-0,6% [-0,8 to -0,3]; p < 0.001). Exenatide plus dapagliflozin was significantly superior to either drug alone for all secondary efficacy endpoints, with greater reductions in fasting plasma and postprandial glucose, more patients with an HbA 1c less than 7,0% (< 53 mmol/mol), greater weight loss, a greater proportion of patients with weight loss of 5% or more, and greater reductions in systolic blood pressure (all p <= 0.025). Adverse events were recorded in 131 (57%) of 231 patients in the exenatide plus dapagliflozin group, 124 (54%) of 230 patients in the exenatide group, and 121 (52%) of 233 patients in the dapagliflozin group. The most common adverse events (>= 5% of patients in any group) were diarrhoea, injection-site nodules, nausea, and urinary tract infections. No episodes of major hypoglycaemia or minor hypoglycaemia were reported. Interpretation Co-initiation of exenatide and dapagliflozin improved various glycaemic measures and cardiovascular risk factors in patients with type 2 diabetes inadequately controlled by metformin monotherapy. The dual treatment regimen was well tolerated, with the expected safety profile for this combination. Additional data from an ongoing study (AWARD-10; NCT02597049) will further inform the use of these drug classes in combination.