Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors have complementary mechanisms of action: both lower blood glucose with the advantages of weight loss, a low risk of hypoglycaemia, and a favourable cardiovascular profile. DURATION-8 was a Phase III, multicentre, double-blind, randomised, active- controlled, 28-week study with a 24-week (and subsequent 52-week) extension study. DURATION-8 tested the efficacy and safety of combining exenatide once weekly (ExQW), a glucagon-like peptide-1 receptor agonist, and dapagliflozin (DAPA), a sodium-glucose cotransporter-2 inhibitor, for the treatment of patients with Type 2 diabetes mellitus uncontrolled by metformin alone (baseline glycated haemoglobin [HbA1c]: 8.0–12.0%; mean: 9.3%).1 During 28 weeks of treatment, the combination of ExQW plus DAPA reduced HbA1c, fasting plasma glucose (FPG), postprandial glucose, weight, and systolic blood pressure (SBP) significantly better than ExQW plus placebo (PBO) or DAPA plus PBO, with no unexpected safety signals.1 During the EASD 2017 meeting in Lisbon, Portugal, we presented the results for the same study endpoints after a further 24 weeks of treatment, totalling 52 weeks of double- blind therapy.2
From 8–28 weeks, patients received rescue therapy with added basal insulin based on progressively stricter FPG criteria (from >270 mg/dL to >200 mg/dL). From 36–52 weeks, patients were rescued if their HbA1c was >8.0%. Efficacy analyses excluded measurements after the initiation of rescue therapy. Of 695 randomised patients, 564 (81.2%) completed the study and 523 (75.3%) completed treatment. The most common reasons for discontinuation of treatment or study withdrawal were withdrawals by the patient, adverse events (AE), or being lost to follow-up. All endpoints at 52 weeks were considered exploratory; therefore, no significance can be claimed.
At Week 52, we obtained greater reductions with ExQW plus DAPA compared to ExQW plus PBO or DAPA plus PBO for HbA1c (1.75% versus 1.38% versus 1.23%, respectively), FPG (63.0 versus 45.7 versus 39.7 mg/dL, respectively), 2-hour postprandial glucose (82.4 versus 64.0 versus 59.6 mg/dL, respectively), body weight (3.3 versus 1.5 versus 2.3 kg, respectively), and SBP (4.5 versus 0.7 versus 2.8 mmHg, respectively). Overall, the reductions of these endpoints at Week 52 were comparable with those recorded at Week 28, while treatment differences were maintained.
Over 52 weeks, the combination of ExQW plus DAPA was well tolerated by participants, with comparable rates of AE and serious AE between the three study groups. As expected, the most frequent AE were gastrointestinal and injection-site nodules in ExQW-treated patients and urinary tract infections in DAPA-treated patients. We recorded no episodes of major hypoglycaemia, while minor hypoglycaemia occurred in 1.3%, 0.0%, and 0.4% of patients, respectively. No deaths were recorded in the 28–52-week extension.
In conclusion, over 52 weeks of treatment the combination of ExQW plus DAPA was more effective compared with either treatment alone in patients with Type 2 diabetes mellitus poorly controlled by metformin alone. The improvements observed at Week 28 for glycaemic parameters, body weight, and SBP were maintained over 52 weeks, indicating the durability of the effect of this combination treatment. In addition, treatment with ExQW plus DAPA was well tolerated, with an expected safety profile. Overall, the data indicate the 1-year efficacy and safety of the ExQW plus DAPA combination; however, further studies are required to assess its effects on long-term outcomes and cardiovascular safety/benefit, as well as cost-effectiveness.