Duration-8 Randomised Controlled Trial 1-Year Results: Efficacy and Safety of Once-Weekly Exenatide Plus Once-Daily Dapagliflozin Versus Exenatide or Dapagliflozin Alone - European Medical Journal
×

Browse

Duration-8 Randomised Controlled Trial 1-Year Results: Efficacy and Safety of Once-Weekly Exenatide Plus Once-Daily Dapagliflozin Versus Exenatide or Dapagliflozin Alone

|
3 Mins
Authors:
*Cristian Guja,1 Juan P. Frías,2 Azazuddin Ahmed,3 Peter Öhman,4 Serge Jabbour5
Disclosure:

The DURATION-8 study (NCT02229396) was supported by AstraZeneca. Cristian Guja received personal fees from Quintiles Eastern Holdings Gmbh during the conduct of the study and received personal fees from Alfa Wasserman Pharma, AstraZeneca, Bayer AG, Berlin Chemie Menarini, Merck, Merck Sharp & Dohme, Novo Nordisk, Sanofi, and Worwag Pharma outside the submitted work. Juan P. Frías received grants from AstraZeneca during the conduct of the study; received grants from Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer, Novo Nordisk, Sanofi, and Theracos outside the submitted work; and has served as a consultant for Bristol-Myers Squibb, Novo Nordisk, Sanofi, and Theracos. Azazuddin Ahmed received grants from AstraZeneca during the conduct of the study and received grants from AbbVie, Kowa Pharmaceuticals, Novo Nordisk, and Sanofi outside the submitted work. Peter Öhman is an employee and shareholder of AstraZeneca. Serge Jabbour has served as a consultant for AstraZeneca, Eli Lilly, and Janssen.

Acknowledgements:

The DURATION-8 study was supported by AstraZenaca. Raewyn Poole, Julian Martins, and Amanda Sheldon of inScience Communications, Springer Healthcare (Philadelphia, PA, USA), provided medical writing support for this presentation.

Citation
EMJ Diabet. ;5[1]:77-78. Abstract Review No. AR5.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

Receive our free quarterly newsletters and your choice of journal publication alerts, straight to your inbox.

Join our mailing list

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.

References
Frías JP et al. 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. Lancet Diabetes Endocrinol. 2016;4(12):1004-16. Guja C et al. DURATION-8 randomised controlled trial 1-year results: efficacy and safety of once-weekly exenatide plus once-daily dapagliflozin versus exenatide or dapagliflozin alone [abstract]. Diabetologia. 2017;60(Suppl 1):S5.