Efficacy and Safety Over 2 Years of Exenatide Plus Dapagliflozin in the DURATION-8 Study: A Multicenter, Double-Blind, Phase 3, Randomized Controlled Trial

Abstract

Objective: In patients with type 2 diabetes uncontrolled with metformin, exenatide once weekly (QW) plus dapagliflozin produced greater reductions in glycemic parameters (glycated hemoglobin [HbA1c], fasting plasma glucose [FPG], and 2-h postprandial glucose [2-h PPG]), weight, and systolic blood pressure (SBP) than exenatide QW or dapagliflozin alone after 28 weeks of treatment in DURATION-8. Following a 24-week extension period, improvements were sustained at 52 weeks. In this study, we investigated efficacy and safety at 104 weeks after randomization.

Research design and methods: DURATION-8 was a 104-week, multicenter, double-blind, randomized, active-controlled, phase 3 trial. In total, 695 adults (aged ≥18 years) with type 2 diabetes and inadequate glycemic control (HbA1c 8.0-12.0% [64-108 mmol/mol]) despite stable metformin monotherapy (≥1,500 mg/day) were randomly assigned (1:1:1) to receive exenatide 2 mg QW plus once-daily dapagliflozin 10 mg, exenatide QW plus placebo, or dapagliflozin plus placebo. All 104-week evaluations were exploratory.

Results: At week 104, 431 (62.0%) patients completed treatment. The adjusted least squares mean change (SE) from baseline to week 104 in HbA1c was greater with exenatide QW plus dapagliflozin (-1.70% [0.11]) versus exenatide QW plus placebo (-1.29% [0.12]; P = 0.007) and dapagliflozin plus placebo (-1.06% [0.12]; P < 0.001). Clinically relevant changes in FPG, 2-h PPG, weight, and SBP were also observed with exenatide QW plus dapagliflozin. There were no unexpected safety findings, and exenatide QW plus dapagliflozin was well tolerated, with no episodes of major hypoglycemia.

Conclusions: In this exploratory analysis, among those individuals who completed the trial without rescue therapy, there was clinically relevant efficacy over 2 years with exenatide QW plus dapagliflozin, with no unexpected safety findings.

Trial registration: ClinicalTrials.gov NCT02229396.

© 2020 by the American Diabetes Association.

Figures

Figure 1

Adjusted least squares mean (LSM) change in HbA1c (A), mean urine glucose/creatinine ratio (B), adjusted LSM change in FPG (C), adjusted LSM change in 2-h PPG (D), adjusted LSM change in body weight (E), adjusted LSM change in SBP (F), and mean eGFR (G) over 104 weeks of treatment. Error bars show 95% CIs. *P < 0.05, **P < 0.01, ***P < 0.001 vs. exenatide QW plus dapagliflozin (P values at weeks 52 and 104 are nominal).

Figure 1

Adjusted least squares mean (LSM) change in HbA1c (A), mean urine glucose/creatinine ratio (B), adjusted LSM change in FPG (C), adjusted LSM change in 2-h PPG (D), adjusted LSM change in body weight (E), adjusted LSM change in SBP (F), and mean eGFR (G) over 104 weeks of treatment. Error bars show 95% CIs. *P < 0.05, **P < 0.01, ***P < 0.001 vs. exenatide QW plus dapagliflozin (P values at weeks 52 and 104 are nominal).