Changes in glycemic variability, gastric emptying and vascular endothelial function after switching from twice-daily to once-weekly exenatide in patients with type 2 diabetes: a subpopulation analysis of the twin-exenatide study

Background We investigated the changes in blood glucose fluctuation, gastric emptying, and vascular endothelial function by switching from an exenatide twice-daily formulation (BID) to a once-weekly formulation (QW) since the evaluation of postprandial glucose excursion and glycemic variability (GV) by continuous glucose monitoring (CGM) after switching was lacking. Methods Twenty-nine patients with type 2 diabetes treated with exenatide BID were included in this study and switched to exenatide QW for 24 weeks. GV assessed by CGM, gastric emptying (by 13 C-acetate breath test) and vascular endothelial function (by reactive hyperemia - peripheral arterial tonometry) were evaluated at baseline and 24 weeks after switching. Results HbA1c decreased significantly from the baseline to week 24, while postprandial glucose levels after breakfast and dinner significantly increased (both P <0.05). However, the increases in GV indices were modest and not statistically significant at week 24. Vascular endothelial function was also not significantly changed after switching (P >0.05). Gastric emptying was significantly accelerated at week 24 (Tmax 83.4 ± 12.1 min vs. 58.2 ± 16.4 min) (P <0.001) and correlated with increased postprandial glucose levels after breakfast and dinner (both P <0.05). Conclusions Despite the increase in postprandial glucose associated with accelerated gastric emptying after switching from exenatide BID to QW, change in GV was modest and no significant deterioration in vascular endothelial function was observed after switching. These results support the superiority of treatment with exenatide QW over exenatide BID in clinical practice; however, attention should be paid to the monitoring and management of postprandial glucose levels when selecting exenatide QW. Trial registration Clinical trial registry number; UMIN000016390 and jRCTs031180320. Approval date of Registry and the Registration: December 12, 2014.

Efficacy and safety over 2 years of exenatide plus dapagliflozin in the DURATION-8 study: a multicenter, double-blind, phase 3, randomized controlled trial

<b>OBJECTIVE: </b>In patients with type 2 diabetes uncontrolled with metformin, exenatide once weekly (QW) plus dapagliflozin produced greater reductions in glycemic parameters (glycated haemoglobin [HbA_1c], fasting plasma glucose [FPG], and 2-hour 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. Here, we investigated efficacy and safety at 104 weeks after randomization. <p><b>RESEARCH DESIGN AND METHODS:</b> DURATION-8 was a 104-week, multicenter, double-blind, randomized, active‑controlled, phase 3 trial. In total, 695 adults (age ≥18 years) with type 2 diabetes and inadequate glycemic control (HbA_1c, 8.0%–12.0% [64–108 mmol/mol]) despite stable metformin monotherapy (≥1500 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. </p> <p><b>RESULTS: </b>At week 104, 431 (62.0%) patients completed treatment. The adjusted least squares mean (LSM) change [standard error] from baseline to week 104 in HbA_1cwas greater with exenatide QW plus dapagliflozin (–1.70% [0.11]) versus exenatide QW plus placebo (–1.29% [0.12]; <i>P</i>=0.007) and dapagliflozin plus placebo (–1.06% [0.12]; <i>P</i><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. </p> <p><b>CONCLUSIONS: </b>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.<b></b></p>

Efficacy and safety over 2 years of exenatide plus dapagliflozin in the DURATION-8 study: a multicenter, double-blind, phase 3, randomized controlled trial

<b>OBJECTIVE: </b>In patients with type 2 diabetes uncontrolled with metformin, exenatide once weekly (QW) plus dapagliflozin produced greater reductions in glycemic parameters (glycated haemoglobin [HbA_1c], fasting plasma glucose [FPG], and 2-hour 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. Here, we investigated efficacy and safety at 104 weeks after randomization. <p><b>RESEARCH DESIGN AND METHODS:</b> DURATION-8 was a 104-week, multicenter, double-blind, randomized, active‑controlled, phase 3 trial. In total, 695 adults (age ≥18 years) with type 2 diabetes and inadequate glycemic control (HbA_1c, 8.0%–12.0% [64–108 mmol/mol]) despite stable metformin monotherapy (≥1500 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. </p> <p><b>RESULTS: </b>At week 104, 431 (62.0%) patients completed treatment. The adjusted least squares mean (LSM) change [standard error] from baseline to week 104 in HbA_1cwas greater with exenatide QW plus dapagliflozin (–1.70% [0.11]) versus exenatide QW plus placebo (–1.29% [0.12]; <i>P</i>=0.007) and dapagliflozin plus placebo (–1.06% [0.12]; <i>P</i><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. </p> <p><b>CONCLUSIONS: </b>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.<b></b></p>