Efficacy and Safety of Dulaglutide 3.0 mg and 4.5 mg Versus Dulaglutide 1.5 mg in Metformin-Treated Patients With Type 2 Diabetes in a Randomized Controlled Trial (AWARD-11)

Abstract

Objective: To compare efficacy and safety of dulaglutide at doses of 3.0 and 4.5 mg versus 1.5 mg in patients with type 2 diabetes inadequately controlled with metformin.

Research design and methods: Patients were randomly assigned to once-weekly dulaglutide 1.5 mg, 3.0 mg, or 4.5 mg for 52 weeks. The primary objective was determining superiority of dulaglutide 3.0 mg and/or 4.5 mg over 1.5 mg in HbA_1c reduction at 36 weeks. Secondary superiority objectives included change in body weight. Two estimands addressed efficacy objectives: treatment regimen (regardless of treatment discontinuation or rescue medication) and efficacy (on treatment without rescue medication) in all randomly assigned patients.

Results: Mean baseline HbA_1c and BMI in randomly assigned patients (N = 1,842) was 8.6% (70 mmol/mol) and 34.2 kg/m², respectively. At 36 weeks, dulaglutide 4.5 mg provided superior HbA_1c reductions compared with 1.5 mg (treatment-regimen estimand: -1.77 vs. -1.54% [-19.4 vs. -16.8 mmol/mol], estimated treatment difference [ETD] -0.24% (-2.6 mmol/mol), P < 0.001; efficacy estimand: -1.87 vs. -1.53% [-20.4 vs. -16.7 mmol/mol], ETD -0.34% (-3.7 mmol/mol), P < 0.001). Dulaglutide 3.0 mg was superior to 1.5 mg for reducing HbA_1c, using the efficacy estimand (ETD -0.17% [-1.9 mmol/mol]; P = 0.003) but not the treatment-regimen estimand (ETD -0.10% [-1.1 mmol/mol]; P = 0.096). Dulaglutide 4.5 mg was superior to 1.5 mg for weight loss at 36 weeks for both estimands (treatment regimen: -4.6 vs. -3.0 kg, ETD -1.6 kg, P < 0.001; efficacy: -4.7 vs. -3.1 kg, ETD -1.6 kg, P < 0.001). Common adverse events through 36 weeks included nausea (1.5 mg, 13.4%; 3 mg, 15.6%; 4.5 mg, 16.4%) and vomiting (1.5 mg, 5.6%; 3 mg, 8.3%; 4.5 mg, 9.3%).

Conclusions: In patients with type 2 diabetes inadequately controlled by metformin, escalation from dulaglutide 1.5 mg to 3.0 mg or 4.5 mg provided clinically relevant, dose-related reductions in HbA_1c and body weight with a similar safety profile.

Trial registration: ClinicalTrials.gov NCT03495102.

Figure 1

Patient disposition. *Patient randomly assigned at two different investigator sites, only counted once in randomization total; †Includes patients who discontinued the study.

Figure 2

Primary and secondary efficacy outcomes by estimand. A: Change in HbA_1c from baseline to 36 weeks and 52 weeks, ANCOVA with multiple imputation (treatment-regimen estimand). B: Change in HbA_1c from baseline to 36 weeks (primary time point) and 52 weeks, mixed-model for repeated measure (MMRM; efficacy estimand). C: Change in HbA_1c by study week, MMRM (efficacy estimand). D: Proportion of patients achieving HbA_1c <7% (53 mmol/mol) at 36 and 52 weeks, logistic regression with imputation of missing end point data as not achieving target (treatment-regimen estimand). E: Proportion of patients achieving HbA_1c <7% (53 mmol/mol) at 36 and 52 weeks, longitudinal logistic regression (efficacy estimand). F: Change in body weight from baseline to 36 and 52 weeks, ANCOVA with multiple imputation (treatment-regimen estimand). G: Change in body weight from baseline to 36 and 52 weeks, MMRM (efficacy estimand). H: Change in body weight by study week, MMRM (efficacy estimand). Data presented as LSM ± SE unless otherwise indicated; †P < 0.05, ††P < 0.001 vs. dulaglutide 1.5 mg, respectively. *Nominal P value, not adjusted for multiplicity; comparison vs. dulaglutide 1.5 mg did not achieve statistical superiority using the graphical testing approach. Note that 36-week LSMs in bar graphs for efficacy estimand are from MMRM analysis performed at the 36-week primary database lock, whereas LSMs in the line graphs (C and H) are from MMRM analyses including all data through the final 52-week time point. The efficacy estimand included patients with a nonmissing baseline value and at least one nonmissing postbaseline value of the response variable: n = 1,780 patients for HbA_1c (1.5 mg, n = 591; 3.0 mg, n = 595; 4.5 mg, n = 594) and n = 1,809 patients for body weight (1.5 mg, n = 601; 3.0 mg, n = 604; 4.5 mg, n = 604). For the treatment-regimen estimand, data were included from all randomly assigned patients with imputation of missing end point values. BL, baseline; DU, dulaglutide; HbA_1c, glycated hemoglobin.