Efficacy of Dulaglutide Expanded Doses by Baseline A1C Categories: Post Hoc Analysis of AWARD-11

Abstract

The AWARD-11 trial demonstrated the safety and efficacy of dulaglutide (DU) once weekly doses of 3 mg and 4.5 mg compared to DU 1.5 mg in patients with type 2 diabetes (T2D) inadequately controlled with metformin monotherapy. This exploratory post hoc analysis of AWARD-11 assessed the effect of dulaglutide on A1C reduction by clinically-relevant baseline A1C subgroups (<8%; 8%-<9%; 9%-<10%; ≥10%) and the proportion of patients achieving A1C <7% in these subgroups through 36 and 52 weeks. Patients were randomized to once weekly DU 1.5 mg (n=612), 3 mg (n=616), or 4.5 mg (n=614). All patients initiated once weekly DU 0.75 mg for 4 weeks, followed by stepwise dose escalation every 4 weeks to the randomized dose. A mixed effects model for repeated measures was used within the A1C subgroups to assess the change in A1C from baseline at 36 and 52 weeks. A longitudinal logistic regression model was used within subgroups to analyze the proportion of patients achieving A1C <7% at 36 and 52 weeks. Efficacy analyses used data collected up to initiation of rescue medication or premature treatment discontinuation, if either occurred. DU 1.5 mg reduced A1C across all baseline A1C categories at 36 weeks (range, -1.0 to -2.2%) and effects were sustained through 52 weeks (range, -1.0 to -2.1%). A1C reductions were greater in patients randomized to DU 3 mg or 4.5 mg versus 1.5 mg in each A1C subgroup, with greater dose-related improvements in patients with higher baseline A1C through 36 weeks (A1C subgroup, least-squares mean change in A1C [%] with 1.5 mg, 3 mg, and 4.5 mg, respectively: A1C<8%, -1.0, -1.2, -1.2; A1C 8-<9%, -1.4, -1.6, -1.8; A1C 9-<10%, -2.1, -2.2, -2.3; A1C ≥10%, -2.2, -2.5, -3.2; interaction p<0.001). More patients randomized to 3 mg or 4.5 mg achieved A1C <7% versus those on 1.5 mg at 36 weeks regardless of baseline A1C, but the difference across dose groups was greater at higher baseline A1Cs. Over half of patients randomized to DU 4.5 mg achieved A1C <7% in every baseline A1C category (A1C<8%, 75%, 87%, 83%; A1C 8-<9%, 61%, 64%, 73%; A1C 9-<10%, 46%, 51%, 64%; A1C ≥10%, 19%, 33%, 55% for DU 1.5 mg, 3 mg, and 4.5 mg, respectively; interaction p=0.096). Similar patterns of dose-related improvement in A1C and proportions of patients achieving A1C <7% across baseline A1C categories were observed at 52 weeks. Gastrointestinal adverse events were similar between A1C subgroups. Glycemic control as measured by A1C and proportion of patients achieving A1C <7% was improved with DU dose escalation from 1.5 mg to 3 mg or 4.5 mg across a spectrum of clinically relevant baseline A1C categories without increasing incidence of GI adverse events. Patients at higher baseline A1Cs (9%-<10% and ≥10%) had larger dose-related improvements in glycemic control than those at lower baseline A1Cs (<8% and 8%-<9%). The majority of patients randomized to DU 4.5 mg achieved glycemic target across all categories of baseline A1C.