OR26-08 Efficacy and Safety of Higher Dulaglutide Doses (3.0 MG and 4.5 MG) When Added to Metformin in Patients With Type 2 Diabetes: A Phase 3, Randomized, Double-Blind, Parallel ARM Study (Award-11)

Dulaglutide (DU) approved at doses of 0.75 and 1.5 mg once-weekly is an effective glucose lowering agent for treatment of type 2 diabetes (T2D). We hypothesized that higher investigational DU doses may provide further improvements in glucose control and body weight (BW) with an acceptable safety profile. The primary objective was to demonstrate superiority of once-weekly DU 3 mg and/or 4.5 mg to DU 1.5 mg for A1C change from baseline (BL) at 36 weeks (wks) in patients (pts) with inadequately controlled T2D on metformin therapy. Secondary objectives (controlled for multiplicity) included change in BW and % of pts achieving A1C <7% at 36 wks. Patients were randomized (1:1:1) to once-weekly DU 1.5 mg (n=612), DU 3 mg (n=616), and DU 4.5 mg (n=614). All pts initiated once-weekly DU 0.75 mg for 4 wks, followed by step-wise dose escalation every 4 wks to the randomized dose of 1.5 mg, 3 mg, or 4.5 mg. Two estimands were defined for efficacy analyses: an efficacy estimand (data on-treatment without rescue medication) and a treatment-regimen estimand (all data regardless of adherence or initiation of rescue). At BL, patients had a mean of: age 57.1 yrs, T2D duration 7.6 yrs, and A1C 8.6%, BW 95.7 kg, and BMI 34.2 kg/m(2). Using the efficacy estimand, the DU 3 mg and 4.5 mg doses were superior to the DU 1.5 mg dose for A1C change from BL (1.5 mg, 1.53%; 3 mg, 1.71% [p=0.003]; 4.5 mg, 1.87% [p<0.001]), % of patients achieving HbA1c <7% (1.5 mg, 57%; 3.0 mg, 65% [p=0.006]; 4.5 mg, 71% [p<0.001]) and BW change from BL (1.5 mg, 3.1 kg; 3 mg, 4.0 kg [p=0.001]; 4.5 mg, 4.7 kg [p<0.001]). Using the treatment-regimen estimand, DU 4.5 mg was superior to DU 1.5 mg for A1C change, while the DU 3 mg dose did not achieve statistical significance (1.5 mg, 1.54%; 3.0 mg, 1.64% [p=0.096]; 4.5 mg, 1.77% [p<0.001]). Using the treatment-regimen estimand, more patients achieved A1C <7% with higher DU doses (1.5 mg, 50%; 3 mg, 56%; 4.5 mg, 62%) and results for BW change were similar to the efficacy estimand (1.5 mg, 3.0 kg; 3 mg, 3.8 kg; 4.5 mg, 4.6 kg), but the approach for type I error control did not permit formal statistical comparisons of these secondary objectives using this estimand. The safety profile for the higher DU doses was consistent with that known for 1.5 mg. The most commonly reported adverse events were nausea (DU 1.5 mg, 13.4%; DU 3 mg, 15.6%; DU 4.5 mg, 16.4%), vomiting (DU 1.5 mg, 5.6%; DU 3 mg, 8.3%; DU 4.5 mg, 9.3%), and diarrhea (DU 1.5 mg, 7.0%; DU 3 mg, 11.4%; DU 4.5 mg, 10.7%). Treatment discontinuation due to adverse events through 36 wks was low and similar across dose groups (DU 1.5 mg, 4.2%; DU 3 mg, 5.5%; DU 4.5 mg, 5.0%). In pts with T2D and inadequate glycemic control on metformin, escalation from DU 1.5 mg to DU 3 mg or DU 4.5 mg once-weekly provided clinically relevant, dose-related improvements in glycemic control and BW with an acceptable safety profile.