Higher-dose Trulicity lowers A1C and weight modestly in AWARD-11 trial

Weekly dulaglutide (Trulicity) at 4.5 mg lowered A1C by 1.77 percentage points at 36 weeks in adults with type 2 diabetes, compared with 1.54 points for the 1.5 mg dose, according to results from the AWARD-11 trial published Jan. 4, 2021, in the journal Diabetes Care ^[1]. The difference between the two doses was statistically significant, the authors reported ^[1].

The same study found that the 4.5 mg dose produced 4.6 kg of weight loss at 36 weeks, versus 3.0 kg with 1.5 mg — a difference of 1.6 kg ^[1].

The trial randomly assigned 1,842 patients at 203 sites in 15 countries to one of three once-weekly doses: 1.5 mg, 3.0 mg or 4.5 mg. Treatment lasted 52 weeks, with the main efficacy measurement taken at 36 weeks ^[1]. Participants were adults with type 2 diabetes for at least six months who had not previously taken insulin or a GLP-1 drug and were taking metformin at 1,500 mg per day or more for at least three months. Their average starting A1C was 8.6%, and their average body mass index was 34.2 ^[1].

Everyone started on 0.75 mg and increased the dose every four weeks until reaching the assigned level, a stepwise approach the paper describes as consistent with U.S. labeling recommendations ^[1].

The results were not the same for both higher doses. The 4.5 mg dose beat 1.5 mg on A1C under both of the study's statistical analyses, with an estimated difference of 0.24 percentage points (P < 0.001) under one and 0.34 points under the other ^[1]. The 3.0 mg dose was superior to 1.5 mg under one analysis (estimated difference 0.17 points, P = 0.003) but not the other (0.10 points, P = 0.096) ^[1].

Gastrointestinal side effects rose with dose. Through 36 weeks, nausea was reported by 13.4% of patients on 1.5 mg, 15.6% on 3.0 mg and 16.4% on 4.5 mg. Vomiting was reported by 5.6%, 8.3% and 9.3%, respectively ^[1]. The authors described the safety profile across doses as similar ^[1].

The paper's conclusion was that moving from 1.5 mg to 3.0 mg or 4.5 mg gave "clinically relevant, dose-related reductions" in A1C and body weight ^[1].

Why it matters for patients

The gap between doses was real but narrow. The extra A1C reduction from 4.5 mg over 1.5 mg was about a quarter of a percentage point, and the extra weight loss was 1.6 kg, or roughly 3.5 pounds, at 36 weeks ^[1]. The 3.0 mg dose did not clearly separate from 1.5 mg on A1C in one of the two analyses ^[1].

Higher doses also brought more nausea and vomiting ^[1]. Because the trial escalated the dose gradually, the results reflect what happens when patients step up over weeks rather than starting at the top dose ^[1].

AWARD-11 did not include a semaglutide group, so it cannot show how dulaglutide at these doses compares with semaglutide. Any such comparison has not been established by this trial. The study also enrolled only people who had not taken a GLP-1 medicine before, so it does not answer what happens when patients switch from another drug in this class ^[1].

What happens next

The paper reports the trial's efficacy results at 36 weeks and safety data collected over 52 weeks ^[1]. Whether the 3.0 mg and 4.5 mg doses were submitted for regulatory review in the United States, and on what timeline, is not disclosed in the publication ^[1].