Background: As the disease progresses, many patients with type 2 diabetes have difficulty in reaching treatment goals. We aimed to assess the efficacy and safety of tirzepatide, a novel GIP and GLP-1 receptor agonist, compared with dulaglutide in Japanese patients with type 2 diabetes.
Method: This multicentre, randomized, double-blind, parallel, active-controlled, phase 3 trial was conducted in 46 medical research centres and hospitals in Japan. Adults aged 20 years or older with type 2 diabetes who had discontinued oral antihyperglycaemic monotherapy or were treatment-naïve were included. Participants were randomly assigned (1:1:1:1) to receive tirzepatide (5, 10, or 15 mg) or dulaglutide (0.75 mg) once per week using a computer-generated random sequence with an Interactive Web Response System. Participants were stratified based on baseline HbA1c (≤8.5% or >8.5%), baseline BMI (<25 or ≥25 kg⁄m2), and washout of antidiabetic medication. Participants, investigators, and the sponsor were masked to treatment assignment. The starting dose of tirzepatide was 2.5 mg once per week for 4 weeks, which was then increased to 5 mg in the tirzepatide 5 mg treatment group. For the tirzepatide 10 and 15 mg treatment groups, increases by 2.5 mg occurred once every 4 weeks until the assigned dose was reached. The primary endpoint was mean change in HbA1c from baseline at week 52 measured in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03861052.
Results: Between May 7, 2019, and March 31, 2021, 821 participants were assessed for study eligibility and 636 were randomly assigned to receive at least one dose of tirzepatide 5 mg (n = 159), 10 mg (n = 158), or 15 mg (n = 160), or dulaglutide 0.75 mg (n = 159). 615 (97%) participants completed the study and 21 (3%) discontinued. Participants had a mean age of 56.6 years (SD 10.3) and were mostly male (481 [76%]).
At week 52, HbA1c decreased from baseline by a least-squares mean of −2.4 (SE 0.1) for tirzepatide 5 mg, −2.6 (0.1) for tirzepatide 10 mg, −2.8 (0.1) for tirzepatide 15 mg, and −1.3 (0.1) for dulaglutide. Estimated mean treatment differences versus dulaglutide were −1.1 (95% CI −1.3 to −0.9) for tirzepatide 5 mg, −1.3 (−1.5 to −1.1) for tirzepatide 10 mg, and −1.5 (−1.71 to −1.4) for tirzepatide 15 mg (all p < 0.0001).
Tirzepatide was associated with dose-dependent reductions in bodyweight with a least-square mean difference of −5.8 kg (SE 0.4; −7.8% reduction) for 5 mg, −8.5 kg (0.4; −11.0% reduction) for 10 mg, and −10.7 kg (0.4; −13.9% reduction) for 15 mg of tirzepatide compared with −0.5 kg (0.4; −0.7% reduction) for dulaglutide.
The most common treatment-emergent adverse events were nausea (19 [12%] participants in the 5 mg group vs 31 [20%] in the 10 mg group vs 32 [20%] in the 15 mg group all receiving tirzepatide vs 12 (8%) in the group receiving dulaglutide), constipation (24 [15%] vs 28 [18%] vs 22 [14%] vs 17 [11%]), and nasopharyngitis (29 [18%] vs 25 [16%] vs 22 [14%] vs 26 [16%]). The most frequent adverse events were gastrointestinal (23 [4%] of 636).
Interpretation: Tirzepatide was superior compared with dulaglutide for glycaemic control and reduction in bodyweight. The safety profile of tirzepatide was consistent with that of GLP-1 receptor agonists, indicating a potential therapeutic use in Japanese patients with type 2 diabetes.
Funding: Eli Lilly and Company.