Efficacy and safety of tirzepatide monotherapy compared with dulaglutide in Japanese patients with type 2 diabetes (SURPASS J-mono): a double-blind, multicentre, randomised, phase 3 trial.

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. METHODS: This multicentre, randomised, 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 HbA(≤8·5% or >8·5%), baseline BMI (<25 or ≥25 kg/m), 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 HbAfrom baseline at week 52 measured in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03861052. FINDINGS: 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, HbAdecreased 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. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.