Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial

Background Despite advancements in care, many people with type 2 diabetes do not meet treatment goals; thus, development of new therapies is needed. We aimed to assess efficacy, safety, and tolerability of novel dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist tirzepatide monotherapy versus placebo in people with type 2 diabetes inadequately controlled by diet and exercise alone. Methods We did a 40-week, double-blind, randomised, placebo-controlled, phase 3 trial (SURPASS-1), at 52 medical research centres and hospitals in India, Japan, Mexico, and the USA. Adult participants (>= 18 years) were included if they had type 2 diabetes inadequately controlled by diet and exercise alone and if they were naive to injectable diabetes therapy. Participants were randomly assigned (1:1:1:1) via computer-generated random sequence to once a week tirzepatide (5, 10, or 15 mg), or placebo. All participants, investigators, and the sponsor were masked to treatment assignment. The primary endpoint was the mean change in glycated haemoglobin (HbA(1c)) from baseline at 40 weeks. This study is registered with ClinicalTrials.gov, NCT03954834. Findings From June 3, 2019, to Oct 28, 2020, of 705 individuals assessed for eligibility, 478 (mean baseline HbA(1c) 7.9% [63 mmol/mol], age 54.1 years [SD 11.9], 231 [48%] women, diabetes duration 4.7 years, and body-mass index 31.9 kg/m(2)) were randomly assigned to tirzepatide 5 mg (n=121 [25%]), tirzepatide 10 mg (n=121 [25%]), tirzepatide 15 mg (n=121 [25%]), or placebo (n=115 [24%]). 66 (14%) participants discontinued the study drug and 50 (10%) discontinued the study prematurely. At 40 weeks, all tirzepatide doses were superior to placebo for changes from baseline in HbA(1c), fasting serum glucose, bodyweight, and HbA(1c) targets of less than 7.0% (<53 mmol/mol) and less than 5.7% (<39 mmol/mol). Mean HbA(1c) decreased from baseline by 1.87% (20 mmol/mol) with tirzepatide 5 mg, 1.89% (21 mmol/mol) with tirzepatide 10 mg, and 2.07% (23 mmol/mol) with tirzepatide 15 mg versus +0.04% with placebo (+0.4 mmol/mol), resulting in estimated treatment differences versus placebo of -1.91% (-21 mmol/mol) with tirzepatide 5 mg, -1.93% (-21 mmol/mol) with tirzepatide 10 mg, and -2.11% (-23 mmol/mol) with tirzepatide 15 mg (all p<0.0001). More participants on tirzepatide than on placebo met HbA(1c) targets of less than 7.0% (<53 mmol/mol; 87-92% vs 20%) and 6.5% or less (>= 48 mmol/mol; 81-86% vs 10%) and 31-52% of patients on tirzepatide versus 1% on placebo reached an HbA(1c) of less than 5.7% (<39 mmol/mol). Tirzepatide induced a dosedependent bodyweight loss ranging from 7.0 to 9.5 kg. The most frequent adverse events with tirzepatide were mild to moderate and transient gastrointestinal events, including nausea (12-18% vs 6%), diarrhoea (12-14% vs 8%), and vomiting (2-6% vs 2%). No clinically significant (<54 mg/dL [<3 mmol/L]) or severe hypoglycaemia were reported with tirzepatide. One death occurred in the placebo group. Interpretation Tirzepatide showed robust improvements in glycaemic control and bodyweight, without increased risk of hypoglycaemia. The safety profile was consistent with GLP-1 receptor agonists, indicating a potential monotherapy use of tirzepatide for type 2 diabetes treatment. Copyright (C) 2021 Elsevier Ltd. All rights reserved.