Lancet (London, England)

Current treatment options for youth-onset type 2 diabetes are limited and have demonstrated lower glycaemic efficacy than those for adult-onset type 2 diabetes. We aimed to assess the safety and efficacy of tirzepatide, a glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist, compared with placebo in youth-onset type 2 diabetes. We conducted a phase 3, double-blind, placebo-controlled, multicentre (39 sites), multinational (eight countries) trial over 30 weeks, followed by an open-label extension for 22 weeks in which all participants received tirzepatide. Participants aged 10 to <18 years with youth-onset type 2 diabetes inadequately controlled with metformin and/or basal insulin were randomly assigned (1:1:1) to receive tirzepatide 5 mg, 10 mg, or placebo administered by subcutaneous injection with a single-dose pen. Randomisation was stratified by age group (&#x2264;14 years or >14 years) and antihyperglycaemic medication use (metformin, basal insulin, or both). All participants, investigators, and the sponsor were masked to treatment assignment during the 30-week double-blind period. The primary endpoint was change in glycated haemoglobin (HbA 1c ) from baseline to week 30. Data from all participants who received at least one dose of study drug were used to analyse efficacy and safety. This completed trial is registered with ClinicalTrials.gov (NCT05260021). Between April 12, 2022, and Dec 27, 2023, 146 participants were screened, of whom 99 (60 [61%] female, 39 [39%] male; mean age 14&#xb7;7 years [SD 1&#xb7;8]; mean baseline HbA 1c 8&#xb7;04% [1&#xb7;23]) were randomly assigned to tirzepatide 5 mg (n=32), tirzepatide 10 mg (n=33), or placebo (n=34). At week 30, tirzepatide was superior to placebo in reducing HbA 1c , with a mean reduction of 2&#xb7;23% in the pooled tirzepatide group versus an increase of 0&#xb7;05% in the placebo group (estimated treatment difference -2&#xb7;28%; 95% CI -2&#xb7;87 to -1&#xb7;69; p<0&#xb7;0001). Glycaemic efficacy was sustained up to 52 weeks with tirzepatide treatment. Tirzepatide also resulted in significant reductions in BMI of 7&#xb7;4% and 11&#xb7;2% for the 5 mg and 10 mg groups, respectively, compared with 0&#xb7;4% in the placebo group at 30 weeks. The most common adverse events with tirzepatide treatment were gastrointestinal, all mild to moderate in severity, and decreased over time. Two (6%) patients in the tirzepatide 5 mg group discontinued study drug due to an adverse event. The safety profile of tirzepatide was consistent with that reported in adults. No deaths were reported during the study period. Tirzepatide demonstrated significant improvements in glycaemic control and BMI compared with placebo. These effects were sustained over 1 year. Eli Lilly and Company.

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. 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 (&#x2265;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. From June 3, 2019, to Oct 28, 2020, of 705 individuals assessed for eligibility, 478 (mean baseline HbA 1c 7&#xb7;9% [63 mmol/mol], age 54&#xb7;1 years [SD 11&#xb7;9], 231 [48%] women, diabetes duration 4&#xb7;7 years, and body-mass index 31&#xb7;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&#xb7;0% (<53 mmol/mol) and less than 5&#xb7;7% (<39 mmol/mol). Mean HbA 1c decreased from baseline by 1&#xb7;87% (20 mmol/mol) with tirzepatide 5 mg, 1&#xb7;89% (21 mmol/mol) with tirzepatide 10 mg, and 2&#xb7;07% (23 mmol/mol) with tirzepatide 15 mg versus +0&#xb7;04% with placebo (+0&#xb7;4 mmol/mol), resulting in estimated treatment differences versus placebo of -1&#xb7;91% (-21 mmol/mol) with tirzepatide 5 mg, -1&#xb7;93% (-21 mmol/mol) with tirzepatide 10 mg, and -2&#xb7;11% (-23 mmol/mol) with tirzepatide 15 mg (all p<0&#xb7;0001). More participants on tirzepatide than on placebo met HbA 1c targets of less than 7&#xb7;0% (<53 mmol/mol; 87-92% vs 20%) and 6&#xb7;5% or less (&#x2264;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&#xb7;7% (<39 mmol/mol). Tirzepatide induced a dose-dependent bodyweight loss ranging from 7&#xb7;0 to 9&#xb7;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. 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. Eli Lilly and Company.

According to current consensus guidelines for type 2 diabetes management, bodyweight management is as important as attaining glycaemic targets. Retatrutide, a single peptide with agonist activity at the glucose-dependent insulinotropic polypeptide (GIP), GLP-1, and glucagon receptors, showed clinically meaningful glucose-lowering and bodyweight-lowering efficacy in a phase 1 study. We aimed to examine the efficacy and safety of retatrutide in people with type 2 diabetes across a range of doses. In this randomised, double-blind, double-dummy, placebo-controlled and active comparator-controlled, parallel-group, phase 2 trial, participants were recruited from 42 research and health-care centres in the USA. Adults aged 18-75 years with type 2 diabetes, glycated haemoglobin (HbA 1c ) of 7&#xb7;0-10&#xb7;5% (53&#xb7;0-91&#xb7;3 mmol/mol), and BMI of 25-50 kg/m 2 were eligible for enrolment. Eligible participants were treated with diet and exercise alone or with a stable dose of metformin (&#x2265;1000 mg once daily) for at least 3 months before the screening visit. Participants were randomly assigned (2:2:2:1:1:1:1:2) using an interactive web-response system, with stratification for baseline HbA 1c and BMI, to receive once-weekly injections of placebo, 1&#xb7;5 mg dulaglutide, or retatrutide maintenance doses of 0&#xb7;5 mg, 4 mg (starting dose 2 mg), 4 mg (no escalation), 8 mg (starting dose 2 mg), 8 mg (starting dose 4 mg), or 12 mg (starting dose 2 mg). Participants, study site personnel, and investigators were masked to treatment allocation until after study end. The primary endpoint was change in HbA 1c from baseline to 24 weeks, and secondary endpoints included change in HbA 1c and bodyweight at 36 weeks. Efficacy was analysed in all randomly assigned, except inadvertently enrolled, participants, and safety was assessed in all participants who received at least one dose of study treatment. The study is registered at ClinicalTrials.gov, NCT04867785. Between May 13, 2021, and June 13, 2022, 281 participants (mean age 56&#xb7;2 years [SD 9&#xb7;7], mean duration of diabetes 8&#xb7;1 years [7&#xb7;0], 156 [56%] female, and 235 [84%] White) were randomly assigned and included in the safety analysis (45 in the placebo group, 46 in the 1&#xb7;5 mg dulaglutide group, and 47 in the retatrutide 0&#xb7;5 mg group, 23 in the 4 mg escalation group, 24 in the 4 mg group, 26 in the 8 mg slow escalation group, 24 in the 8 mg fast escalation group, and 46 in the 12 mg escalation group). 275 participants were included in the efficacy analyses (one each in the retatrutide 0&#xb7;5 mg group, 4 mg escalation group, and 8 mg slow escalation group, and three in the 12 mg escalation group were inadvertently enrolled). 237 (84%) participants completed the study and 222 (79%) completed study treatment. At 24 weeks, least-squares mean changes from baseline in HbA 1c with retatrutide were -0&#xb7;43% (SE 0&#xb7;20; -4&#xb7;68 mmol/mol [2&#xb7;15]) for the 0&#xb7;5 mg group, -1&#xb7;39% (0&#xb7;14; -15&#xb7;24 mmol/mol [1&#xb7;56]) for the 4 mg escalation group, -1&#xb7;30% (0&#xb7;22; -14&#xb7;20 mmol/mol [2&#xb7;44]) for the 4 mg group, -1&#xb7;99% (0&#xb7;15; -21&#xb7;78 mmol/mol [1&#xb7;60]) for the 8 mg slow escalation group, -1&#xb7;88% (0&#xb7;21; -20&#xb7;52 mmol/mol [2&#xb7;34]) for the 8 mg fast escalation group, and -2&#xb7;02% (0&#xb7;11; -22&#xb7;07 mmol/mol [1&#xb7;21]) for the 12 mg escalation group, versus -0&#xb7;01% (0&#xb7;21; -0&#xb7;12 mmol/mol [2&#xb7;27]) for the placebo group and -1&#xb7;41% (0&#xb7;12; -15&#xb7;40 mmol/mol [1&#xb7;29]) for the 1&#xb7;5 mg dulaglutide group. HbA 1c reductions with retatrutide were significantly greater (p<0&#xb7;0001) than placebo in all but the 0&#xb7;5 mg group and greater than 1&#xb7;5 mg dulaglutide in the 8 mg slow escalation group (p=0&#xb7;0019) and 12 mg escalation group (p=0&#xb7;0002). Findings were consistent at 36 weeks. Bodyweight decreased dose dependently with retatrutide at 36 weeks by 3&#xb7;19% (SE 0&#xb7;61) for the 0&#xb7;5 mg group, 7&#xb7;92% (1&#xb7;28) for the 4 mg escalation group, 10&#xb7;37% (1&#xb7;56) for the 4 mg group, 16&#xb7;81% (1&#xb7;59) for the 8 mg slow escalation group, 16&#xb7;34% (1&#xb7;65) for the 8 mg fast escalation group, and 16&#xb7;94% (1&#xb7;30) for the 12 mg escalation group, versus 3&#xb7;00% (0&#xb7;86) with placebo and 2&#xb7;02% (0&#xb7;72) with 1&#xb7;5 mg dulaglutide. For retatrutide doses of 4 mg and greater, decreases in weight were significantly greater than with placebo (p=0&#xb7;0017 for the 4 mg escalation group and p<0&#xb7;0001 for others) and 1&#xb7;5 mg dulaglutide (all p<0&#xb7;0001). Mild-to-moderate gastrointestinal adverse events, including nausea, diarrhoea, vomiting, and constipation, were reported in 67 (35%) of 190 participants in the retatrutide groups (from six [13%] of 47 in the 0&#xb7;5 mg group to 12 [50%] of 24 in the 8 mg fast escalation group), six (13%) of 45 participants in the placebo group, and 16 (35%) of 46 participants in the 1&#xb7;5 mg dulaglutide group. There were no reports of severe hypoglycaemia and no deaths during the study. In people with type 2 diabetes, retatrutide showed clinically meaningful improvements in glycaemic control and robust reductions in bodyweight, with a safety profile consistent with GLP-1 receptor agonists and GIP and GLP-1 receptor agonists. These phase 2 data also informed dose selection for the phase 3 programme. Eli Lilly and Company.

Retatrutide is a GIP, GLP-1, and glucagon triple hormone receptor agonist, under clinical development for type 2 diabetes, obesity, and related complications. We aimed to assess the efficacy and safety of retatrutide as a monotherapy in people with type 2 diabetes that is inadequately controlled by diet and exercise alone. In this 40-week, phase 3, randomised, double-blind, placebo-controlled trial at 48 sites in the USA, Mexico, and India, we recruited adults (aged &#x2265;18 years) with type 2 diabetes that is inadequately controlled by diet and exercise alone, glycated haemoglobin (HbA 1c ) between 7&#xb7;0% and 9&#xb7;5% (53-80 mmol/mol), and BMI of at least 23 kg/m 2 . Participants were randomly assigned (1:1:1:1) to receive retatrutide (4 mg, 9 mg, or 12 mg) or placebo by once-weekly subcutaneous injection. The primary endpoint was the change in HbA 1c concentration from baseline to week 40. A key secondary endpoint was the percentage change in bodyweight from baseline to week 40. This trial is registered with ClinicalTrials.gov, NCT06354660, and is completed. Between April 10, 2024, and April 21, 2025, 930 participants were screened and 537 (296 [55%] female and 241 [45%] male) were randomly assigned: 134 to retatrutide 4 mg, 133 to retatrutide 9 mg, 136 to retatrutide 12 mg, and 134 to placebo. Baseline mean age was 48&#xb7;8 years (SD 12&#xb7;1), mean HbA 1c concentration was 7&#xb7;9% (SD 1&#xb7;1), mean duration of diabetes was 2&#xb7;5 years (SD 4&#xb7;4), and mean BMI was 35&#xb7;8 kg/m 2 (SD 7&#xb7;0). 490 (91%) participants completed the treatment period on study drug and 504 (94%) completed the study. For the treatment regimen estimand, the mean change from baseline in HbA 1c concentration was -1&#xb7;69% (SE 0&#xb7;11) with retatrutide 4 mg, -1&#xb7;86% (0&#xb7;10) with 9 mg, and -1&#xb7;94% (0&#xb7;08) with 12 mg, versus -0&#xb7;81% (0&#xb7;12) with placebo, resulting in estimated treatment differences versus placebo of -0&#xb7;88% (95% CI -1&#xb7;18 to -0&#xb7;59) with retatrutide 4 mg, -1&#xb7;04% (-1&#xb7;32 to -0&#xb7;76) with 9 mg, and -1&#xb7;12% (-1&#xb7;39 to -0&#xb7;85) with 12 mg (all p<0&#xb7;0001). The mean percentage change from baseline in bodyweight was -11&#xb7;5% (SE 0&#xb7;7) with retatrutide 4 mg, -13&#xb7;9% (0&#xb7;8) with 9 mg, and -15&#xb7;3% (0&#xb7;8) with 12 mg, versus -2&#xb7;6% (0&#xb7;5) with placebo. The most frequent adverse events with retatrutide were generally mild to moderate gastrointestinal events, which subsided over time. Study intervention discontinuations due to adverse events were 2-5% with retatrutide and 0% with placebo. No severe hypoglycaemia was reported. Two deaths occurred during the study, both in the retatrutide 4 mg group and unrelated to the study drug. Retatrutide showed significant improvements in glycaemic control and bodyweight reduction as a monotherapy in adults with type 2 diabetes that is inadequately controlled with diet and exercise alone, with an adverse event profile consistent with molecules with GLP-1 agonist activity, supporting its potential as an effective treatment for type 2 diabetes. Eli Lilly and Company.