Results of the First Phase 3 Study of Retatrutide in Participants With Type 2 Diabetes (TRANSCEND-T2D-1)

Author: Harpreet Singh Bajaj, MD, MPH

Endocrinologist, LMC Diabetes & Endocrinology (Toronto)
Chair, Endocrine and Metabolic Research, Centricity Canada
Past Chair, Clinical Practice Guidelines, Diabetes Canada

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Disclosures

Speaking/Consulting Honoraria :

  • Novo Nordisk
  • Eli Lilly and Company

Trial/Research Support :

  • Amgen
  • AstraZeneca
  • Boehringer Ingelheim
  • Ceapro
  • Eli Lilly and Company
  • Gilead
  • Janssen
  • Kowa Pharmaceuticals
  • Madrigal Pharmaceuticals
  • Merck KGaA
  • Novo Nordisk
  • Pfizer
  • Sanofi
  • Tricida
Retatrutide: Novel Triple Receptor Agonist
1. Coskun T, et al. Cell Metab. 2022;34:1234-1247.e9. 2. Urva S, et al. Lancet. 2022;400:1869-1881. GCGR=glucagon receptor; GIP=glucose-dependent insulinotropic polypeptide; GIPR=GIP receptor; GLP-1R=glucagon-like peptide-1 receptor; SC=subcutaneous.
Retatrutide Phase 3 Program Across Obesity & Complications
TRANSCEND-T2D-1 Study Design
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aInadequate glycemic control with diet and exercise alone. Note: Temporary dose reduction for intolerable GI symptoms can be initiated for a 4-week period only during dose escalation (the first 20 weeks of the study) and should be followed by a dose re-escalation attempt. https://clinicaltrials.gov/study/NCT06354660 (Accessed May 19, 2026). BMI=body mass index; GI=gastrointestinal; HbA1c=glycated hemoglobin; PBO=placebo; QW=once weekly; RETA=retatrutide; T2D=type 2 diabetes
Primary objective: To demonstrate the superiority of retatrutide (4 mg, 9 mg, 12 mg) vs. placebo in glycemic control at Week 40
Primary Endpoint
Change from baseline in HbA1c at Week 40
Key Secondary Endpointsa (at Week 40)
  • Incidence of participant with HbA1c of <7.0%, ≤6.5%, and <5.7%b.
  • Change from baseline in fasting serum glucoseb.
  • Change from baseline in body weight.
  • Incidence of participant reaching weight reduction of ≥5%; ≥10%; and ≥15%b.
  • Incidence of participant with HbA1c ≤6.5% and reaching ≥10% body weight reduction from baseline.
  • Percent change from baseline in lipid parameters (non–HDL-C and triglycerides)b.
  • Change in systolic blood pressureb
ᵃStrongly controlled for type I error. ᵇFor retatrutide 9 and 12 mg ONLY.
HbA1c=glycated hemoglobin; HDL-C=high-density lipoprotein cholesterol.
Statistical Methods and Estimands
What is the treatment difference in mean change in HbA1c from baseline at Week 40 between retatrutide 4 mg, 9 mg, and/or 12 mg doses vs. placebo in individuals who meet eligibility criteria…
Efficacy Estimand

…assuming the following intercurrent events did not occur

  • Permanent discontinuation of study intervention.
  • Initiation of additional anti-hyperglycemic medicationsa

All randomized participants (ITT) MMRM or ANCOVA with missing endpoints imputed

Treatment Regimen Estimand

…regardless of adherence to study intervention or initiation of additional anti-hyperglycemic medications

All randomized participants (ITT) ANCOVA with missing endpoints imputed

ᵃAdditional AHMs refers to any AHM used for >14 days.
ANCOVA=analysis of covariance; HbA1c=glycated hemoglobin; ITT=intent-to-treat; MMRM=mixed model for repeated measures.
Baseline Demographics
a>90 days prior to Visit 1. Notes: Data are shown as mean (SD) unless stated otherwise. Data from all randomized participants with non-missing data. BMI=body mass index; FSG=fasting serum glucose; HbA1c=glycated hemoglobin; N=number of participants; PBO=placebo; RETA=retatrutide; SD=standard deviation; T2D=type 2 diabetes.
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Participant Disposition
Notes: Study completion is defined as completing both the 40-week treatment period and the safety follow-up period, regardless of completion of study intervention. If participants discontinue the study during the treatment period, they also discontinue the study intervention, either earlier or at the same time. PBO=placebo; RETA=retatrutide.
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Primary Endpoint: HbA1c Over 40 Weeks With Retatrutide
***p<0.001. p-values are for MBE change difference vs. PBO. Notes: Data presented are MBE ± SE, and MBE difference (95% CI). EE analysis was conducted using MMRM. TRE analysis was conducted using ANCOVA. Data are from all randomized participants. ANCOVA=analysis of covariance; CI=confidence interval; EE=efficacy estimand; HbA1c=glycated hemoglobin; MBE=model-based estimate; MMRM=mixed model for repeated measures; N=number of participants; PBO=placebo; RETA=retatrutide; SE=standard error; TRE=treatment regimen estimand.
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Indirect Comparison of Change in HbA1c From Baseline in Similar Phase 3 Studies (Efficacy Estimand)
Notes: This indirect comparison is for illustrative purposes and is not intended to draw conclusions based on the results of different studies. In SUSTAIN-1, semaglutide was a once-weekly subcutaneous injection. 1. Sorli C, et al. Lancet Diabetes Endocrinol. 2017;5:251-260. 2. Rosenstock J, et al. Lancet. 2021;398:143-155. GCG=glucagon; GIP=glucose-dependent insulinotropic polypeptide; GLP-1=glucagon-like peptide-1; HbA1c=glycated hemoglobin; PBO=placebo; RA=receptor agonist; RETA=retatrutide; Sema=semaglutide; TZP=tirzepatide.
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Proportion of Participants Reaching HbA1c Targets at Week 40 With Retatrutide
RETA vs. PBO: ***p<0.001. p-values are for risk difference vs. PBO. Data are from all randomized participants. Notes: Data presented are MBE ± SE. HbA1c target <5.7% was not controlled for type I error for the RETA 4 mg arm. HbA1c=glycated hemoglobin; MBE=model-based estimate; N=number of participants with non-missing value at the specified time point; PBO=placebo; RETA=retatrutide; SE=standard error
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Fasting Serum Glucose Over Time With Retatrutide vs. PBO
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RETA vs. PBO: ***p<0.001. p-values are for MBE change difference vs. PBO. Notes: Data presented are MBE ± SE, and MBE difference (95% CI). EE analysis was conducted using MMRM. The comparison of RETA 4 mg vs. PBO was not controlled for type I error. CI=confidence interval; EE=efficacy estimand; MBE=model-based estimate; MMRM=mixed model for repeated measures; N=number of participants; PBO=placebo; RETA=retatrutide; SE=standard error.
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Percent Change From Baseline in Body Weight With Retatrutide
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RETA vs. PBO: ***p<0.001. p-values are for MBE change difference vs. PBO. Notes: Data presented are MBE ± SE, and MBE difference (95% CI). EE analysis was conducted using MMRM. TRE analysis was conducted using ANCOVA. Data are fromall randomized participants. ANCOVA=analysis of covariance; CI=confidence interval; EE=efficacy estimand; MBE=model-based estimate; MMRM=mixed model for repeated measures; N=number of participants; PBO=placebo; RETA=retatrutide; SE=standard error; TRE=treatment regimen estimand
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Indirect Comparison of Percent Change in Body Weight From Baseline in Similar Phase 3 Studies (Efficacy Estimand)
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Notes: This indirect comparison is for illustrative purposes and is not intended to draw conclusions based on the results of different studies. Percent weight change data for SUSTAIN-1 were estimated from literature-reported weight change (kg). In SUSTAIN-1, semaglutide was a once-weekly subcutaneous injection. 1. Sorli C, et al. Lancet Diabetes Endocrinol. 2017;5:251-260. 2. Rosenstock J, et al. Lancet. 2021;398:143-155. BMI=body mass index; GCG=glucagon; GIP=glucose-dependent insulinotropic polypeptide; GLP-1=glucagon-like peptide-1; PBO=placebo; RA=receptor agonist; RETA=retatrutide; Sema=semaglutide; TZP=tirzepatide
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Proportion of Participants Reaching Weight Reduction Thresholds at Week 40 With Retatrutide
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**p<0.01, ***p<0.001 vs. PBO. Notes: Data presented are MBE ± SE. EE analysis from logistic regression model. The weight reduction thresholds of ≥20% and ≥25% were not controlled for type I error for any RETA dose and the threshold of ≥15% was also not controlled for type I error in the RETA 4 mg arm. EE=efficacy estimand; MBE=model-based estimate; N=number of participants; PBO=placebo; RETA=retatrutide; SE=standard error.
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Proportion of Participants Reaching HbA1c ≤6.5% AND ≥10.0% Weight Reduction at Week 40 With Retatrutide
TRANSCEND_T2D_1_dv_036761_14
***p<0.001 vs. PBO. Notes: Data presented are MBE ± SE. EE analysis from logistic regression model. EE=efficacy estimand; HbA1c=glycated hemoglobin; MBE=model-based estimate; N=number of participants; PBO=placebo; RETA=retatrutide; SE=standard error
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Percentage Change in Lipid and Blood Pressure Parameters From Baseline to Week 40 With Retatrutide
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RETA vs. PBO: *p<0.05, **p<0.01, ***p<0.001. p-values are for MBE percent change difference. Notes: Data presented are MBE. EE analysis was conducted using MMRM. The comparisons of RETA 9 mg and 12 mg vs. PBO for triglycerides and non–HDL-c were controlled for type I error. No other endpoints or dose comparisons were included in the multiplicity adjustment procedure. For systolic BP, RETA 9 mg and 12 mg adjusted for multiplicity. All other doses across systolic and diastolic BP not adjusted for multiplicity. BP=blood pressure; CV=coefficient of variation; EE=efficacy estimand; HDL-c=high-density lipoprotein calculated; LDL-c=low-density lipoprotein calculated; MBE=model-based estimate; MMRM=mixed model for repeated measures; N=number of participants; PBO=placebo; RETA=retatrutide
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Efficacy Estimated
Overview of Adverse Events
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aDeaths are also included as serious AEs and discontinuation due to AEs. bMACE (confirmed by Clinical Endpoint Committee) includes: deaths due to cardiovascular cause, myocardial infarction, hospitalization for unstable angina, hospitalization/urgent visit for heart failure, coronary interventions (such as CABG or PCI), and cerebrovascular events, including cerebrovascular accident (stroke) and TIA. Notes: Data are reported for the safety data points set. Safety population defined as all participants who were randomly assigned a study intervention and who received ≥1 dose of double-blind study intervention. MedDRA Version 28.1 (September 2025). AE=adverse event; CABG=coronary artery bypass graft; MACE=major adverse cardiovascular event; MedDRA=Medical Dictionary for Regulatory Activities; n=number of participants in the specified category; N=all randomly assigned participants who took ≥1 dose of study intervention; PBO=placebo; PCI=percutaneous coronary intervention; RETA=retatrutide; TEAE=treatment-emergent AE; TIA=transient ischemic attack.
Adverse Events Occurring in ≥5% of Participants in Any Group
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Notes: Data are reported for the safety data points set. Safety population defined as all participants who were randomly assigned a study intervention and who received ≥1 dose of double-blind study intervention. MedDRA Version 28.1 (September 2025). AE=adverse event; MedDRA=Medical Dictionary for Regulatory Activities; n=number of participants in the specified category; N=all randomly assigned participants who took ≥1 dose of study intervention; PBO=placebo; RETA=retatrutide.
Adverse Events Leading to Treatment Discontinuation Reported by Preferred Term
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Notes: Data are reported for the safety data points set. Safety population defined as all participants who were randomly assigned a study intervention and who received ≥1 dose of double-blind study intervention. MedDRA Version 28.1 (September 2025).
AE=adverse event; GI=gastrointestinal; MedDRA=Medical Dictionary for Regulatory Activities; n=number of participants in the specified category; N=all randomly assigned participants who took ≥1 dose of study intervention; PBO=placebo; RETA=retatrutide
TRANSCEND-T2D-1: Retatrutide Efficacy Summary
Retatrutide met the primary and all key secondary endpoints for both estimands
Superior glycemic control vs. placebo
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  • HbA1c improvement up to -1.9%
  • Up to 85% reaching HbA1c ≤6.5%, and up to 46% near-normoglycemia (<5.7%)
Superior weight reduction vs. placebo
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with up to -16.8% weight reduction (-17 kg/-37 lb)
Up to 68% of retatrutide-treated participants reached HbA1c of ≤6.5% and ≥10% weight reduction
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dv-036761-22
Clinically meaningful improvements
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in cardiometabolic markers: Systolic blood pressure, non–HDL-C, and triglycerides
HbA1c=glycated hemoglobin; HDL-C=high-density lipoprotein cholesterol.
TRANSCEND-T2D-1: Retatrutide Safety Summary

Overall safety profile generally consistent with GLP-1 RA−based therapy

  • The most common AEs with retatrutide were gastrointestinal, mostly mild to moderate, and occurred primarily during dose escalation.
  • Treatment discontinuation due to an AE was 2-5%.
  • Treatment discontinuation due to a GI AE was 0-3%.
  • No new safety signals were observed.
  • No severe hypoglycemia was reported.
AE=adverse event; GI=gastrointestinal; GLP-1=glucagon-like peptide-1; RA=receptor agonist.
The LANCET
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