Retatrutide is an investigational once-weekly subcutaneous injectable developed by Eli Lilly. It is a triple hormone receptor agonist that simultaneously targets the GIP (glucose-dependent insulinotropic polypeptide), GLP-1 (glucagon-like peptide-1), and glucagon receptors. This triple mechanism is designed to reduce body weight by decreasing appetite, increasing energy expenditure, and improving metabolic function. In the Phase 3 TRIUMPH-1 trial, retatrutide 12 mg produced a mean body weight reduction of 25.9% at 80 weeks and up to 30.3% at 104 weeks in adults with obesity.

How much weight can patients lose with retatrutide?

In the Phase 3 TRIUMPH-1 trial, adults with obesity treated with retatrutide 12 mg lost a mean of 25.9% of their body weight at 80 weeks (efficacy estimand) versus 2.2% with placebo. In the 104-week extension, participants on retatrutide 12 mg lost an average of 30.3% of their initial body weight. At 80 weeks, 97.3% of participants on retatrutide 12 mg achieved at least 5% weight loss, 76.2% achieved at least 20% weight loss, and 45.3% achieved at least 30% weight loss. Additionally, 65.3% of participants on retatrutide 12 mg achieved a BMI below 30 kg/m², compared to 7.6% on placebo.

How is retatrutide administered?

Retatrutide is administered as a once-weekly subcutaneous injection. In the TRIUMPH-1 trial, dosing began at 2 mg and was gradually escalated over 16 weeks to target maintenance doses of 4 mg, 9 mg, or 12 mg once weekly. This gradual dose escalation approach is designed to improve tolerability, particularly for gastrointestinal side effects.

What are the side effects of retatrutide?

The most common adverse events with retatrutide in the TRIUMPH-1 trial were gastrointestinal in nature, including nausea (42.4% with 12 mg vs 14.8% with placebo), diarrhea (32.0% vs 13.5%), constipation (26.1% vs 10.9%), and vomiting (25.3% vs 4.8%). These GI events were predominantly mild to moderate in severity and occurred mainly during the dose escalation period. Other common adverse events included decreased appetite, headache, fatigue, and dizziness. Adverse events leading to treatment discontinuation occurred in 11.3% of participants on retatrutide 12 mg versus 4.9% on placebo, with GI events accounting for 4.6% of discontinuations in the 12 mg group.

Who is eligible for retatrutide treatment?

In the TRIUMPH-1 Phase 3 trial, retatrutide was studied in adults with obesity, defined as a BMI of 30 kg/m² or higher. The trial enrolled 2339 participants with a mean baseline BMI of 40 kg/m² and mean body weight of 248.5 lbs (112.7 kg). The study included participants across all obesity classes: Class 1 (BMI 30–<35, 20.6%), Class 2 (BMI 35–<40, 35.2%), and Class 3 (BMI ≥40, 42.1%). Disease-specific sub-groups included patients with obstructive sleep apnea (N=243) and knee osteoarthritis (N=574). Retatrutide is investigational and not yet approved; eligibility for any future approved indication will be defined by prescribing information.

How does retatrutide compare to other GLP-1 receptor agonists?

Unlike existing GLP-1 receptor agonists (such as semaglutide) or dual GIP/GLP-1 receptor agonists (such as tirzepatide), retatrutide is a triple hormone receptor agonist that additionally activates the glucagon receptor. This added glucagon receptor activity is thought to increase energy expenditure, which may contribute to retatrutide's greater weight loss versus agents targeting fewer receptors. In the TRIUMPH-1 trial, retatrutide 12 mg achieved a mean body weight reduction of 25.9% at 80 weeks and 30.3% at 104 weeks — among the highest weight loss results reported in a Phase 3 obesity trial to date. Retatrutide is investigational; head-to-head comparative trials with other agents have not been completed.

The First Phase 3 Obesity Study of Retatrutide, a GIP, GLP-1, and Glucagon Receptor Agonist, in People with Obesity (TRIUMPH-1)

Name: TRIUMPH-1 Results Presentation — ADA 2026
Creator: Ania M. Jastreboff
Keywords: retatrutide, TRIUMPH-1, obesity, weight loss, triple hormone receptor agonist, GIP receptor agonist, GLP-1 receptor agonist, glucagon receptor agonist, once-weekly injection, body weight reduction, 25% weight loss, 30% weight loss, obstructive sleep apnea, knee osteoarthritis, cardiometabolic outcomes, blood pressure reduction, triglyceride reduction, prediabetes normoglycemia, quality of life IWQOL, apnea-hypopnea index, Eli Lilly, phase 3 clinical trial, ADA 2026, randomized controlled trial

The First Phase 3 Obesity Study of Retatrutide, a GIP, GLP-1, and Glucagon Receptor Agonist, in People with Obesity
(TRIUMPH-1)

ADA Scientific Sessions

June 6, 2026

Authors: Ania M. Jastreboff, MD, PhD

Harvey & Kate Cushing Professor, Yale University School of Medicine

Internal Medicine, Endocrinology & Metabolism

Pediatrics, Pediatric Endocrinology

Director, Yale Obesity Research Center (Y-Weight)

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Disclosures

RESEARCH SUPPORT:

Amgen
Boehringer Ingelheim
Eli Lilly
NIH/NIDDK
Novo Nordisk
Rhythm Pharmaceuticals

OPTIONS/SHARES:

Intellihealth
Metsera
State 4 Tx – academic co-founder
Syntis Bio

SCIENTIFIC ADVISORY BOARD:

Amgen
AstraZeneca
Boehringer Ingelheim
Biohaven
Eli Lilly
i2o
Kailera
Metsera
Novo Nordisk
Pfizer
Regeneron
Roche/Genentech
Scholar Rock
Structure Therapeutics
Viking
Wave
WW (WeightWatchers)
Zealand Pharmaceuticals

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OSA=obstructive sleep apnea; OA=osteoarthritis.

true

AHI=Apnea-Hypopnea Index; OA=osteoarthritis; OSA=obstructive sleep apnea; PAP=positive airway pressure; PSG=polysomnography; WOMAC=Western Ontario and McMaster Universities Osteoarthritis Index.

true

Randomized, double-blind, Phase 3 trial of weekly retatrutide vs. placebo

in participants with obesity, including subsets of participants with OSA or knee OA

Giblin K, et al. Diabetes Obes Metab. 2026; https://clinicaltrials.gov/study

BMI=body mass index; MTD=maximum tolerated dose; OA=osteoarthritis; OSA=obstructive sleep apnea; PBO=placebo;

RETA=retatrutide

true

TRIUMPH-1 Overall Study

HDL=high-density lipoprotein; hsCRP=high-sensitivity C-reactive protein.

true

Baseline Demographics

Overall Study and Baskets

OA basket: Participants were older and included more female participants.
OSA basket: More Hispanic participants and more male participants.

OA=osteoarthritis; OSA=obstructive sleep apnea.

true

Anthropometric Measures

TRIUMPH-1 Overall Study

Average baseline BMI = class 3 obesity (BMI ≥40 kg/m2)

Data are shown as mean (SD) unless stated otherwise
BMI=body mass index; PBO=placebo; RETA=retatrutide; SD=standard deviation

true

Participant Disposition

PBO: 75% completed the study, with ~64% completing on treatment
RETA: ~89%-91% completed the study, with ~75%-87% completing on treatment

PBO=placebo; RETA=retatrutide

Weight Reduction Over 80 Weeks With Retatrutide

TRIUMPH-1 Primary Outcome

With RETA 4 mg, a dose which had only one up-titration step, weight reduction was an average of 19% at 80 weeks

With RETA 12 mg, weight reduction was an average of 28.3% at 80 weeks

All groups p<0.001 vs. PBO.PBO=placebo; RETA=retatrutide; EE=Efficacy Estimand; TRE=Treatment Regimen Estimand.All groups

true

Weight Reduction Over 104 Weeks With Retatrutide

TRIUMPH-1 Extension

All Addendum Participants

N=532 total

Participants in the extension lost up to an average of 30% of their initial weight at 104 weeks

All groupp<0.001 vs. PBO.BMI=body mass index; EE=Efficacy Estimand; MTD=maximum tolerated dose; PBO=placebo; RETA=retatrutide; TRE=Treatment Regimen Estimand.

true

Percent of Participants Reaching

Weight Reduction Thresholds with Retatrutide at Week 80

Efficacy Estimand

Clinically meaningful weight reduction in nearly all participants treated with RETA,including reaching higher weight reduction thresholds of ≥30% and ≥35%

***p<0.001 vs. PBO.PBO=placebo; RETA=retatrutide.

true

Percentage of Participants Reaching

BMI and WtHR Targets with Retatrutide at Week 80

Efficacy Estimand

The efficacy observed with RETA potentially allows for a treat-to-target approach rather than relative change in weight approach, though data are needed to demonstrate health benefits with targets

***p<0.001 vs. PBO.BMI=body mass index; PBO=placebo; RETA=retatrutide; WtHR=waist-to-height ratio.

TRIUMPH-1- OA Basket

Knee Osteoarthritis

N=574 total

Absolute Change in WOMAC Pain Subscale Score

RETA resulted in a WOMAC pain score reduction more than the clinically significant threshold of 4 points

Which translates to up to more than a 70% decrease in pain with RETA

***p<0.001 vs. PBO.BMI=body mass index; OA=osteoarthritis; PBO=placebo; RETA=retatrutide; WOMAC=Western Ontario and McMaster Universities Osteoarthritis Index.

true

TRIUMPH-1 OSA Basket

Obstructive Sleep Apnea

N=243 total

Absolute Change in Apnea Hypopnea Index (AHI)

RETA resulted in an AHI reduction more than the clinically significant threshold of 15 events per hr

Which translates to up to more than a 60% decrease in AHI with RETA

*p<0.05, **p<0.01, ***p<0.001 vs PBO.

AHI=Apnea-Hypopnea Index; BMI=body mass index; OSA=obstructive sleep apnea; PBO=placebo; RETA=retatrutide.

Cardiometabolic Measures at 80 weeks with Retatrutide

Efficacy Estimand

Greater improvements in blood pressure, lipids, hsCRP, and glycemia in all RETA arms than with PBO

***p<0.001 vs PBO
BP=blood pressure; hsCRP=high-sensitivity C-reactive protein; LDL-C=low-density lipoprotein cholesterol; PBO=placebo; RETA=retatrutide; SBP=systolic blood pressure;TG=triglycerides.

true

Patient-Reported Outcomes at Week 80 with Retatrutide

Impact of Weight on Quality of Life (IWQOL)

Efficacy Estimand

Greater improvements in physical function and psychosocial quality of life measures with RETA than with PBO

***p<0.001 vs. PBO. IWQOL-Lite-CT=Impact of Weight on Quality of Life–Lite Clinical Trials; PBO=placebo; RETA=retatrutide.

true

Overview of Adverse Events

Treatment-emergent adverse events were reported in 80.7% of the participants in the PBO group and 87%-89.2% of participants in the RETA groups
Serious adverse events were reported in 5.5% of the participants in the PBO group and 7.7%-10.5% of participants in the RETA groups

^aAll deaths were adjudicated by an external committee of physicians as to whether the death was a cardiovascular-related death or not. AE=adverse event; PBO=placebo; RETA=retatrutide.

true

Adverse Events Occurring in ≥5% of Participants

UTIs were reported in 6.8%-8.1% of participants in RETA arms, and 4.8% with PBO, mostly mild to moderate in severity, resolved on treatment, and did not lead to discontinuation; 92% were in female participants

AE=adverse event; COVID-19=coronavirus disease 2019; PBO=placebo; RETA=retatrutide UTI=urinary tract infection.

true

AEs Leading to Treatment Discontinuation

Discontinuation due to adverse event occurred in 4%-11% of participants who received RETA and 5% of those who received PBO
Gastrointestinal adverse events were the most common reason for treatment discontinuation; 2.2-4.6% in the RETA arms and 1.2% in the PBO arm

AE=adverse event; PBO=placebo; PT=preferred term; RETA=retatrutide.

true

Adverse Event of Special Interest

Most prevalent AESI were dysesthesia, injection site reactions, GI AEs, and reported hypotension, with the latter being more common in participants taking anti-hypertensive medications

AESI=adverse event of special interest; GI=gastrointestinal; MACE=major adverse cardiovascular event; PBO=placebo; RETA=retatrutide.

TRIUMPH-1: Summary of Phase 3 Obesity Trial With Retatrutide

Retatrutide, a once-weekly triple hormone receptor agonist, was generally well-tolerated and provided substantial reductions in weight as well as clinically meaningful improvements in health outcomes for patients with obesity, OSA, and knee OA

Disclosures

TRIUMPH-1

Study Design and Participant Disposition

TRIUMPH-1: Retatrutide Phase 3 Obesity Trial

Study Overview

TRIUMPH-1: Retatrutide Phase 3 Obesity Trial

Key Inclusion and Exclusion

Study Design

Primary and Key Secondary Endpoints

TRIUMPH-1

Participant Characteristics

OA basket: Participants were older and included more female participants.

OSA basket: More Hispanic participants and more male participants.

Average baseline BMI = class 3 obesity (BMI ≥40 kg/m2)

PBO: 75% completed the study, with ~64% completing on treatmentRETA: ~89%-91% completed the study, with ~75%-87% completing on treatment

TRIUMPH-1

Primary and Secondary Outcomes

With RETA 4 mg, a dose which had only one up-titration step, weight reduction was an average of 19% at 80 weeks

With RETA 12 mg, weight reduction was an average of 28.3% at 80 weeks

Participants in the extension lost up to an average of 30% of their initial weight at 104 weeks

Clinically meaningful weight reduction in nearly all participants treated with RETA,including reaching higher weight reduction thresholds of ≥30% and ≥35%

TRIUMPH-1

Primary Outcomes of the Knee OA and OSA Baskets

RETA resulted in an AHI reduction more than the clinically significant threshold of 15 events per hr

Which translates to up to more than a 60% decrease in AHI with RETA

TRIUMPH-1

Cardiometabolic Measures and Patient-Reported Outcomes

Greater improvements in blood pressure, lipids, hsCRP, and glycemia in all RETA arms than with PBO

Greater improvements in physical function and psychosocial quality of life measures with RETA than with PBO

TRIUMPH-1

Safety and Tolerability

Treatment-emergent adverse events were reported in 80.7% of the participants in the PBO group and 87%-89.2% of participants in the RETA groups

Serious adverse events were reported in 5.5% of the participants in the PBO group and 7.7%-10.5% of participants in the RETA groups

UTIs were reported in 6.8%-8.1% of participants in RETA arms, and 4.8% with PBO, mostly mild to moderate in severity, resolved on treatment, and did not lead to discontinuation; 92% were in female participants

Discontinuation due to adverse event occurred in 4%-11% of participants who received RETA and 5% of those who received PBO

Gastrointestinal adverse events were the most common reason for treatment discontinuation; 2.2-4.6% in the RETA arms and 1.2% in the PBO arm

Most prevalent AESI were dysesthesia, injection site reactions, GI AEs, and reported hypotension, with the latter being more common in participants taking anti-hypertensive medications

TRIUMPH-1: Summary

TRIUMPH-1: Summary of Phase 3 Obesity Trial With Retatrutide

Retatrutide, a once-weekly triple hormone receptor agonist, was generally well-tolerated and provided substantial reductions in weight as well as clinically meaningful improvements in health outcomes for patients with obesity, OSA, and knee OA

PBO: 75% completed the study, with ~64% completing on treatment
RETA: ~89%-91% completed the study, with ~75%-87% completing on treatment