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Retatrutide-Obesity

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What are the results of retatrutide from TRIUMPH-3 in adults with severe obesity and established cardiovascular disease?

In TRIUMPH-3, retatrutide 9 mg and 12 mg met the primary endpoint with average weight loss of up to 22.6% (55.8 lbs) at 80 weeks. The most common adverse events were diarrhea, nausea, constipation, decreased appetite, and hyperglycemia.

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Content Overview

What is the TRIUMPH-3 study design in adults with severe obesity and established cardiovascular disease?
TRIUMPH-3 Inclusion and Exclusion Criteria
What are the efficacy outcomes of TRIUMPH-3?
What are the cardiovascular outcomes of TRIUMPH-3?
What are the safety outcomes of TRIUMPH-3?
What are the future plans for retatrutide?
References

What is the TRIUMPH-3 study design in adults with severe obesity and established cardiovascular disease?

Retatrutide is an investigational, once-weekly, triple hormone receptor agonist of the

glucose-dependent insulinotropic polypeptide (GIP) receptor,
glucagon-like peptide-1 (GLP-1) receptor, and
glucagon receptor.¹

TRIUMPH-3 (NCT05882045) is a phase 3, randomized, multicenter, double-blind, placebo-controlled clinical trial assessing the efficacy and safety of retatrutide 9 mg and 12 mg in participants with severe (Class II or III) obesity, defined as a body mass index (BMI) ≥35 kg/m², and established cardiovascular disease, with or without type 2 diabetes.^1,2,3

The study randomized 1949 participants in a 1:1:2 ratio to receive retatrutide 9 mg, retatrutide 12 mg, or placebo.^2,3 Randomization stratification factors included diabetes status, sex, sodium-glucose cotransporter-2 inhibitor (SGL2i) use, and participation in a dual-energy x-ray absorptiometry (DXA) substudy of approximately 100 participants to assess body composition.¹

Participants randomized to retatrutide initiated treatment at a 2 mg once-weekly dose, which was escalated in 4-week intervals to a target maintenance dose of 9 mg or 12 mg for the 80-week treatment period.² The primary endpoint was assessed at Week 80.^1,3

All participants received individualized lifestyle counseling focusing on

healthy diet rather than caloric restriction, and
at least 150 minutes of moderate-intensity physical activity per week that includes a strength-training component.¹

TRIUMPH-3 Inclusion and Exclusion Criteria

Please refer to Table 1 for key inclusion and exclusion criteria for TRIUMPH-3.¹

**Table 1. TRIUMPH-3 Key Inclusion and Exclusion Criteria**¹
Key Inclusion Criteria	Key Exclusion Criteria
adult male or female sex, aged ≥18 years, with a history of ≥1 unsuccessful dietary effort to reduce body weight BMI ≥35 kg/m² (Class II or III obesity) established CVD, defined as ≥1 of prior myocardial infarction, prior ischemic or hemorrhagic stroke, or symptomatic peripheral arterial disease either no diagnosis of type 2 diabetes with an HbA1c <6.5% at screening, or a diagnosis of type 2 diabetes with an HbA1c ≥6.5% to ≤10.5% and stable treatment with ≤3 oral glucose-lowering medications for ≥90 days prior to screening^a	change in body weight >5 kg within 90 days of screening obesity induced by other endocrinologic disorders or monogenetic or syndromic forms of obesity history of type 1 diabetes renal impairment, eGFR <30 mL/min/1.73 m² history of pancreatitis acute or chronic hepatitis or other liver disease^b diagnosis or history of malignant disease within 5 years of screening^c uncontrolled thyroid disease, with TSH levels outside the central laboratory reference range family or personal history of MTC or MEN2 calcitonin level at screening ≥20 ng/L (if eGFR ≥60 mL/min/1.73 m²) or ≥35 ng/L (if estimated glomerular filtration rate <60 mL/min/1.73 m²) acute MI, CVA, coronary artery revascularization, hospitalization for unstable angina, or hospitalization for CHF within 90 days of screening NYHA Functional Classification Class IV congestive heart failure history of unstable MDD or other severe psychiatric disorder within the last 2 years active suicidal ideation or any history of a suicide attempt use, within 90 days prior to screening, of a GLP-1 receptor agonist or GIP/GLP-1 receptor agonist, chronic systemic glucocorticoid therapy, medication or alternative therapy intended to promote weight loss, or a medication associated with significant weight gain that was started or had its dose changed within 12 months prior to screening

Abbreviations: BMI = body mass index; CVA = cerebrovascular accident; CVD = cardiovascular disease; eGFR = estimated glomerular filtration rate; GIP = glucose-dependent insulinotropic polypeptide; GLP-1 = glucagon-like peptide-1; HbA1c = glycated hemoglobin; MDD = major depressive disorder; MEN2 = multiple endocrine neoplasia syndrome type 2; MI = myocardial infarction; MTC = medullary thyroid cancer; NYHA = New York Heart Association TSH = thyroid-stimulating hormone.
^a Participants with a diagnosis of type 2 diabetes and qualifying HbA1c were permitted to enroll; this exception is reflected in both the inclusion and exclusion criteria above.
^b Participants with nonalcoholic fatty liver disease could participate if their alanine transaminase level at screening was <3.0x the upper limit of normal.
^c Exceptions: basal cell or squamous cell skin cancer that has been resected with no evidence of metastatic disease, or Stage 0 non-invasive cervical cancer.

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What are the primary efficacy obesity outcomes of TRIUMPH-3?

In TRIUMPH-3, the primary efficacy endpoint of the percent change in body weight was met by both doses of retatrutide for the efficacy estimand.³ At 80 weeks, from an average baseline weight of 111.4 kg (245.6 lbs) and BMI of 40.4 kg/m², participants had an average change in body weight of:³

-21.6% (-23.9 kg; -52.7 lbs) with retatrutide 9 mg,
-22.6% (-25.3 kg; -55.8 lbs) with retatrutide 12 mg, and
-3.2% (-3.5 kg; -7.7 lbs) with placebo.³

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What are the cardiovascular outcomes of TRIUMPH-3?

In TRIUMPH-3, major adverse cardiovascular events (MACE) occurred less frequently than anticipated in both the retatrutide and placebo arms.³ Time to first occurrence of MACE-5, MACE-3, and hazard ratios are presented in Table 3.³

**Table 3. TRIUMPH-3 Time to First Occurrence of MACE**³
	Retatrutide (Pooled 9 mg and 12 mg)	Placebo	In-Study HR (95% CI)^{b, c}
MACE-5^a, n of events	44	52	0.82 (0.55 to 1.22)
MACE-3^d, n of events	27	23	1.12 (0.64 to 1.96)

Abbreviations: CI = confidence interval; MACE = major adverse cardiovascular events.
^a MACE-5 includes all-cause death, heart attack, stroke, heart failure event, or coronary revascularization.^b Hazard ratio was estimated from a Cox proportional hazards model comparing retatrutide (pooled 9 mg and 12 mg) vs placebo.^c The in-study analysis (pre-specified) includes events that occurred during the study treatment period regardless of adherence to retatrutide or placebo.
^dMACE-3 includes cardiovascular death, heart attack, or stroke.

An additional analysis evaluated the hazard ratios for on-treatment. The on-treatment analysis was not pre-specified and excluded events that occurred more than 35 days after discontinuing retatrutide or placebo. The on-treatment HR (95% CI) for were

0.73 (0.47 to 1.12) for MACE-5, and
0.92 (0.51 to 1.65) for MACE-3.³

In TRIUMPH-3, retatrutide reduced certain cardiovascular risk factors.³ With the highest studied dose (retatrutide 12 mg), participants achieved average reductions of:

-37.0% in triglycerides,
-16.5% in non-HDL cholesterol,
-9.3 mmHg in systolic blood pressure,
-7.5 in (19.0 cm) in waist circumference, and
-51.2% in high-sensitivity C-reactive protein (hsCRP).³

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What are the safety outcomes of TRIUMPH-3?

Adverse events reported in the topline data read out are detailed in Table 4.³

**Table 4. TRIUMPH-3 Adverse Events**³
Adverse Event, %	Retatrutide 9 mg	Retatrutide 12 mg	Placebo
Diarrhea^a	30.1	24.4	8.7
Nausea^a	21.7	22.4	5.8
Constipation^a	18.0	15.7	7.1
Decreased appetite^a	13.5	14.5	3.0
Hyperglycemia^a	3.9	3.1	13.4
Dysesthesia^b	6.4	6.4	1.3
Urinary tract infection^b	6.1	7.0	5.3

^a The most common adverse events.
^bEvents of dysesthesia and urinary tract infection were generally mild to moderate, and the majority resolved during treatment.

Discontinuation rates due to adverse events were 9.8% and 13.5% with retatrutide 9 mg and 12 mg, respectively, compared with 4.8% with placebo.³

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What are the future plans for retatrutide?

Detailed TRIUMPH-3 efficacy and safety data, along with other phase 3 retatrutide results, will be shared at future medical meetings and in peer-reviewed journals.³

Lilly is completing the comprehensive Chemistry, Manufacturing, and Controls (CMC) data package required for a Biologics License Application (BLA) and plans to subsequently submit retatrutide in the first quarter of 2027 for U.S. regulatory review.³

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References

The published reference below is available by contacting 1-800-LillyRx (1-800-545-5979).

Giblin K, Kaplan LM, Somers VK, et al. Retatrutide for the treatment of obesity, obstructive sleep apnea and knee osteoarthritis: rationale and design of the TRIUMPH registrational clinical trials. Diabetes Obes Metab. 2026;28(1):83-93. https://doi.org/10.1111/dom.70209
ClinicalTrials.gov. A study of retatrutide (LY3437943) in participants with obesity and cardiovascular disease (TRIUMPH-3). NCT05882045. https://clinicaltrials.gov/study/NCT05882045
Lilly's triple agonist, retatrutide, successful in two additional Phase 3 obesity trials, delivering significant improvements in weight and A1C. Press release. Eli Lilly and Company; July 23, 2026. Accessed July 23, 2026. https://www.prnewswire.com/news-releases/lillys-triple-agonist-retatrutide-successful-in-two-additional-phase-3-obesity-trials-delivering-significant-improvements-in-weight-and-a1c-302832674.html

Date of Last Review: July 23, 2026

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