TRIUMPH-Outcomes: Cardiovascular Outcomes Trial (CVOT)

Study Overview

TRIUMPH-Outcomes (NCT06383390) is the largest trial in the retatrutide development program, with approximately 10,000 participants, to determine whether retatrutide reduces the risk of major adverse cardiovascular events (MACE) in adults with overweight or obesity and established cardiovascular disease. Cardiovascular outcomes trials (CVOTs) like this have become more important for obesity drugs since the SELECT trial showed that semaglutide reduces cardiovascular risk.

Scientific Rationale

What SELECT Changed

The SELECT trial (2023) showed that semaglutide 2.4 mg reduced MACE by 20% in adults with overweight/obesity and cardiovascular disease. Since then, obesity drugs are expected to show fewer cardiovascular events as well as weight loss.

Why Retatrutide May Show CV Benefits

Multiple mechanisms could contribute to cardiovascular risk reduction:

• Weight loss: Greater weight loss with retatrutide may translate to greater CV risk reduction
• GLP-1 receptor agonism: Established CV benefits from GLP-1 receptor agonists
• GIP receptor effects: Emerging evidence for anti-inflammatory vascular effects
• Glucagon receptor effects: May improve cardiac metabolism, reduce lipotoxicity, and enhance lipid profiles
• Blood pressure reduction: Consistent reductions of 4-8 mmHg in Phase 2
• Anti-inflammatory effects: Reduced CRP and inflammatory markers

Study Design

Population

Approximately 10,000 adults aged 45+ with:

• BMI ≥27 kg/m²
• Established atherosclerotic cardiovascular disease (prior MI, stroke, or peripheral arterial disease)

Design

Event-driven, randomized, double-blind, placebo-controlled trial. The study will continue until a pre-specified number of MACE events have occurred, which is expected to take 3-5 years.

Primary Endpoint

Time to first occurrence of MACE, defined as the composite of:

1. Cardiovascular death
2. Non-fatal myocardial infarction
3. Non-fatal stroke

Key Secondary Endpoints

• Individual MACE components
• All-cause mortality
• Heart failure hospitalization
• Body weight change
• HbA1c change (in participants with diabetes)

Timeline

• Start: April 30, 2024
• Enrollment: closed (ClinicalTrials.gov lists the trial as active, not recruiting)
• Treatment: event-driven
• Primary completion: estimated February 2029 on ClinicalTrials.gov; results would follow

Significance

A positive TRIUMPH-Outcomes result would greatly strengthen retatrutide’s commercial prospects and clinical standing:

• Would support a cardiovascular risk reduction indication
• Would drive payer coverage decisions (insurers increasingly require CVOT data)
• Would differentiate retatrutide from drugs without CV outcomes data
• Could establish triple agonism as superior to single or dual agonism for CV outcomes