TRIUMPH-6: Obesity with Heart Failure (HFpEF)

Study Overview

TRIUMPH-6 evaluates retatrutide in adults with obesity-related heart failure with preserved ejection fraction (HFpEF), a condition where the heart pumps normally but fills poorly, often due to the mechanical and metabolic burden of excess adiposity. This represents a major unmet medical need — HFpEF accounts for approximately 50% of all heart failure cases, and there are limited effective treatments.

Scientific Rationale

The Obesity-HFpEF Phenotype

Obesity-related HFpEF is increasingly recognized as a distinct clinical entity:

• Excess epicardial and pericardial fat restricts cardiac filling
• Plasma volume expansion from obesity increases cardiac preload
• Systemic inflammation from adipose tissue impairs cardiac relaxation
• The combination creates a syndrome of exercise intolerance, dyspnea, and fluid retention

Precedent from Other Weight Loss Agents

Semaglutide demonstrated significant benefits in HFpEF patients in the STEP-HFpEF trial:

• Improved Kansas City Cardiomyopathy Questionnaire (KCCQ) scores
• Reduced body weight and inflammation markers
• Improved exercise capacity (6-minute walk test)

Retatrutide’s greater weight loss potential and additional glucagon receptor activity (which may reduce cardiac lipotoxicity) could provide enhanced benefits.

Study Design

Population

Adults aged 18-80 with:

• HFpEF (ejection fraction ≥50%)
• BMI ≥30 kg/m²
• NYHA functional class II-III
• Elevated NT-proBNP levels

Endpoints

Primary endpoints:

• Composite of cardiovascular death and total worsening heart failure events
• Change in KCCQ clinical summary score

Secondary endpoints:

• 6-minute walk test distance
• Body weight change
• NT-proBNP change
• Exercise capacity improvement
• Quality of life measures

Significance

If successful, TRIUMPH-6 could establish retatrutide as the first triple receptor agonist for obesity-related HFpEF, a condition affecting millions globally with few effective treatment options.