What is retatrutide?

What is Retatrutide?

Retatrutide is an investigational triple-hormone receptor agonist that simultaneously activates GLP-1, GIP, and glucagon receptors, currently in Phase 3 clinical trials for obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD). 1

Mechanism of Action

Retatrutide is a synthetic peptide with a unique triple-agonist mechanism that provides combined endocrine signaling across three distinct metabolic pathways 1:

• GLP-1 receptor activation enhances prandial insulin secretion, suppresses appetite, increases satiety through central nervous system effects, and reduces gastric motility 1
• GIP receptor activation contributes to insulin secretion and metabolic regulation 1
• Glucagon receptor activation promotes lipolysis, lipid oxidation, and increases overall energy expenditure—effects that distinguish retatrutide from dual agonists and contribute to weight-loss outcomes comparable to bariatric surgery 1

This multi-receptor approach represents a new generation of drugs designed to address the rising prevalence of obesity and its metabolic complications 1.

Clinical Development Status

Retatrutide is currently being evaluated in Phase 3 clinical trials through the TRIUMPH program, which includes over 5,800 participants across four studies 2:

• TRIUMPH-1 and TRIUMPH-2: Weight management basket trials with nested protocols for obstructive sleep apnea (OSA) and knee osteoarthritis (OA) 2
• TRIUMPH-3: Weight management trial specifically in populations with cardiovascular disease 2
• TRIUMPH-4: Stand-alone knee osteoarthritis trial 2

The Phase 3 program began on August 28,2023, and is evaluating retatrutide for obesity, type 2 diabetes, and MASLD 3, 1.

Clinical Efficacy Data

Phase 2 trial results demonstrated substantial weight reduction 4:

• At 24 weeks: Mean weight loss ranged from 7.2% (1 mg dose) to 17.5% (12 mg dose), compared to 1.6% with placebo 4
• At 48 weeks: Mean weight loss ranged from 8.7% (1 mg dose) to 24.2% (12 mg dose), compared to 2.1% with placebo 4
• Clinically significant weight loss at 48 weeks: 100% of participants on 8-12 mg achieved ≥5% weight loss, 91-93% achieved ≥10% weight loss, and 75-83% achieved ≥15% weight loss 4

In patients with type 2 diabetes, retatrutide achieved 16.9% mean weight loss after 36 weeks, with HbA1c improvement of 2.2% and 82% of participants reaching HbA1c ≤6.5% 5.

Cardiometabolic Benefits

Beyond weight loss, retatrutide demonstrated improvements across multiple cardiometabolic parameters 6, 5:

• Blood pressure: Systolic BP reduced by 9.88 mm Hg and diastolic BP by 3.88 mm Hg 6
• Glycemic control: Fasting plasma glucose reduced by 23.51 mg/dL and HbA1c by 0.91% 6
• Body composition: BMI reduced by 5.38 and waist circumference by 10.51 cm 6
• Hepatic steatosis: 82% reduction in liver fat content 5
• Lipid profile: Improvements in lipid parameters 5

Safety Profile

The most common adverse events were gastrointestinal symptoms, which were 4, 6:

• Dose-related and mostly mild to moderate in severity 4
• Partially mitigated with a lower starting dose (2 mg vs. 4 mg) 4
• No significant difference in overall adverse event rates compared to placebo (relative risk: 1.11, P = 0.24) 6

Important cardiovascular consideration: Dose-dependent increases in heart rate peaked at 24 weeks and declined thereafter 4. No major safety concerns were identified in Phase 2 trials 5.

Clinical Context and Future Directions

Retatrutide represents an emerging therapy in the evolving landscape of obesity management 7:

• It is positioned alongside other investigational agents such as cagrisema (a combination of semaglutide and cagrilintide) as next-generation treatments for obesity 7
• The triple-agonist mechanism may offer advantages over current GLP-1 receptor agonists and dual agonists like tirzepatide 5
• If approved, retatrutide has the potential to become the most effective pharmacological treatment for obesity while offering substantial benefits in type 2 diabetes management and cardiometabolic risk reduction 5

Access and Cost Considerations

While retatrutide is not yet approved, the broader context of anti-obesity medications highlights significant access barriers 7:

• Current GLP-1 agonists like semaglutide cost approximately $1,500 per month 7
• Only 20% of insured adults have coverage, with no Medicare support and limited Medicaid coverage 7
• These barriers disproportionately affect low-socioeconomic status groups, particularly Hispanic (29.3% uninsured) and Black (14.7% uninsured) adults 7