What is the current evidence regarding retatrutide (LY3437943) for obesity and its related comorbidities?

Retatrutide: Current Evidence for Obesity and Related Comorbidities

Retatrutide is a novel triple receptor agonist (GLP-1R/GIPR/GCGR) currently in Phase III development that has demonstrated unprecedented weight loss of 24.4% at 48 weeks in Phase II trials, surpassing all currently approved obesity medications including tirzepatide. 1, 2

Mechanism of Action

Retatrutide represents a fundamentally different approach from existing incretin-based therapies by simultaneously targeting three distinct metabolic pathways 1, 3:

• Triple receptor activation: Activates glucagon-like peptide-1 receptor (GLP-1R), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon receptor (GCGR) 1, 3
• Appetite suppression and gastric emptying: Delays gastric emptying and reduces food intake through GLP-1R and GIPR pathways 3
• Enhanced energy expenditure: The glucagon receptor component increases metabolic rate and promotes fat oxidation beyond what dual agonists achieve 3

This triple mechanism distinguishes retatrutide from tirzepatide (dual GIP/GLP-1 agonist) and semaglutide (selective GLP-1 agonist), potentially explaining its superior weight loss efficacy 1, 3.

Clinical Efficacy: Phase II Evidence

Weight Loss Outcomes

The Phase II trial data shows retatrutide achieving weight loss that exceeds both tirzepatide (20.9%) and semaglutide (14.9%) at comparable timepoints 1, 2:

• 24 weeks: Mean weight loss of 17.5% 1
• 48 weeks: Mean weight loss of 24.4% 1, 2
• Waist circumference reduction: Nearly 20 cm reduction observed 4

For context, this represents approximately 4-fold greater weight loss than liraglutide (5.2-6.1%) and exceeds tirzepatide's already impressive 20.9% at 72 weeks 5, 1.

Glycemic Control

Phase II trials demonstrated significant HbA1c reductions in patients with type 2 diabetes, though specific percentage reductions were not detailed in the available evidence 2, 3. The glycemic benefits appear dose-dependent and comparable to or exceeding other incretin-based therapies 3.

Metabolic Benefits Beyond Weight Loss

• Liver steatosis improvement: Demonstrated reductions in hepatic fat content 3
• Diabetic kidney disease: Showed favorable effects on renal parameters 3
• Cardiovascular risk factors: Improvements in multiple metabolic parameters, though cardiovascular outcome trials are pending 3

Pharmacokinetics and Dosing

• Half-life: Approximately 6 days, supporting once-weekly subcutaneous administration 2
• Dose proportionality: Pharmacokinetics are dose-proportional, allowing predictable titration 2
• Optimal dosing: Higher doses demonstrated greatest efficacy in Phase II trials 2

The once-weekly dosing aligns with tirzepatide and semaglutide, offering convenience comparable to current best-in-class agents 6, 2.

Safety Profile

Adverse Effects

The safety profile mirrors that of GLP-1R agonists and dual GIP/GLP-1R agonists, with gastrointestinal disorders being the predominant adverse effects 2, 4:

• Most common: Nausea, vomiting, diarrhea, and constipation 2, 4
• Severity: Primarily mild-to-moderate and dose-related 4, 3
• Pattern: Gastrointestinal effects typically decrease over time with continued exposure 3

Tolerability

Phase I and II trials demonstrated acceptable tolerability profiles, with adverse effects manageable through dose titration 2, 3. The gastrointestinal side effect profile is consistent with the class effect seen with semaglutide and tirzepatide 6, 5.

Current Development Status: TRIUMPH Program

Phase III trials (TRIUMPH program) began August 28,2023, enrolling over 5,800 participants across four studies 7:

TRIUMPH Trial Design

• TRIUMPH-1 and TRIUMPH-2: Weight management basket trials with nested OSA and/or knee osteoarthritis protocols 7
• TRIUMPH-3: Weight management trial specifically in patients with cardiovascular disease 7
• TRIUMPH-4: Stand-alone knee osteoarthritis trial 7

Primary Endpoints

• Weight management: Percent change in body weight 7
• Obstructive sleep apnea: Change in Apnea-Hypopnea Index 7
• Knee osteoarthritis: Change in WOMAC pain subscale score 7

This innovative basket trial design allows simultaneous evaluation across multiple obesity-related complications, recognizing that obesity is a chronic disease with systemic consequences 8, 7.

Clinical Context and Positioning

Comparison to Current Therapies

When retatrutide becomes available, the treatment hierarchy for obesity will likely be 8, 6, 5:

1. Retatrutide: For maximum weight loss (24.4% at 48 weeks) when no contraindications exist 1, 2
2. Tirzepatide 15mg: For substantial weight loss (20.9% at 72 weeks) with proven cardiometabolic benefits 6, 5
3. Semaglutide 2.4mg: For patients with established cardiovascular disease requiring proven CV benefit (20% MACE reduction) 6
4. Liraglutide 3.0mg: For patients requiring daily dosing or when weekly injections are not tolerated 6

Unresolved Questions

Critical limitations of current evidence that require Phase III data 1, 3:

• Long-term safety: Phase II trials are limited in duration; 2-3 year safety data are needed 1
• Cardiovascular outcomes: No dedicated cardiovascular outcome trial data yet available 3
• Quality of weight loss: Whether weight loss preserves lean body mass or requires resistance training remains unclear 3
• Cost-effectiveness: Pricing will be critical given the already high cost of tirzepatide ($1,272/month) and semaglutide ($1,619/month) 6, 3
• Real-world effectiveness: Phase III trials will provide data in more diverse populations 1

Common Pitfalls and Caveats

• Premature prescribing: Retatrutide is not yet FDA-approved; Phase III trials are ongoing with results expected in 2025-2026 1, 7
• Overpromising outcomes: While 24.4% weight loss is impressive, this represents mean data from selected trial populations; individual responses will vary 1, 2
• Ignoring lifestyle: Like all obesity pharmacotherapy, retatrutide must be combined with reduced-calorie diet (500-kcal deficit) and ≥150 minutes/week physical activity 6
• Assuming superiority without head-to-head data: Direct comparison trials against tirzepatide are needed to definitively establish superiority 1
• Overlooking contraindications: Expect similar contraindications to GLP-1R agonists (personal/family history of medullary thyroid cancer, MEN2) 6

Practical Implications for Current Practice

Until retatrutide receives FDA approval, clinicians should continue using tirzepatide 15mg weekly as the first-line agent for maximum weight loss, reserving semaglutide 2.4mg for patients with established cardiovascular disease 6, 5. Patients asking about retatrutide should be counseled that:

• Phase III trials are ongoing with results expected in 2025-2026 7
• Current best-in-class therapy (tirzepatide) achieves 20.9% weight loss, which is already transformative 6, 5
• Early Phase II data suggest retatrutide may offer incremental benefit, but long-term safety and real-world effectiveness remain to be established 1, 3