TRIUMPH-2: Phase 3 Pivotal Type 2 Diabetes Trial of Retatrutide

Study Overview

TRIUMPH-2 is the pivotal Phase 3 clinical trial evaluating retatrutide for the treatment of type 2 diabetes in adults. Alongside TRIUMPH-1 (the obesity pivotal trial), TRIUMPH-2 represents a core component of Eli Lilly’s regulatory submission strategy for retatrutide. The trial will provide definitive evidence of the drug’s glycemic efficacy, weight loss benefits, and safety profile in the type 2 diabetes population.

Trial Design

Study Type

TRIUMPH-2 is expected to be a randomized, double-blind, controlled, multicenter, international trial. Based on FDA regulatory requirements for type 2 diabetes drug development, the trial design is anticipated to include:

• Randomization to retatrutide versus placebo and/or an active comparator
• Double-blinding for unbiased assessment
• Background therapy: Participants likely on background metformin, with possible evaluation in other treatment settings
• Treatment duration: At least 40-52 weeks for the primary assessment, with potential extension for longer-term data

Participant Population

Based on Phase 2 criteria and regulatory standards:

• Adults with type 2 diabetes inadequately controlled on current therapy
• HbA1c likely in the range of 7.0-10.5%
• BMI ≥25 or ≥27 kg/m2 (depending on co-primary endpoint strategy)
• Expected enrollment of several thousand participants
• Global enrollment for demographic and geographic diversity

Dose Selection

As with TRIUMPH-1, the specific doses are expected to be selected based on Phase 2 dose-response data. The 8 mg and 12 mg doses demonstrated the most robust glycemic and weight effects in Phase 2 and are strong candidates for Phase 3 evaluation.

Endpoints

Expected primary endpoints:

• Change in HbA1c from baseline (standard regulatory endpoint for diabetes)
• Percent change in body weight from baseline (potential co-primary endpoint)

Expected secondary endpoints:

• Proportion of participants achieving HbA1c <7.0% and <5.7%
• Fasting plasma glucose changes
• Proportion achieving ≥5%, ≥10%, ≥15% weight loss
• Changes in cardiometabolic parameters
• Liver fat content (in imaging substudy)
• Safety and tolerability, including hypoglycemia rates

Context from Phase 2

The Phase 2 type 2 diabetes trial provided a strong foundation for TRIUMPH-2:

• HbA1c reduction: Up to -2.02% at 12 mg, with 95% of participants achieving <7.0% and ~62% achieving <5.7%
• Weight loss: Up to -16.9% at 36 weeks, substantial for a diabetes population
• Active comparator data: Retatrutide at 8 mg and 12 mg significantly outperformed dulaglutide 1.5 mg
• Safety: Consistent incretin-class GI profile; low hypoglycemia rates

Key Questions TRIUMPH-2 Will Address

Glycemic Efficacy Confirmation

Will the potent HbA1c reductions and high rates of glycemic target achievement observed in Phase 2 be replicated in a larger population? Phase 2 results are often modestly attenuated in Phase 3 due to less selected patient populations and greater real-world variability.

Comparative Efficacy

If TRIUMPH-2 includes an active comparator arm (such as semaglutide or tirzepatide), the results could provide direct evidence of how retatrutide’s triple agonism compares to established therapies. This head-to-head data would be highly valuable for clinical decision-making and market positioning.

Durability of Glycemic Control

The longer treatment duration of Phase 3 will reveal whether glycemic improvements are maintained over time or whether there is glycemic drift, as is sometimes observed with other diabetes therapies.

Safety at Scale

The larger Phase 3 population will provide greater sensitivity for detecting uncommon adverse events and will generate more robust data on hypoglycemia rates, pancreatic safety, thyroid safety, and other monitoring parameters.

Hepatic Benefits in Diabetes

Patients with type 2 diabetes have a particularly high prevalence of MASLD. Liver fat assessments in TRIUMPH-2 will be important for characterizing retatrutide’s hepatic effects in this high-risk population.

Significance for the Diabetes Treatment Landscape

If the Phase 3 results confirm Phase 2 findings, retatrutide could represent a significant advancement in type 2 diabetes treatment. The combination of potent glycemic control, substantial weight loss, liver fat reduction, and broad cardiometabolic improvement addresses multiple treatment goals with a single weekly injection. This comprehensive approach aligns with modern diabetes care guidelines that emphasize weight management and cardiovascular risk reduction alongside glycemic targets.

Timeline

• Enrollment: Ongoing (estimated 2024-2025)
• Treatment period: 40-52+ weeks estimated
• Primary results: Expected 2025-2027
• Regulatory implications: TRIUMPH-2 data, combined with TRIUMPH-1, will form the basis for regulatory submission for the type 2 diabetes indication