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Current Research Status and Future Directions Where We Are Now (2026) Retatrutide is currently in Phase 3 clinical development under Eli Lilly's TRIUMPH program, which includes multiple trials: TRIUMPH-3 Obesity without type 2 diabetes Evaluating 12mg vs 9mg vs placebo in adults with BMI ≥30 or ≥27 with comorbidities TRIUMPH-4 Obesity with type 2 diabetes Testing efficacy and safety in patients with both conditions (preliminary: 28.7% weight loss) MASLD/NASH Trials Metabolic dysfunction-associated steatotic liver disease Leveraging glucagon's liver fat reduction effects Cardiovascular Outcomes Long-term CV safety and benefits Following precedent of STEP and SURMOUNT trials for GLP-1 drugs Timeline to FDA Approval 2023: Phase 2 results published (NEJM) 2024-2026: Phase 3 trials ongoing (TRIUMPH program) 2026-2027: Anticipated FDA submission (if trials successful) 2027-2028: Potential FDA approval and commercial launch What Researchers Are Watching The main questions Phase 3 needs to answer: Long-term efficacy: Does weight loss plateau or continue beyond 48 weeks

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Elevated cAMP activates protein kinase A (PKA) and exchange protein directly activated by cAMP (EPAC), thereby enhancing calcium influx through voltage-gated calcium channels (VGCCs) and priming insulin granules for calcium-dependent exocytosis