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The Peptide Effect
Comparison

Retatrutide vs Tirzepatide

Retatrutide (LY3437943) is a next-generation triple hormone receptor agonist targeting GLP-1, GIP, and glucagon receptors, currently in Phase 3 clinical trials by Eli Lilly. Tirzepatide (Mounjaro/Zepbound) is the dual GIP/GLP-1 agonist from the same company, already FDA-approved. Phase 2 data for retatrutide showed up to 24.2% body weight loss at 48 weeks — potentially surpassing even tirzepatide — driven by the added glucagon receptor activity that increases energy expenditure and hepatic fat oxidation.

Side-by-side comparison diagram of Retatrutide and Tirzepatide mechanisms of action
Conceptual comparison — not to scale

Head-to-Head Comparison

CriteriaRetatrutideTirzepatide
Primary mechanismTriple agonist: GLP-1 + GIP + glucagon receptorsDual agonist: GLP-1 + GIP receptors
Best forMaximum weight loss, fatty liver disease (MASLD/MASH), metabolic syndromeWeight loss, type 2 diabetes, patients needing an approved medication now
Route of administrationOnce-weekly subcutaneous injectionOnce-weekly subcutaneous injection
Typical dosage1 mg escalating to 8 mg or 12 mg weekly (Phase 2 protocol)2.5 mg escalating to 5 mg, 10 mg, or 15 mg weekly
Average weight loss~24.2% at 48 weeks (12 mg dose, Phase 2)~22.5% at 72 weeks (15 mg dose, SURMOUNT-1)
Half-life~6 days (once-weekly dosing)~5 days (once-weekly dosing)
FDA statusNot approved — Phase 3 trials ongoing (expected completion 2025–2026)FDA-approved for obesity (Zepbound, 2023) and T2D (Mounjaro, 2022)
Effect on liver fatDramatic reduction — glucagon receptor drives hepatic fat oxidation; 86% MASLD resolution in Phase 2Significant reduction in liver fat (SYNERGY-NASH trial data)
Effect on energy expenditureIncreases resting energy expenditure via glucagon receptor activationDoes not significantly increase energy expenditure
Side effectsNausea (26%), diarrhea (22%), vomiting (14%), constipation (11%) — Phase 2 dataNausea (31%), diarrhea (23%), vomiting (12%), constipation (11%)
Lean mass preservationPotentially better — glucagon receptor may improve lean-to-fat loss ratio~30–40% of weight loss is lean mass (typical for GLP-1 class)
Approximate monthly costNot commercially available — research compound only$1,060–$1,200/month (brand)

When to Choose Each

Choose Retatrutide

Patients awaiting maximum-efficacy obesity treatment, those with fatty liver disease (MASLD/MASH), or individuals interested in the metabolic benefits of glucagon receptor activation — once approved

Choose Tirzepatide

Patients who need an FDA-approved treatment now, those with type 2 diabetes and obesity, or anyone wanting a proven medication with established dosing and safety data

Verdict

Retatrutide represents the most exciting next step in incretin-based obesity treatment, with Phase 2 data showing potentially best-in-class weight loss (~24%) at 48 weeks — a shorter timeframe than tirzepatide's 72-week SURMOUNT-1 trial. The addition of glucagon receptor agonism uniquely drives hepatic fat reduction and increased energy expenditure, making it especially promising for fatty liver disease. However, tirzepatide is available now, FDA-approved, and has a strong clinical evidence base. Retatrutide remains investigational with Phase 3 results pending, so tirzepatide is the clear choice for patients who need treatment today.

References

  1. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-comparator-controlled, parallel-group, phase 2 trial (2023) — PubMed
  2. Triple-hormone-receptor agonist retatrutide for obesity — a Phase 2 trial (2023) — PubMed
  3. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1) (2022) — PubMed
  4. Glucagon receptor agonism in the treatment of metabolic diseases including NAFLD (2022) — PubMed

Frequently Asked Questions

When will retatrutide be FDA-approved?
Retatrutide is currently in Phase 3 trials (TRIUMPH program) run by Eli Lilly. Based on typical FDA timelines, the earliest possible approval would be late 2026 or 2027, assuming positive Phase 3 data and smooth regulatory review. Lilly has not publicly confirmed a target launch date.
Is retatrutide really better than tirzepatide for weight loss?
Phase 2 data showed retatrutide achieving 24.2% weight loss at 48 weeks, compared to tirzepatide's 22.5% at 72 weeks in SURMOUNT-1. However, direct head-to-head trials have not been conducted, and Phase 2 results sometimes differ from Phase 3 confirmatory studies. The added glucagon receptor activity is a meaningful mechanistic advantage, but definitive conclusions require Phase 3 data.
What makes the glucagon receptor component special?
Glucagon receptor activation increases resting energy expenditure (calorie burning) and drives hepatic lipid oxidation (fat burning in the liver). This is a fundamentally different mechanism from GLP-1's appetite suppression. It means retatrutide attacks obesity from both sides — reducing calorie intake (GLP-1/GIP) while increasing calorie expenditure (glucagon). This also makes it uniquely effective for fatty liver disease.
Can I get retatrutide from research peptide vendors?
Some research chemical vendors sell retatrutide for "research purposes only." These products are not FDA-approved, not manufactured under pharmaceutical GMP standards, and their purity and dosing accuracy cannot be guaranteed. Using investigational compounds outside of clinical trials carries significant safety risks and is not recommended by medical professionals.
Could someone switch from tirzepatide to retatrutide once it is approved?
Research suggests that switching between incretin-based medications is generally feasible under physician supervision, as has been seen with semaglutide-to-tirzepatide transitions. If retatrutide receives FDA approval, prescribers would likely develop transition protocols starting at the lowest retatrutide dose and titrating upward, similar to how other medication switches in this class are managed. The added glucagon receptor activity in retatrutide means the side effect profile may differ from tirzepatide, requiring a new adjustment period. Consulting a healthcare provider will be essential for safe transitioning.

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