Retatrutide

Retatrutide (development code LY3437943) is an investigational triple agonist that activates the GLP-1, GIP, and glucagon receptors. Eli Lilly is currently running phase 3 trials for chronic weight management and type 2 diabetes; in phase 2 results, retatrutide produced about 24% weight loss at 48 weeks at the highest dose, exceeding tirzepatide's published numbers.

Retatrutide is not currently approved by the FDA and has no commercial brand name. Gene2Rx surfaces retatrutide pharmacogenetics as forward-looking content for patients enrolled in trials and clinicians following the development program.

GLP1R: same signal-peptide variant (rs10305420 Pro7Leu) that influences semaglutide and tirzepatide response. Leu7 carriers are expected to have slightly greater weight loss and modestly higher nausea risk on retatrutide.

GIPR: the Glu354Gln variant (rs1800437) reduces GIP-receptor function. By analogy with tirzepatide, Gln354 carriers are expected to have higher GI side-effect risk on retatrutide. This is not yet established directly in retatrutide trials.

GCGR: the glucagon receptor adds the third arm of activity. No common GCGR variants are known to substantially alter retatrutide response in published data; this is an open research question.

The strongest pharmacogenetic signal expected for retatrutide is on the GIPR arm. Tirzepatide trial data established that Gln354 carriers have ~1.8-fold higher odds of moderate-to-severe nausea or vomiting; the same biology should produce a similar effect for retatrutide. The GLP1R signal-peptide effect should also carry over from semaglutide and tirzepatide.

The GCGR component contributes additional weight loss in retatrutide compared with dual agonists, but no common variant has been identified that meaningfully alters this effect.

GLP1R Typical + GIPR Normal Function

• Effect: Average weight loss and GI side-effect risk for retatrutide.
• Recommendation: Standard trial titration.

GIPR Decreased / Poor Function (Gln354 carrier)

• Effect: Likely higher risk of moderate-to-severe nausea or vomiting on retatrutide, by analogy with tirzepatide.
• Recommendation: Slower dose escalation if available; if intolerable, GLP-1-only agents (e.g., semaglutide) are unaffected by this variant.

GLP1R Enhanced Response

• Effect: Slightly greater weight loss; modestly higher nausea risk from the GLP-1 arm.

Indeterminate / Not Available

• Recommendation: Standard titration; monitor response.

Retatrutide is not currently FDA-approved. It is available in clinical trials only. The pharmacogenetic guidance on this page is extrapolated from semaglutide and tirzepatide research and represents Gene2Rx's best current interpretation. Direct retatrutide pharmacogenetic data should be expected as the phase 3 program reads out.

Approved alternatives in the same class include semaglutide (Ozempic / Wegovy), a GLP-1-only agonist, and tirzepatide (Mounjaro / Zepbound), a GLP-1 / GIP dual agonist.

• NEJM, 2023 — Triple Hormone Receptor Agonist Retatrutide for Obesity (phase 2)
• Nature, 2025 — GLP1R / GIPR variants and incretin response
• ClinicalTrials.gov, retatrutide trials

Learn more about how genetics may affect your response to Retatrutide and related medications:

• Retatrutide Pharmacogenetics: Triple Agonist Genetics (Investigational)
• Why Isn't Ozempic or Wegovy Working for Me? The GLP1R Connection
• Tirzepatide (Mounjaro, Zepbound) Not Working: GLP1R and GIPR Genetics