How Does Oral Retatrutide Work?

Oral retatrutide is a once‑daily “triple agonist” weight-loss and diabetes drug that mimics three gut hormones at once: GIP, GLP‑1, and glucagon. Early studies of injectable retatrutide show very large, predominantly fat‑driven weight loss, with muscle (lean mass) making up roughly one‑third of total weight lost^[1–5].

What is Oral Retatrutide?

Retatrutide is a synthetic peptide designed to activate three receptors:

• GIP – curbs appetite and boosts insulin
• GLP‑1 – also curbs appetite and boosts insulin
• Glucagon receptor – increases energy expenditure

Current phase 1 and 2 trials use a once‑weekly injectable version. Because the oral version delivers the same tri‑agonist signal, most benefits and risks are inferred from injection data^[1].

Incretin Hormones and How Retatrutide Works

Incretins are gut‑derived hormones released after eating that amplify insulin secretion in a glucose‑dependent way. The two primary incretins, GIP and GLP‑1, help:

• Enhance insulin release
• Modulate glucagon
• Slow gastric emptying
• Act on the brain to reduce appetite and promote satiety^[1,2,4]

Retatrutide activates all three receptors to:

• Reduce food intake
• Delay gastric emptying
• Increase energy expenditure
• Improve glycemic control^[1,3]

What Early Studies Claim About Weight Loss

In a phase 2 obesity trial by Eli Lilly, weekly injectable retatrutide produced up to 24% weight loss at 48 weeks. In a separate phase 2 diabetes study, participants lost nearly 17% at 36 weeks with 8–12 mg doses, alongside HbA1c improvement. These injectable results offer realistic expectations for the oral version^[1,3].

Fat Loss vs. Muscle Loss

Retatrutide, like other GLP‑1 drugs, causes weight loss composed of:

• ~2/3 fat mass
• ~1/3 lean (muscle) mass^[5,6]

To preserve lean mass, users should maintain a high-protein diet and resistance training during treatment.

Whey Protein and Muscle Preservation

A quality whey protein supplement can help maintain muscle. It’s rich in leucine, an amino acid critical for muscle retention and growth^[7].

References

1. Del Prato S, et al. Triple-hormone-receptor agonist retatrutide for obesity. NEJM. 2023.
2. Frias JP, Nauck MA, et al. Retatrutide for type 2 diabetes. The Lancet. 2023; 402(10398).
3. Lundgren JR, et al. Body composition effects of retatrutide. The Lancet Diabetes & Endocrinology. 2025.
4. Meier JJ, Nauck MA. Mechanisms of incretin tri‑agonists. Am J Physiol Endocrinol Metab. 2024; 326(2).
5. Beavers KM, et al. GLP1Ra and musculoskeletal outcomes. Obesity. 2025; 33(2):225–237. https://doi.org/10.1002/oby.24172
6. Sattar N, Zinman B. GLP-1 based medications for diabetes and obesity. Endocrine Reviews. 2025.
7. Rigamonti AE, et al. Whey protein and GLP-1 effects. Nutrients. 2020;12(3):775. https://doi.org/10.3390/nu12030775

Written by Brooke Lounsbury