Retatrutide Is Insane… But Is It Actually Better?

Physionic

Apr 4, 2026

Episode description

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0:00 - Introduction
1:12 - Insulin Resistance and Metabolism
4:39 - Semaglutide, Hunger, and Gastrointestinal Problems
6:16 - A Better Peptide!
8:49 - Retatutride: A New King
11:11 - Main Points

References
[1] Rosenstock J, Frias J, Jastreboff AM, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. Lancet. 2023;402(10401):529-544. doi:10.1016/S0140-6736(23)01053-X

[2] Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial. N Engl J Med. 2023;389(6):514-526. doi:10.1056/NEJMoa2301972

[3] Coskun T, Urva S, Roell WC, et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept. Cell Metab. 2022;34(9):1234-1247.e9. doi:10.1016/j.cmet.2022.07.013

[4] Drucker DJ. Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. Cell Metab. 2018;27(4):740-756. doi:10.1016/j.cmet.2018.03.001

[5] Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. 2021;385(6):503-515. doi:10.1056/NEJMoa2107519

[6] Karagiannis T, Malandris K, Avgerinos I, et al. Subcutaneously administered tirzepatide vs semaglutide for adults with type 2 diabetes: a systematic review and network meta-analysis of randomised controlled trials. Diabetologia. 2024;67(7):1206-1222. doi:10.1007/s00125-024-06144-1

[7] Yu X, Chen S, Funcke JB, et al. The GIP receptor activates futile calcium cycling in white adipose tissue to increase energy expenditure and drive weight loss in mice. Cell Metab. 2025;37(1):187-204.e7. doi:10.1016/j.cmet.2024.11.003

[8] Zhang A, Liu Q, Xiong Y, et al. Tirzepatide reduces body weight by increasing fat utilization via the central nervous system-adipose tissue axis in male mice. Diabetes Obes Metab. 2025;27(5):2844-2856. doi:10.1111/dom.16294

[9] Salem V, Izzi-Engbeaya C, Coello C, et al. Glucagon increases energy expenditure independently of brown adipose tissue activation in humans. Diabetes Obes Metab. 2016;18(1):72-81. doi:10.1111/dom.12585

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Mindsip insights from this episode:

Utilize GLP-1 peptides to suppress hunger through CART gene activation

GLP-1 peptides suppress hunger by increasing a gene called CART, which stands for 'cocaine and amphetamine regulated transcript'.

#GLP1

#hunger

Trick glucagon receptor for fat burning and increased metabolism

Retatrutide tricks the glucagon receptor into performing its secondary jobs of fat burning (lipolysis) and increasing metabolic rate (thermogenesis).

#metabolism

#weight-loss

Understand lean mass loss beyond muscle with weight loss peptides

The 'lean mass loss' from weight loss peptides is not purely muscle, as it also reflects a loss of stored sugar (glycogen) and water.

#muscle

#weight-loss

Demonstrate glucagon's role in retatrutide effectiveness

Animal studies confirmed the glucagon component's importance by showing that blocking its receptor made retatrutide less effective at maintaining metabolism.

#metabolism

Leverage retatrutide to combat insulin resistance

At higher doses, 80% of people with severe insulin resistance achieved huge improvements in their long-term blood sugar marker, HbA1c, using retatrutide.