Semaglutide vs tirzepatide vs retatrutide: receptor targets compared

The three peptides represent successive designs in incretin pharmacology: single-receptor (GLP-1), dual-receptor (GIP/GLP-1), and triple-receptor (GIP/GLP-1/glucagon) agonism. Comparing them lets a laboratory study how adding receptor targets changes signaling, receptor selectivity, and assay behavior.

Each has a fatty-acid or diacid side chain that promotes albumin binding, which is why all three have multi-day half-lives in the published literature.

Semaglutide is a modified analog of human GLP-1(7-37) with an amino-acid substitution that resists DPP-4 degradation and a C18 diacid side chain. The STEP 1 trial (Wilding et al., NEJM 2021) is the primary reference for its once-weekly use in adults with overweight or obesity.

Tirzepatide is a 39-amino-acid peptide based on the GIP sequence, engineered to activate both GIP and GLP-1 receptors, with a C20 diacid side chain. The SURMOUNT-1 trial (Jastreboff et al., NEJM 2022) is the primary reference for once-weekly use in obesity.

Retatrutide (development code LY3437943) is a single peptide with agonist activity at GIP, GLP-1, and glucagon receptors. The phase 2 obesity trial (Jastreboff et al., NEJM 2023) is the primary published reference. According to Eli Lilly, retatrutide is in phase 3 trials, has not been approved by any regulator, and is available to people only through Lilly-sponsored clinical trials; FDA has stated it cannot be used in compounding.

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