GLP-1 Agonists Compared: Semaglutide, Tirzepatide and Retatrutide

GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) are gut hormones released after a meal that potentiate glucose-dependent insulin secretion; together they are called incretins. Glucagon is the pancreatic hormone that raises blood glucose and increases hepatic energy expenditure. Each has its own G-protein-coupled receptor. The three peptides in this comparison differ in which of these receptors they activate.

Semaglutide: 31 amino acids, a GLP-1(7-37) analogue, C187H291N45O59, about 4,113.6 g/mol, C18 fatty diacid at lysine 26, Aib at position 8. Tirzepatide: 39 amino acids, a GIP-based backbone, C225H348N48O68, about 4,813.5 g/mol, C20 fatty diacid at lysine 20, Aib at positions 2 and 13. Retatrutide: 39 amino acids, a GIP-based backbone, C221H342N46O68, about 4,731 g/mol, C20 fatty diacid on a lysine side chain, Aib substitutions for protease resistance.

The shared design elements are deliberate. Aib at the second position blocks dipeptidyl peptidase-4, the enzyme that inactivates native incretins within minutes. The fatty-diacid chain binds serum albumin, extending circulating half-life from minutes to days. The differences lie in the backbone sequence, which determines receptor selectivity.

Semaglutide activates the GLP-1 receptor only. Tirzepatide activates the GIP receptor with high affinity and the GLP-1 receptor with lower affinity, and is described as a biased agonist at the latter. Retatrutide activates the GIP receptor most potently, with additional activity at the GLP-1 and glucagon receptors. The series therefore moves from one receptor to three, and the open scientific questions are what each additional receptor contributes: the GIP component in tirzepatide, and the glucagon component in retatrutide.

In vitro, the three are compared in receptor-binding and cAMP assays in cell lines expressing each receptor individually, which is where the selectivity figures above come from. In preclinical models they are compared for effects on glucose homeostasis, energy expenditure, adiposity and hepatic lipid content. Clinically, tirzepatide has been compared directly with semaglutide in published trials, and retatrutide's programme is more recent. For a research laboratory the practical point is that the three are best understood as variations on one design rather than three unrelated compounds.

All three are large, lipidated peptides that require a well-developed reversed-phase HPLC method to resolve the main peak from deamidated, oxidised and truncated variants, and all three are identity-confirmed by mass spectrometry against the theoretical mass of the full modified structure. Regent Peptides supplies all three, UK manufactured, with every batch tested by Janoshik Analytical; semaglutide in two strengths, retatrutide in six and tirzepatide in seven.

Semaglutide and tirzepatide are approved prescription medicines in several jurisdictions; retatrutide is investigational. The research-grade peptides supplied here are not those products, are not medicines, and are supplied solely for in-vitro laboratory research. They are not for human use.