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Cagrilintide vs Tirzepatide
Two different receptor strategies in metabolic research. Tirzepatide is a dual GIP/GLP-1 incretin agonist characterized across the SURMOUNT program. Cagrilintide is a long-acting amylin analog acting on a separate satiety pathway, which is why the two are studied in combination rather than as substitutes.
Cagrilintide
Cagrilintide is a lipidated, fibrillation-resistant analogue of human islet amyloid polypeptide (amylin), a 37-residue beta-cell hormone co-secreted with insulin. The parent hormone is highly amyloidogenic, which historically limited its druggability; cagrilintide was engineered from a pramlintide-like backbone with three substitutions that suppress fibril formation and stabilize the helical segment, together with acylation of the Lys1 side chain by a C20 diacid via a gamma-glutamyl linker. The fatty diacid confers reversible, non-covalent albumin binding, which slows renal clearance and gives pharmacokinetics compatible with once-weekly subcutaneous administration in the published trial program. Pharmacologically, cagrilintide is a non-selective agonist at the calcitonin receptor and at the amylin receptors AMY1R, AMY2R and AMY3R, which are calcitonin-receptor heterodimers formed with receptor activity-modifying proteins. Cryo-electron microscopy structures show cagrilintide adopting an amylin-like bypass binding mode across these receptors, with a phenylalanine anchor at the transmembrane bundle and an intramolecular salt bridge stabilizing the peptide helix, while inducing conformational dynamics distinct from native amylin. Downstream signalling is predominantly Gs-coupled cAMP accumulation in amylin-responsive nuclei of the hindbrain, notably the area postrema and nucleus tractus solitarius. Rodent knockout work indicates that the effect on body weight depends on AMY1R and AMY3R specifically rather than on the calcitonin receptor alone. Because amylin and GLP-1 receptor signalling converge on partly non-overlapping central circuits, co-administration with semaglutide has been studied as a mechanistically complementary combination.
Tirzepatide
Tirzepatide (LY3298176) is a synthetic dual agonist peptide that activates both the glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR). Structurally, it is a 39-amino acid peptide based on the native GIP sequence with modifications enabling GLP-1R activation, coupled to a C18 fatty diacid chain via a linker for albumin binding that extends plasma half-life to approximately 5 days, enabling once-weekly dosing. GLP-1R agonism reduces appetite through hypothalamic and brainstem satiety pathways, slows gastric emptying, and augments glucose-stimulated insulin release from pancreatic beta cells while suppressing glucagon. GIPR agonism complements this by further potentiating insulin secretion in a glucose-dependent manner and may modulate adipocyte lipid metabolism, reduce glucagon secretion, and enhance the anorectic effects of GLP-1R signaling through central GIPR circuits in the hypothalamus and area postrema. Tirzepatide received FDA approval for type 2 diabetes (Mounjaro, May 2022) and obesity (Zepbound, November 2023), representing the first approved dual GLP-1/GIP agonist.
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