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308 Historically, a natural menopausal transition has been recognized as a life stage marked by gradually decreasing levels of estradiol (E2, the predominant ovarian estrogen) and progesterone accompanied by increasing levels of FSH and LH, beginning in earnest about two years before and stabilizing about two years after the last menstrual period

The critical design decisions included: GIP backbone selection : Starting from GIP rather than GLP-1, as GIP naturally has weak cross-reactivity with GLP-1R, providing a scaffold for optimization Aib2 substitution : Replacing Ala2 with alpha-aminoisobutyric acid for DPP-4 resistance (identical strategy to semaglutide) C-terminal extension : Adding a GGPSSGAPPPS (Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser) 11-residue C-terminal extension that enhances GLP-1R binding C-20 fatty diacid acylation : Attaching an eicosanedioic acid (C-20 diacid) at Lys20 via a Glu-2xOEG linker for albumin binding The resulting molecule exhibits approximately 5:1 selectivity for GIPR over GLP-1R it is a full GIPR agonist and a partial GLP-1R agonist, yet clinically achieves superior outcomes to selective full GLP-1R agonists [7]

Studies suggest it stimulates the formation of new functional synapses in the brain, indicating potential to not only slow cognitive decline but possibly reverse aspects of certain cognitive dysfunctions

5 February 2025