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If we extend this observation to adult neurogenesis, promoter hypermethylation might not be responsible for the final repression of intrinsic fate-determination TFs, which occurs in later stages of neuronal development (Figure 1)

How the cagrilintide + tirzepatide stack compares Feature Components Cagrilintide + Tirzepatide Cagrilintide + Tirzepatide CagriSema (Cag + Sema) Cagrilintide + Semaglutide Cagrilintide + Retatrutide Cagrilintide + Retatrutide Feature Receptor coverage Cagrilintide + Tirzepatide AMY + GLP-1R + GIPR (3 families) CagriSema (Cag + Sema) AMY + GLP-1R (2 families) Cagrilintide + Retatrutide AMY + GLP-1R + GIPR + GCGR (4 families) Feature Combination clinical data Cagrilintide + Tirzepatide Preclinical only (Valdecantos 2024) CagriSema (Cag + Sema) Phase 3 REDEFINE-1: ~22.7% at 68 weeks Cagrilintide + Retatrutide None (fully speculative) Feature Best monotherapy result Cagrilintide + Tirzepatide Tirzepatide: 25.5% at 84 weeks CagriSema (Cag + Sema) Semaglutide: ~14.9% at 68 weeks Cagrilintide + Retatrutide Retatrutide: 28.7% at 68 weeks Feature GIP receptor Cagrilintide + Tirzepatide Yes (tirzepatide) CagriSema (Cag + Sema) No Cagrilintide + Retatrutide Yes (retatrutide) Feature Glucagon receptor Cagrilintide + Tirzepatide No CagriSema (Cag + Sema) No Cagrilintide + Retatrutide Yes (retatrutide) Feature Dysesthesia risk Cagrilintide + Tirzepatide No CagriSema (Cag + Sema) No Cagrilintide + Retatrutide Yes (retatrutide) Feature FDA-approved component Cagrilintide + Tirzepatide Yes (tirzepatide as Mounjaro / Zepbound) CagriSema (Cag + Sema) Semaglutide approved