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The mechanistic hypothesis: Semaglutide activates GLP-1R, appetite suppression, glycemic control Cagrilintide activates amylin receptors, appetite suppression via the area postrema, slowing of gastric evacuation Two independent mechanisms of appetite suppression → a supra-additive effect In Phase 1b and Phase 2 trials the combination showed a stronger effect than either component alone : Semaglutide alone: −14.9 % (STEP-1) Cagrilintide alone (Phase 2): −10.8 % CagriSema combination (Phase 2): −15.6 % CagriSema Phase 3 (REDEFINE 1): −25.3 % CagriSema thus becomes the largest body-weight signal reported in the published incretin literature to date , stronger than Tirzepatide (−22.5 % in SURMOUNT-1) and comparable to Retatrutide

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Regarding small molecule inhibitors targeting NNMT, challenges include the identification of efficient and selective inhibitors with robust in vivo activity (Barrows et al., 2022)

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