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Nature Metabolism, 1 (1), 47
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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The most extensively documented mechanism involves upregulation of vascular endothelial growth factor, known as VEGF, and the broader angiogenic program
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