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Two fundamentally different combination bets, both with strong preclinical rationale: 🔹 CagriSema: GLP-1 + long-acting amylin analogue -Complementary appetite circuits (hypothalamus + hindbrain, homeostatic + hedonic) -REDEFINE 1 showed 22.7% vs 16.1% for semaglutide alone -In DIO rats, ~1/3 of weight loss came from preserved energy expenditure, not just reduced intake But no published human data confirms the energy expenditure effect translates clinically 🔹 Tirzepatide: GIP + GLP-1 dual agonism - GIP's independent effect on appetite in humans remains modest and debated - Preclinically, GIPR agonism improved insulin sensitivity independent of weight loss by enhancing glucose disposal and lipid uptake in adipose tissue - GIPR activation also upregulated metabolic gene programs in brown fat and shows emerging effects on central appetite circuits - A newer finding: GIPR agonism blocked GLP-1-induced nausea in animal models while preserving weight loss, potentially explaining tirzepatide's tolerability advantage Two different mechanistic stories
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