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About 10% of tirzepatide participants had a heart-rate increase above 20 bpm during escalation, compared with 3% on placebo. A lean Japanese cohort reached +10 to +13 bpm, and 23% of Japanese participants at 15 mg crossed the abnormal-pulse threshold versus 7% of other participants, despite only 17% higher exposure. Lean and East Asian bodies showed greater cardiovascular sensitivity than exposure alone predicted

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In vivo studies show that muscle-specific triple knockout of FoxO1/3/4 abolishes the induction of 29 atrogenes-including E3 ligases, autophagy mediators, deubiquitinases (e.g., USP14), and proteasome subunits (e.g., Psmd11)-under catabolic stimuli, preserving muscle mass and strength (Sanchez et al., 2014)

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