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N Engl J Med 2021;384:9891002

18,20 In the SURMOUNT-3 trial, individuals who received tirzepatide after a comprehensive 12-week lifestyle intervention achieved a mean 25% weight reduction, compared to 4.8% in the placebo group, 178 suggesting a benefit for staged lifestyle intervention with GLP-1s

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These include not only effects of weight loss, but also improvements in endothelial function, reductions in low-grade inflammation (evidenced by a significant decrease in high-sensitivity C-reactive protein levels), and potential plaque stabilization [73]

This introduces variability in pharmacodynamics, as GLP-1RA penetration into specific brain regions may differ based on sex, compound properties, and age ( This raises important questions for ongoing trials such as EVOKE, which may uncover sex-specific differences and justify subsequent investigations of GLP-1 analogues in female populations