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Study Strengths & Limitations Strengths: Large, international, double-blind RCT with adjudicated endpoints Comprehensive, repeated adiposity measures using standardised protocols Sophisticated statistical handling including multiple imputation models for missing data Pre-specified analysis with clear hypotheses Limitations: Predominantly White (77%) and male (63%) cohortgeneralisability to other populations requires confirmation Industry-funded (Novo Nordisk), though with independent academic oversight Post-randomisation analyses of weight/waist changes are observational and cannot prove causation The paradoxical association in placebo between weight loss and increased MACE suggests unintentional weight loss from comorbiditya key confounder The Bottom Line for Clinicians Semaglutide provides robust cardiovascular protection in patients with obesity and established CVD, independent of baseline adiposity and largely independent of weight-loss magnitude

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