Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have reshaped obesity treatment, yet weight-loss outcomes remain highly uneven in real-world care. Using a federated biomedical platform integrating 23 million de-identified U.S. patient records, we analyzed 135,349 individuals treated with GLP-1RAs and stratified them as “super responders” (>15% weight loss), “moderate responders” (5–15% weight loss), “minimal weight-loss group” (<5% weight loss), and “weight regainers”. super responders reversed nearly two decades of age-associated weight gain in one year, representing approximately a decade more weight reversal than moderate responders. Compared with Wegovy (semaglutide), Zepbound (tirzepatide) showed 47% higher odds (CI: 33–61%) of super-response and 30% lower odds (CI: 23–37%) of minimal weight-loss. Likewise, relative to Ozempic (semaglutide), Mounjaro (tirzepatide) showed 284% (CI: 265–304%) higher odds of super-response and 48% (CI: 46–51%) lower odds of minimal weight-loss. AI-enabled curation processed more than 14 million clinical notes and 15 million structured records covering 1,426 disease terms across the year before and after GLP-1RA initiation. Wegovy and Ozempic super responders showed marked post-treatment increases in vomiting compared with pre-treatment baselines, as reflected by pre-to-post rate ratios (RR 0.37, p=0.014 and RR 0.09, p<0.001). In contrast, Zepbound super responders showed significantly lower post-treatment vomiting relative to baseline (RR 2.34, p<0.001), indicating brand-specific gastrointestinal tolerability profiles. Ozempic (RR 0.24, p<0.001) and Mounjaro (RR 0.17, p<0.001) super responders each showed significant post-treatment increases in diagnoses of protein–energy malnutrition, suggesting a need for whole-body compositional imaging to distinguish beneficial fat loss from unintended lean-mass loss. Novel signals for therapeutic expansion also emerged. Compared with pre-treatment baselines, Zepbound showed significantly reduced post-treatment encounters for recurrent major depressive disorder (pre-to-post RR 12.6, p<0.001) and asthma (pre-to-post RR 2.6, p<0.001). Patient stratification prior to therapy initiation revealed pre-treatment signatures that can guide GLP-1RA choice, with Zepbound super responders showing lower sleep apnea prevalence (baseline RR 0.42, p<0.001) and higher muscle stiffness prevalence (baseline RR 2.4, p=0.037). This study pinpoints actionable physiological signatures and GLP-1RA brand-specific opportunities that emerge from heterogeneous real-world responses, outlining a map for guided precision obesity interventions.