Featured Publications

Semaglutide is often optimized for weight loss, but whether longer-term cardiovascular benefit tracks achieved weight loss or therapeutic exposure levels remains unclear. Using a federated deidentified U.S. electronic health record network of 29 million patients, including 505,874 semaglutide-treated individuals, we leveraged multimodal AI technologies to analyze 47,199 patients with baseline cardiovascular disease. We quantified dose escalation and weight change during the 0-2-year period after semaglutide initiation (landmark period) and assessed cardiovascular outcomes during the 2-4-year period (post-landmark). In propensity-matched comparisons during the landmark period, semaglutide was associated with lower cardiovascular events than metformin, DPP-4 and SGLT2 inhibitors. Higher maximum semaglutide dose was associated with greater weight loss during the landmark period (3.15% additional weight loss per 1 mg increase; r=0.97, P<0.001), and lower post-landmark risk of all-cause mortality (RR 0.42, p<0.001), composite cardiovascular events (death, myocardial infarction, or stroke; RR 0.51, p<0.001), cerebrovascular disease (RR 0.50, p<0.001), heart failure (RR 0.55, p<0.001), and valvular/rheumatic heart disease (RR 0.71, p=0.025). In contrast, greater achieved weight loss during the landmark period did not show a consistent monotonic association with lower post-landmark cardiovascular risk (All-cause mortality p-value=0.14, composite cardiovascular endpoint p-value=0.55). Integrating insights from a single cell GLP1R expression atlas was used to infer how semaglutide pharmacology may tie into heart-specific signaling, beyond what is reflected by body-weight reduction alone. The strongest prevalence-weighted GLP1R signal was observed in the pancreas, followed by the heart, where GLP1R engagement potential (GEP) was considerable across cardiomyocyte, cardiac endothelial, and rarer immune cell populations. Together, semaglutide cardiovascular benefit appears organized more by maximum dose attained than by achieved weight-loss magnitude, setting the stage for beyond-obesity trial designs that integrate whole-body spatial intelligence.

GLP-1 receptor agonist (GLP-1RA) discontinuation has been associated with weight regain. However, the real-world association between discontinuation of GLP-1RA prescriptions and weight change has not been explored. We assessed weight trajectories of 4,182 patients in the six months following their last GLP-1RA prescription. Approximately two-thirds of patients showed stable weight or continued weight loss during this period post the last known GLP-1RA prescription. In a representative subset of patients with clinician-documented discontinuation near the last prescription (N=300), a similar distribution of weight regain in a minority of patients was observed vs no regain in the majority of patients during the six-month post-GLP-1RA prescription period. To mirror clinical trial-style discontinuation definitions, we also evaluated cohorts with no subsequent GLP-1RA prescription for 1 year after the last prescription (semaglutide N=1,755; tirzepatide N=1,312), observing weight regain in a minority of patients (39.3% semaglutide; 26.6% tirzepatide) and no weight regain in the majority (60.7% semaglutide; 73.4% tirzepatide) in the year following the last known GLP-1RA prescription. Exercise counseling was documented more frequently among patients with durable weight loss post-last GLP1 prescription compared with those with weight regain (26.2% vs. 14.7%; p=0.04). Further studies are warranted to infer the mechanisms underlying these real-world patterns.

GLP-1 receptor agonists (GLP-1RAs) such as semaglutide and tirzepatide have transformed obesity care and weight management, delivering unprecedented levels of weight loss in real-world practice. Several studies have demonstrated reversal of weight loss and other cardiometabolic benefits after patients discontinue GLP-1RAs. However, it is not clear whether this reversal is universal or if there are subsets of patients who are more likely to experience continued benefit after their therapeutic exposure. This question has recently been further complicated by the trend for patients to obtain GLP-1RA prescriptions  from other sources such as online providers or medical spas.

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.