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Abstract Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for obesity and type 2 diabetes, yet substantial variability in weight-loss response remains poorly understood. We conducted a retrospective cohort study using de-identified electronic health records and performed 1:1 propensity matching on age, sex, type 2 diabetes status, baseline BMI and weight, index year, and follow-up duration. The matched cohorts included 10,339 tirzepatide-treated and 10,339 semaglutide-treated patients. Patients were categorized by maximum weight loss over 2 years into five response groups. Adverse events were identified through AI-enabled curation of clinical notes. Weight-loss trajectories, demographic patterns, adverse-event profiles, and pre- to posttreatment disease-prevalence changes were compared across drugs. Patients treated with tirzepatide lost more weight than those treated with semaglutide (mean reduction, 14.7 vs. 10.8%; P < 0.001). High-response rates (≥15% weight loss in year 1) were nearly doubled with tirzepatide (42.6 vs. 21.6%; P < 0.001), accompanied by faster monthly weight-loss velocity (2.54 vs. 2.18%). AI-enabled curation showed that tirzepatide was associated with lower prevalence of gastrointestinal and systemic adverse events. For both tirzepatide and semaglutide, women were more represented among high responders than the minimal weight-loss group (<5% weight loss) and White patients were more represented among high responders, whereas Black and Hispanic patients were more represented among the minimal weight-loss group. In this large, propensity-matched real-world cohort, tirzepatide was associated with greater and faster weight loss than semaglutide, with marked demographic variations in outcomes, highlighting the need for next-generation obesity clinical trials and routine care decisions to incorporate the growing body of evidence from widespread use of incretin therapies across diverse patient populations.

Abstract Background: Alzheimer’s disease (AD) progression is commonly summarized through cognitive and global staging measures, yet routine care captures multidomain deterioration across cognition, function, neuropsychiatric symptoms, caregiver dependence, and systemic physiology. After EVOKE and EVOKE+ showed no population-level slowing of early symptomatic AD progression with oral semaglutide, a key unresolved question is whether disease phase, functional reserve, multimorbidity, and the temporal ordering of decline identify clinically distinct trajectories that are not captured by average trial effects. Methods: We conducted a retrospective observational study using de-identified electronic health record data from a federated network of more than 29 million patients. Large language model (LLM)-enabled extraction was used to recover standardized cognitive, functional, global severity, and neuropsychiatric assessment scores from clinical notes. Functional decline was defined from FAQ, ADCS-ADL, and ADCS-MCI-ADL; cognitive decline was defined from MMSE and MoCA. We reconstructed longitudinal AD trajectories, compared outcome-domain representation in contemporary AD trials, characterized patient-level timing of functional versus cognitive decline, and evaluated clinical trajectories among patients who initiated semaglutide after AD diagnosis. Physician adjudication showed high extraction accuracy for the main reportable instrument set. Findings: Among 131,824 patients with structured AD diagnoses, 42,242 had at least one LLM-derived outcome assessment from clinical notes and 341 initiated semaglutide after AD diagnosis. Normalized trajectories over decades of routine clinical care showed long prediagnostic decline and AD diagnosis-proximal acceleration, with the composite score decreasing from 0.99 at 25.1 years before AD diagnosis to 0.64 at 4.9 years after AD diagnosis. Compared with matched non-AD controls, AD patients showed marked post-index functional separation, including lower ADCS-MCI-ADL scores at year 4 (28.1 versus 47.0 points; P<0.001) and higher FAQ impairment across follow-up. We also evaluated clinical outcome and physiologic trajectories in semaglutide-treated AD patients and matched non-semaglutide AD controls; in paired score-change analyses, semaglutide-treated patients had more favorable MMSE change than matched controls (+0.4 versus −2.3 points; P=0.022) and more favorable MoCA change (−0.3 versus −2.2 points; P=0.049), whereas functional, global severity, and neuropsychiatric comparisons were not statistically significant and were limited by smaller sample sizes. Among 3,467 patients with at least two repeated functional assessments or two repeated cognitive assessments, 2,883 (83.2%) had confirmed functional decline and 2,535 (73.1%) had confirmed cognitive decline, with both functional and cognitive decline observed in 2,169 (62.6%) patients. Among the 2,169 patients, cognitive decline preceded functional decline (“cognitive decline-first”) in 1,123 patients (51.8%), functional decline preceded cognitive decline (“functional decline-first”) in 741 patients (34.2%), and both declines were confirmed on the same date in 305 patients (14.1%). Cognitive decline-first was more prevalent. Overall, 631 patients (29.1%) had cognitive decline at least 12 months before functional decline and 327 patients (15.1%) had functional decline at least 12 months before cognitive decline. Cognitive decline-first patients had higher medication burden and greater note-derived symptom burden. Functional decline-first patients were enriched for APOE ε3/ε3 (OR 2.82, 95% CI 1.17–6.76; P=0.023), supporting the need for trajectory-aware and genetically stratified approaches in semaglutide trial design and interpretation. In general, AD was also accompanied by systemic physiologic divergence from matched controls, including prediagnostic weight decline and postdiagnostic albumin and hemoglobin decline. In matched paired score-change analyses, semaglutide-treated AD patients showed more favorable MMSE change than matched non-semaglutide AD controls and more favorable MoCA change, whereas functional, global severity, and neuropsychiatric comparisons were not statistically significant and were limited by smaller sample sizes. Interpretation: LLM-enabled clinical-note phenotyping reveals that AD progression in routine care is multidomain and temporally heterogeneous, with functional decline-first and cognitive decline-first subsets that differ in medication and note-derived phenotype burden. These findings do not establish semaglutide efficacy in AD, but they suggest that EVOKE and EVOKE+ leave open a stratification question: whether treatment-associated trajectories vary by disease phase, functional reserve, multimorbidity, and the temporal ordering of functional and cognitive decline. Prospective validation, physician adjudication, and matched comparator analyses are needed before these phenotypes can guide trial enrichment or clinical decision-making.

Abstract Historically, HER2 status in invasive breast cancer has been categorized as HER2-positive (IHC 3+, IHC 2+/ISH+) or HER2-negative (IHC 0, IHC 1+, IHC 2+/ISH-). Patients meeting IHC 0 with membrane staining (HER2-ultralow) criteria may benefit from HER2-targeted therapies such as trastuzumab deruxtecan. This cohort study assessed the prevalence of HER2-ultralow expression by re-scoring HER2 IHC slides using Mayo Clinic electronic health record data. Three hundred patients with advanced breast cancer (Stages III-IV) and documented HER2 IHC 0 status (January 2017–March 2023) were identified. One slide per patient was digitized and independently re-scored by two Mayo Clinic pathologists following the 2023 ASCO-CAP guidelines, including tumor staining percentage to denote HER2-ultralow status. A sensitivity analysis was performed by a third independent pathologist. The re-scored patients had a mean age of 57.7 years (SD = 13.6). Most samples (95%, n = 285) remained scored IHC 0 by at least one pathologist; 60% of these met HER2-ultralow criteria per at least one pathologist. HER2-ultralow prevalence ranged from 43% to 45% per pathologist, with 57% overall interpathologist concordance. Samples with no observable staining comprised most of the concordant cases. Treatment patterns were similar between HER2-ultralow and no-staining groups; however, time to treatment failure (TTF) varied between groups across lines of therapy (LOT). In HR− positive cohorts, median TTF for LOT1 was 7.73 months in patients with HER2-ultralow versus 9.43 months with no observable IHC staining. In HR− negative cohorts, median TTF was 5.00 months for HER2-ultralow versus 3.17 months with no observable IHC staining. Similar TTF trends were observed in LOT2-LOT3. Approximately three in five samples originally classified as IHC 0 met HER2-ultralow criteria, suggesting many patients may benefit from HER2-directed therapy if reclassified. These findings highlight potential challenges of identifying HER2-ultralow expression and suggest the need for enhanced pathologist training, adherence to best practices, and integration of digital pathology and artificial intelligence solutions. Trial Registration: ClinicalTrials.gov_identifier: NCT03734029

GLP-1 receptor agonists have reshaped obesity therapeutics, but their impact on neuropsychiatric outcomes remains poorly characterized. From 29 million patients in a large federated data platform across the USA, including 489,785 semaglutide treated patients, we conducted an observational study integrating longitudinal neuropsychiatric outcomes. From this population, we assembled a cohort of 63,215 patients with baseline neuropsychiatric conditions before treatment initiation and evaluated 24 incident neuropsychiatric outcomes. In propensity-matched comparator analyses, during the 2 year time-period from treatment initiation, semaglutide was associated with broadly lower neuropsychiatric event risk than metformin, SGLT2 inhibitors, and DPP-4 inhibitors. Within the semaglutide-treated cohort, higher attained dose during the first two years after the first prescription ("pre-landmark period") was associated with significantly lower incidence during the following two years ("post-landmark period") of diagnostic codes associated with substance-related disorders (P<0.001), mood disorders (P<0.001), anxiety- and stress-related disorders (P<0.001), CNS atrophies (P<0.001), neuromuscular disorders (P=0.013), eating/sleep/behavioral disorders (P=0.022), and personality/impulse-control disorders (P=0.028). Consistent with previous clinical trials, the post-landmark incidence of dementia or CNS degenerative diseases was similar between the high-dose and low-dose semaglutide cohorts (P=0.15). For most neuropsychiatric diagnoses, post-landmark incidence was strongly associated with the maximum attained semaglutide dose during the pre-landmark period, but incident cognitive symptoms and speech/language symptoms were more closely linked to the pre-landmark weight-loss magnitude (p<0.001 and p<0.003, respectively). Bulk and single-cell transcriptomic analyses demonstrated GLP1R expression in CNS tissues (hypothalamus, caudate, putamen, nucleus accumbens, cerebellum) and peripheral nerves. Age-associated heterogeneity in GLP1R expression was evident in several of these compartments including the caudate nucleus, suggesting dynamic changes in the availability of the neurobiological substrate for semaglutide response. Together, these data support a model in which semaglutide confers a sustained, dose-dependent, weight loss-independent benefit across multiple neuropsychiatric conditions via direct CNS target engagement. This observational study motivates prospective clinical studies and mechanistic analyses to clarify the impact of GLP-1 receptor agonists on human neuropsychiatric pathways and disease processes.

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, we analyzed 135,349 individuals treated with semaglutide and tirzepatide formulations 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”. Ozempic, Wegovy, Mounjaro, and Zepbound had similar proportions of patients classified as moderate responders, ranging from 40 to 42%. Rates of super responders were highest for Zepbound (34%), followed by Wegovy (26%), Mounjaro (24%) and Ozempic (10%). Among moderate and super responders, the average weight after one year of treatment was similar to the average weight approximately 10 and 20 years prior to treatment initiation, respectively. Compared to patients with minimal or moderate response, super responders were more likely to be younger (mean age 51 years versus 55 years), female (80% versus 58-65%), and white (90% versus 80%). Baseline clinical characteristics enriched among super responders compared to the minimal response group included fibromyalgia (rate ratio [RR]: 0.2, p = 0.002) and osteoarthritis (RR: 0.5, p = 0.001) for Zepbound, and psoriasis (RR: 2.5, p  = 0.03) for Wegovy. These results highlight significant heterogeneity in weight trajectories following sustained exposure to a GLP-1RA therapy and identifies factors associated with increased weight loss, likely reflecting a combination of biological, behavioral, and social factors. These insights motivate further prospective analyses to help guide the development of more tailored weight loss intervention strategies.