The U.S. Medicare GLP-1 Bridge program and existing Part D pathways are expanding access to tirzepatide therapy for older adults, including Zepbound through the Bridge for weight management and Mounjaro through Part D coverage for type 2 diabetes. This necessitates identification of clinical vulnerabilities in geriatric patients that may emerge during pharmacologic weight loss. Here we evaluated incident malnutrition, protein-energy malnutrition (PEM), appetite suppression, dehydration, and sarcopenia in the context of tirzepatide-associated weight loss among adults aged 65 years or older, and we quantified associated mortality, intensive care unit (ICU) admission, and hospitalization relative to comparator cohorts of patients who were prescribed other antidiabetic medications (metformin, DPP4 or SGLT2 inhibitors) or underwent bariatric surgery. Incident frailty-related phenotypes rose with larger achieved weight loss. Specifically, anorexia increased from 2.9% (at ≤5% weight loss) to 10.2% (at 30-40%); dehydration from 1.8% to 4.8%; malnutrition from 0.8% to 3.1%; and PEM from 0.5% to 2.9%. Median tirzepatide treatment duration increased from 1.2 months at ≤5% weight loss to 13.2 months at 30-40%, whereas duration was largely invariant by baseline BMI from 40. The development of frailty phenotypes after tirzepatide initiation was associated with increased rates of mortality (RR 25, 95% CI 18-35), ICU admission (RR 20, 95% CI 16-25), and hospitalization (RR 11, 95% CI 9.8-12) relative to tirzepatide-treated patients who did not develop malnutrition. Baseline features enriched among patients who developed frailty phenotypes after tirzepatide initiation were older age, advanced diabetes, pre-existing MAFLD/MASH, and cardiorenal comorbidities. Physician-reviewed cause-of-death among decedents with incident frailty phenotypes after tirzepatide initiation showed respiratory failure, septic shock, advanced malignancy, and multiorgan failure as leading causes of death. Overall, in this observational study of Medicare-age-eligible adults, incident frailty phenotyping during tirzepatide-associated weight loss identified vulnerable subgroups with baseline cardiometabolic burden, highlighting the need for comprehensive clinical decision support and multimodal patient monitoring with increasing weight-loss.

Background/Objectives: Oral semaglutide (Wegovy pill) and orforglipron (Foundayo) were recently approved for chronic weight management. Their safety and effectiveness have not been evaluated in real-world practice, particularly during the first few months when dose escalation, early treatment response, and tolerability may shape adherence.Methods: We retrospectively analyzed de-identified electronic health records through September 2026, including 16,220 oral Wegovy and 1,106 Foundayo recipients. Propensity matching on demographics, baseline characteristics including cardiometabolic burden, incretin history, the date of treatment initiation, and clinical visit frequency yielded 756 adult patients per drug. Clinical notes were curated with large language models (LLM), validated by physician adjudication.Results: In the unmatched cohorts, prior incretin exposure was recorded in 56.0% of oral Wegovy users versus 63.8% of Foundayo users (P<0.001). Prior injectable Wegovy use predominated among subsequent oral Wegovy users, whereas prior Zepbound use predominated among subsequent Foundayo users (both P<0.001). Dose escalation by day-90 lagged the recommended schedules for both agents. In matched cohorts, despite similar pre-treatment weight trajectories, mean weight change by 90 days after GLP-1 pill initiation was −3.1% with oral Wegovy (n=26) versus +0.4% with Foundayo (n=18), corresponding to a 3.55-percentage-point difference (95% CI, 1.02-6.08; P=0.007). Post-treatment initiation, LLM-curated clinical notes with physician adjudication confirmed weight-gain in a higher percentage of Foundayo users (5.3%) than oral Wegovy users (2.4%) (RR 2.20; P=0.016). Higher documentation of abnormal lipids was also evident from the LLM-curated notes among Foundayo users (1.7%) versus oral Wegovy users (5; P=0.009). Serial diagnostic lab testing showed a decrease in triglycerides during oral Wegovy use (−31.6 mg/dL; P=0.011, n=19) and a decrease in non-HDL cholesterol during Foundayo use (−30.5 mg/dL; P=0.04, n=11). Statins use did not meaningfully change upon Foundayo initiation, whereas significant statin-record frequency decrease was observed upon oral Wegovy prescribing (4.8% to 1.8%; P=0.020). Among Foundayo users, those with post-index statin co-prescriptions had numerically higher documented prevalence of abnormal lipids as expected, but also dizziness, and elevated liver enzymes than those without post-index statin co-prescriptions. Furthermore, adverse liver events and elevated liver enzymes were also numerically more frequent among Foundayo users than matched oral Wegovy users, presenting an emerging hypothesis that warrants prospective validation considering the FDA's postmarketing requirement to evaluate Foundayo liver safety and a subsequent FDA adverse-event report of hepatic failure. Conclusions: In a small subset of patients with follow-up weight measurements approximately 90 days after treatment initiation, oral Wegovy was associated with greater weight loss than Foundayo in routine care. Larger-scale and prospective follow-up analyses are warranted to more robustly compare the safety and effectiveness of these agents.

Zepbound (tirzepatide) is among the most effective obesity medicines for weight reduction, in both clinical trial and real-world settings. Product marketing largely centers on weight-loss magnitude, which may reinforce the expectation that larger reductions are always better. Using de-identified EHRs, we compared 1,039 Zepbound initiators (1.7%) whose first-year weight loss reached ≥30% (“excessive weight loss”) with 20,668 Zepbound initiators (34.7%) who lost 5%-15% (“moderate weight loss”). After 1:4 propensity score matching (837 versus 3,348 patients), large language model (LLM)-curation extracted 24 adverse events that physician notes explicitly attributed to weight loss. The rate of any weight loss-attributable adverse event was significantly higher with excessive weight loss, at 39.4 versus 14.4 per 100 patient-years, representing 294 (35.1%) versus 479 (14.3%) patients (rate ratio [RR]: 2.78, 95% confidence interval [CI] 2.40-3.21; P<0.001). Falls, weakness, syncope, alopecia, low blood pressure, gastro-intestinal symptoms, and muscle loss were significantly enriched in the excessive weight loss cohort after false-discovery-rate correction (all q<0.001). Hospitalization was documented in 215 patients (25.7%) with excessive weight loss versus 527 patients (15.7%) with moderate weight loss (RR: 1.63, 1.42-1.87), Intensive care admission in 44 patients (5.3%) versus 77 patients (2.3%) (RR: 2.29, 1.59-3.28) (both q<0.001), and newly recorded heart-failure diagnosis in 11 patients (1.3%) versus 16 patients (0.5%) (RR: 2.75, 1.28-5.91; q=0.028). Laboratory tests and vital measurements recorded within 30 days of the lowest achieved body weight corroborated these findings, including significant enrichments in systolic (<90 mmHg) or diastolic (<60 mmHg) hypotension (RR: 3.19, 95% CI 2.51-4.05), anemia (RR: 1.86, 1.45-2.40), hyponatremia (RR: 2.74, 1.63-4.60), hypokalemia (RR: 2.34, 1.58-3.46), hypocalcemia (RR: 3.25, 1.87-5.68), hypoalbuminemia (RR: 2.93, 1.83-4.70), and hypoproteinemia (RR: 3.89, 2.32-6.52) in excessive weight loss patients (all q<0.001). While residual confounding and documentation differences may contribute to some real-world associations, the significantly greater burden of adverse events, hospitalization rates, laboratory test anomalies, and vital-sign abnormalities among Zepbound patients with excessive weight loss warrants further investigation. These findings support moving towards individualized weight-loss goals, motivate the need for prospective studies into the risk-benefit profile of Zepbound, and call for closer scrutiny of pharmaceutical marketing to clarify that the greatest weight reduction may not translate into better health outcomes.