Incident Frailty and Mortality Risk with Significant Tirzepatide-Associated Weight Loss in Medicare-Age Patients

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 <30 to >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.