Muscle Health in the Era of Incretin-Based Weight Loss: Implications for Patients with Cardiovascular-Kidney-Metabolic Syndrome.

Abstract

Background Preserving lean body mass (LBM) is increasingly recognized as a critical determinant of survival and disease progression in individuals with cardiovascular-kidney-metabolic (CKM) syndrome. Sarcopenia is significantly associated with higher risk of all-cause, cardiovascular (CVD), and non-CVD mortality, as well as greater odds of advancing to later CKM stages. While incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual GLP-1/gastric inhibitory polypeptide (GIP) receptor agonists, are now cornerstones of CKM management, emerging evidence suggests a potential association with loss of LBM and skeletal muscle in vulnerable patients. The key gap in knowledge is that most trials and real-world evaluations prioritize weight and cardio-kidney-metabolic endpoints, while muscle mass, strength, functional trajectories, frailty progression, and patient-reported impacts are inconsistently measured, especially in high-risk CKM populations. This review synthesizes clinical trial and real-world evidence to characterize body composition changes with incretin-based therapies and proposes a conceptual, stepwise framework to maintain patient-centered muscle health. PubMed, Scopus, and Web of Science were searched for English-language peer-reviewed studies (January 2004-January 2026) evaluating incretin-based therapies and LBM outcomes; ClinicalTrials.gov and WHO ICTRP were also queried for trials with muscle-related endpoints. Summary Across incretin agents, weight loss is typically fat-predominant; however, available studies suggest approximately 25-39% of total weight loss may reflect LBM reduction over 36-72 weeks. Major evidence gaps include: (1) limited longitudinal data linking LBM loss to strength, mobility, frailty, falls, disability, and patient-reported function; (2) sparse head-to-head comparisons to clarify agent- and dose-specific muscle effects across the CKM continuum; (3) underrepresentation of high-risk CKM subgroups most vulnerable to protein-energy wasting, anabolic resistance, and polypharmacy; and (4) lack of scalable risk prediction and monitoring tools to detect early adverse body-composition trajectories. Key Messages Despite rapid expansion of incretin-based therapies across the CKM continuum, muscle health is rarely measured, yet it strongly shapes survival, frailty, and functional independence. Muscle preservation is a key consideration in benefit-risk assessment and merits explicit tracking in both clinical trials and routine practice. We outline a patient-centered, stepwise roadmap that pairs incretin prescribing with baseline muscle-risk characterization, serial tracking of body composition (e.g., DXA/BIA/BIS where feasible), simple functional measures, and early mitigation strategies (resistance training, nutrition optimization, and, when appropriate, adjunct anabolic/anti-catabolic approaches). Priorities to advance the field include pragmatic long-term studies in high-risk CKM populations and standardized capture of functional and patient-reported outcomes.