Effects of multicomponent exercise on frailty in older adults with type 2 diabetes: Differential responses by metabolic frailty phenotype

Background: Frailty in older adults with type 2 diabetes mellitus (T2DM) is metabolically heterogeneous, but whether multicomponent exercise (MCE) produces phenotype-specific functional benefit remains unclear. We asked two linked clinical questions: does a supervised 24-week MCE program improve physical function and frailty versus usual care, and are those effects modified by metabolic frailty phenotype (anorexic-malnourished [AM] phenotype vs sarcopenic-obese [SO] phenotype)? Methods: In this 24-week, phenotype-stratified, parallel-group randomized controlled trial, 146 community-dwelling adults aged ≥65 years with long-standing T2DM and frailty/pre-frailty who met predefined AM or SO criteria were randomized within phenotype to supervised MCE or usual care (AM-Control/MCE 31; SO-Control/MCE 42). Co-primary outcomes were Short Physical Performance Battery (SPPB) score and Fried frailty phenotype count. Key secondary outcomes were 4-m gait speed, five-chair-stand time, and grip strength. Covariate-adjusted generalized estimating equation models of change from baseline to 12 and 24 weeks included intervention, phenotype, visit, and all interactions, and adjusted for baseline outcome, age, sex, BMI, baseline HbA1c, metformin, SGLT2 inhibitor, GLP-1RA, insulin, diabetic retinopathy, diabetic peripheral neuropathy, chronic kidney disease stage ≥3, and hypertension. Benjamini-Hochberg false-discovery-rate correction was applied across functional outcome comparisons. Conclusions: A supervised 24-week MCE program improved physical function and frailty in older adults with T2DM and frailty/pre-frailty. Functional gains were larger in the SO than AM phenotype for several performance-based outcomes, suggesting phenotype-dependent responsiveness. Because this trial deliberately focused on two endpoint phenotypes and excluded intermediate presentations, the findings should be interpreted as clinically informative but not definitive for phenotype-guided care. Trial Registration: Registered prospectively in the Chinese Clinical Trial Registry (ChiCTR), a WHO ICTRP primary registry (registration no ChiCTR2400090109; http://www.chictr.org.cn/), on 24 September 2024, before enrollment.