Background/Objectives: In obesity-associated type 2 diabetes (T2DM), therapeutic benefit increasingly requires assessment of not only HbA1c and total body weight, but also the composition and functional quality of weight change. We evaluated a myoprotective fat-loss phenotype, defined as a reduction in adiposity accompanied by preservation of lean mass and handgrip strength. Methods: This secondary patient-level analysis included 166 adults with T2DM who completed 12 months of follow-up without changing treatment in a real-world tertiary diabetes cohort. Patients received metformin alone or metformin combined with a sulfonylurea, a DPP-4 inhibitor, an SGLT2 inhibitor, a GLP-1 receptor agonist, or insulin. Body composition was assessed by bioimpedance and muscle function by handgrip dynamometry. The primary phenotype required a reduction in fat mass ≥5%, a loss of lean mass <3%, and a decrease in handgrip ≤1 kg. Phenotype distributions were compared between treatment groups; patient-level associations and adjusted contrasts were explored using correlation analyses and baseline-adjusted regression models with robust HC3 standard errors. Results: Fat-mass reduction ≥5% occurred in 58/166 patients (34.9%), lean-mass preservation in 129/166 (77.7%), and handgrip preservation in 143/166 (86.1%). The complete myoprotective phenotype was present in 35/166 patients (21.1%) and differed significantly across treatment groups (χ2 = 131.58; permutation p < 0.0001). It was most frequent in the GLP-1 receptor agonist group (13/23; 56.5%) and the SGLT2 inhibitor group (12/25; 48.0%), less frequent with metformin monotherapy (9/46; 19.6%) and DPP-4 inhibitors (1/17; 5.9%), and absent in the sulfonylurea and insulin groups. GLP-1 receptor agonists showed the greatest crude fat-mass loss, whereas lean-mass loss, skeletal-muscle-mass change, and handgrip change did not differ significantly across groups after false-discovery-rate correction. Conclusions: Myoprotective fat-loss phenotypes can be identified in obesity-associated T2DM using body composition and handgrip measures. These observational findings support the assessment of the quality, not just the magnitude, of weight loss in diabetes care and require validation in larger prospective studies.
