Analysis of 670,422 patients revealed tirzepatide caused progressively greater lean body mass loss than semaglutide, with excess muscle loss reaching 2% at 12 months. The "Depletive" phenotype—losing over 20% total weight with more than 5% muscle loss—occurred in 10.3% of tirzepatide users versus 6.7% on semaglutide. Patients with baseline musculoskeletal pain showed dramatically higher muscle loss, particularly on tirzepatide, with cervicalgia patients losing 14.3 percentage points more lean mass. This finding challenges the assumption that greater weight loss always equals better outcomes. The muscle-wasting disparity may stem from tirzepatide's dual mechanism targeting both GLP-1 and GIP receptors, as single-cell analysis revealed GIP receptors are more widely distributed across muscle tissue compartments than GLP-1 receptors. For the millions using these medications, this suggests tirzepatide users may need more aggressive resistance training and protein supplementation to preserve muscle mass. However, this preprint awaits peer review, and the observational design cannot establish definitive causation. The muscle preservation advantage of semaglutide could influence treatment selection, particularly for older adults where sarcopenia poses significant health risks.