Weight loss (WL) has an important role in managing obesity and type 2 diabetes, but preserving lean body mass (LBM) during WL is essential for maintaining muscle function and metabolic health. Significant WL with incretin mimetic-based therapies, similar to bariatric surgery, raises concerns regarding disproportionate LBM loss, which may lead to physical frailty. Recent analyses have suggested that high adherence to a ketogenic diet may mitigate LBM loss while improving physical function, even with substantial WL. However, more research is needed to understand the mechanisms behind LBM preservation in nutritional ketosis and the role of other lifestyle interventions. Future studies of pharmacological, surgical, and lifestyle-driven WL interventions should also assess LBM, physical function, and frailty. Research in this area is essential for developing strategies that optimize patient outcomes, especially for those who are considering their options for the treatment of obesity.