Introduction: Overweight and obesity are becoming increasingly prevalent. Incretin-based obesity treatments—glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual glucagon-like peptide-1 receptor/glucose-dependent insulinotropic polypeptide receptor agonists (GIP/GLP-1 RAs or dual agonists)—are a major stride in the evolution of obesity management. However, like weight loss with other means, they are associated with an inadvertent significant loss of lean body mass, including muscle. This has led to a resurgence in research for the preservation of lean body mass, the loss of which occurs with weight loss. The purpose of this narrative review is to discuss the mechanisms involved with lean body loss and capture the research landscape of the different classes of pharmacological agents being developed to address this problem. Methodology: We queried PubMed, Medline, and Scopus for randomized controlled trials and phase II or phase III trials using key words to capture the breath of this topic—obesity, weight loss, muscle loss, lean mass, and muscle preservation. Animal studies were excluded. We analyzed the studies conducted to date. Results: Weight loss, regardless of the method used to achieve it, is inadvertently accompanied by lean body mass loss, to varying degrees. There are several mechanisms that govern the loss of lean body mass and, more specifically, the loss of muscle mass; as such, several classes of medications have been explored, targeting different pathways and receptors—including bimagrumab (activin receptor agonist), tesamorelin (growth hormone releasing hormone agonists), and enobosarm (selective androgen receptor modulator). Most of these drugs are in the early phases of research development, but some show great promise. Conclusion: This narrative review attempts to detail the physiology of muscle mass loss when accompanied by weight loss and identify pharmacological targets that can be utilized to minimize it with mechanisms, effects, side effects, and research developmental progress.

Background: SGLT2 inhibitors (SGLT-2i) and GLP1 receptor agonists (GLP-1 RA) are recommended as the first line therapy for the management of type 2 diabetes mellitus (T2DM), particularly in patients with chronic kidney disease (CKD), cardiovascular disease (CVD), and heart failure (HF). Despite their established efficacy, there is limited evidence available to predict which subset of patients will respond favorably to them. We conducted this study to identify baseline characteristics to predict the response to therapy with SGLT-2i and GLP-1 RA. Methods: A retrospective analysis of the medical records was conducted at the Veteran Affairs Medical Center (VAMC) in Omaha, Nebraska, USA. Veterans who had completed 6–12 months of treatment with SGLT-2i or GLP-1 RA were included. Favorable treatment outcomes were a ≥0.5% reduction in glycosylated hemoglobin (HbA1c) or a ≥5% reduction in body weight; and those who achieved both outcomes were classified as adequate responders. Results: Patients in the GLP-1 RA group had 2.11 (95% CI: 1.45, 3.07) times the odds of achieving an adequate response as compared to patients in the SGLT-2i group in the unadjusted analysis, p < 0.001. HbA1c > 8% and older age was significantly associated with achieving an adequate response. Conclusions: Treatment with GLP-1 RA should be considered in Veterans with these characteristics.