Diabesity: an old term, a modern challenge - multi-omics and precision anti-obesity pharmacotherapy in type 2 diabetes.

Type 2 diabetes mellitus (T2DM) and obesity are closely interconnected but heterogeneous conditions in which treatment response, safety, body weight, glycemic control, and long-term clinical outcomes vary substantially between individuals. This narrative review evaluates emerging anti-obesity pharmacotherapy in patients with coexisting T2DM and obesity and examines the translational role of multi-omics in future precision treatment selection. Distinct from reviews focused primarily on obesity pharmacotherapy or omics-based disease stratification, the present review emphasizes the interface between contemporary drug mechanisms, T2DM-associated metabolic heterogeneity, candidate molecular signatures, and the level of evidence required for clinically actionable prescribing. We summarize evidence for approved and investigational oral incretin therapies, dual and triple receptor agonists, amylin-based strategies, established antidiabetic drugs, and adjunctive approaches targeting body composition. Throughout the review, we distinguish established clinical evidence from mechanistic rationale, candidate biomarkers, exploratory associations, and hypothetical future precision applications. We also separate metabolic efficacy endpoints, such as body weight and HbA1c, from intermediate cardiometabolic risk markers and from cardiovascular or kidney outcomes demonstrated in dedicated outcome trials. At present, no genomic, metabolomic, lipidomic, proteomic, microbiome, or integrated multi-omics signature has been clinically validated to select a specific anti-obesity medication for patients with T2DM and obesity. Major unresolved issues include the need for prospective biomarker validation, direct comparative trials, standardized assays, externally validated and calibrated prediction models, preservation of skeletal muscle health and physical function, long-term safety, treatment durability, affordability, and equitable implementation. Multi-omics should therefore be viewed as an investigational framework for generating and testing precision-treatment hypotheses rather than as a basis for routine prescribing.