The medical management of obesity has been transformed by the introduction of obesity medicines (OMs), based on the actions of glucagon-like peptide-1 and other nutrient-stimulated hormones, enabling the achievement of unprecedented weight reduction through pharmacotherapy. Here we review our current understanding of key issues surrounding obesity treatment, weight reduction, and improving health for people living with obesity. Key gaps in our knowledge of fundamental aspects of energy homeostasis are identified with a focus on their translational importance for improving outcomes. We discuss the utility of weight and health metrics, heterogeneity in achievement of clinical outcomes, individualization of treatment targets and goals, strengths and limitations of clinical trial, observational and real-world data (RWD), opportunities for improving the joint use of lifestyle management and OMs, gaps in our understanding of the long-term safety and side effects of current and emerging medicines, and the potential negative effects of losing weight. Collectively, while not intended as guidance for treatment, this document highlights the considerable progress and new research opportunities for interrogating basic and clinical science with the goal of translating advances in endocrine science into optimized outcomes for a broad range of individuals along the continuum of the weight journey.
