COPD is a chronic disease of the lungs, but heterogeneous with respect to clinical manifestations and disease progression. This has consequences for health risk assessment, stratification and management. Heterogeneity can be driven by pulmonary events but also by systemic consequences (e.g. cachexia and muscle weakness) and co-morbidity (e.g. osteoporosis, diabetes and cardiovascular disease). This paper shows how a metabolic perspective on COPD has contributed significantly to understanding clinical heterogeneity and the need for a paradigm shift from reactive medicine towards predictive, preventive, personalized and participatory medicine. These insights have also lead to a paradigm shift in nutritional therapy for COPD from initial ignorance or focusing on putative adverse effects of carbohydrate overload on the ventilatory system to beneficial effects of nutritional intervention on body composition and physical functioning as integral part of disease management. The wider implications beyond COPD as disease have been as clinical model for translational cachexia research.