Cardiometabolic disease (CMD) is a leading cause of global morbidity and mortality. CMDs are characterized by a combination of (non-)modifiable risk factors, which pose significant challenges for their prevention, management, and treatment. A comprehensive understanding of the underlying disease mechanisms and common pathways involved in various CMDs is necessary to develop effective interventions that can address the multiple determinants and risk factors of CMDs at different levels. This review focuses on two prevalent CMDs, heart failure with preserved ejection fraction and atherosclerosis, and provides an overview of their pathophysiological mechanisms, diagnosis, and treatment strategies.