Interplay between MASLD, obesity and type 2 diabetes: epidemiology, shared pathways and clinical implications

Metabolic dysfunction-associated steatotic liver disease (MASLD), obesity and type 2 diabetes mellitus (T2DM) are interconnected global epidemics that frequently coexist and mutually reinforce disease progression and adverse clinical outcomes. MASLD, the most prevalent chronic liver disease worldwide, is now recognised as a hepatic manifestation of systemic metabolic dysfunction. The coexistence of the triad markedly accelerates MASLD progression, heightens cardiometabolic risk and shifts mortality patterns towards cardiovascular disease, the leading cause of death in affected populations. However, most available data describe MASLD in association with either obesity or T2DM individually, while robust epidemiological or mechanistic evidence for their combined overlap remains scarce. This review synthesises current evidence on the epidemiological overlap and shared risk architecture linking MASLD, obesity and T2DM. We examine integrated pathophysiological and molecular mechanisms underpinning this triad, including insulin resistance, lipotoxicity, mitochondrial dysfunction, endoplasmic reticulum stress, transcriptional and epigenetic dysregulation and gut-liver axis perturbations. We further discuss the clinical implications of this shared biology, emphasising integrated screening strategies and presenting an evidence-based algorithm for non-invasive identification of advanced hepatic fibrosis within the triad. We review evidence-based therapeutic approaches, including mechanism-based pharmacological therapies, and highlight their differential effects on weight, glycaemic control and liver disease severity. Emerging research priorities and future directions for integrated cardiometabolic care are also outlined. Collectively, the review underscores the need for integrated hepatic-cardiometabolic care to improve clinical outcomes across this metabolic triad.