Alfredo Caturano, Davide Nilo, Giovanni Di Lorenzo, Maria Rocco, Giuseppina Tagliaferri, Alessia Piacevole, Mariarosaria Donnarumma, Ilaria Iadicicco, Simona Maria Moretto, Carlo Acierno, Celestino Sardu, Vincenzo Russo, Marco Alfonso Perrone, Erica Vetrano, Raffaele Galiero, Raffaele Marfella, Leonilde Bonfrate, Luca Rinaldi, Caterina Conte, Ferdinando Carlo Sasso
The coexistence of type 2 diabetes (T2D), metabolic dysfunction-associated steatotic liver disease (MASLD), and cardiovascular disease (CVD) defines a clinical profile that is frequently observed in clinical practice. In addition to being highly prevalent, patients with this triad of diseases experience accelerated vascular aging and poor prognosis. Insulin resistance remains the common symptom; however, the systemic impact of this extends far beyond glucose handling, shaping inflammation, oxidative stress, and endothelial dysfunction. In this review, we highlight how these intertwined conditions challenge current diagnostic frameworks and therapeutic approaches. Moreover, we discuss under-recognized aspects, such as the contribution of gut-derived metabolites and adipose dysfunction, which often remain neglected in routine care despite strong mechanistic evidence. We also summarize the potential of noninvasive tools, biomarkers, and cardioprotective agents, such as sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and tirzepatide. While promising, these agents still face gaps in translation to everyday hepatology and cardiology clinics. Our message is that prevention and care should not be compartmentalized. Instead, an integrated, patient-centered approach, with early screening and multidisciplinary management, is needed to address this complex interplay. Moreover, recognizing the shared pathways of T2D, MASLD, and CVD may help clinicians anticipate potential complications and design more effective and sustainable strategies for long-term outcomes.