Cardiovascular Health in the Shadow of Diabetes and Metabolic Dysfunction-Associated Steatotic Liver Disease: An Emerging Paradigm

Abstract

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.

Keywords: cardiovascular disease; insulin resistance; metabolic dysfunction-associated steatotic liver disease; oxidative stress cardiometabolic risk; type 2 diabetes mellitus.

Fig. 1.

Pathophysiological mechanisms linking insulin resistance and obesity to liver injury in MASLD. Insulin resistance increases glycolysis and hepatic lipogenesis while reducing apolipoprotein B (ApoB) synthesis and peripheral lipolysis, leading to excess reactive oxygen species (ROS), lipid peroxidation, and hepatic insulin resistance (IR). Obesity further contributes through free fatty acid (FFA)-induced activation of toll-like receptors (TLRs) and receptors for advanced glycation end-products (RAGEs), alterations in the glycerol-3-phosphate pathway, and gut microbiome dysbiosis with elevated bile acids, ethanol, endotoxins, short-chain fatty acids (SCFAs), and trimethylamine-N-oxide (TMAO). These mechanisms converge via oxidative and endoplasmic reticulum (ER) stress, activating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-$\kappa$B) and c-Jun N-terminal kinase (JNK) pathways, which drive hepatocellular apoptosis, hepatic stellate cell (HSC) activation, Kupffer cell activation, reduced cholesterol 7 alpha-hydroxylase (CYP7A1), and progression from hepatic lipid accumulation to chronic inflammation and fibrosis. AT, Antithrombin; MASLD, metabolic dysfunction-associated steatotic liver disease; PAI-1, plasminogen activator inhibitor-1; FGF15, fibroblast growth factor 15; IRS-1, insulin receptor substrate 1; IL-6, Interleukin-6. $\uparrow$ increased, $\downarrow$ decreased.

Fig. 2.

Gut-liver-heart axis in obesity, metabolic dysfunction-associated steatotic liver disease (MASLD), and type 2 diabetes mellitus (T2DM). Altered gut microbiome composition (increased Bacteroidetes, decreased Firmicutes) leads to higher levels of gut microbial metabolites in the bloodstream, including bile acids (deoxycholic acid [DCA]; lithocholic acid [LCA]), short-chain fatty acids (SCFAs), ethanol, endotoxins, and trimethylamine-N-oxide (TMAO). These changes promote glucagon-like peptide-1 (GLP-1) modulation, gut barrier dysfunction, hepatocellular damage, adipose tissue inflammation, hepatic insulin resistance (IR), impaired glucose tolerance (IGT), and cardiovascular injury. FXR, farnesoid X receptor; GPCRs, G protein-coupled receptors, $\uparrow$ increased, $\downarrow$ decreased.