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

Cardiovascular diseases (CVDs) remain the leading cause of death worldwide and their prevalence continues to rise. Between 1990 and 2019, the number of individuals living with CVD nearly doubled, and current projections anticipate a dramatic escalation in cases and deaths by 2050 [1, 2]. These trends are largely driven by the global increase in metabolic risk factors, particularly type 2 diabetes mellitus (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD) [3, 4].

T2D represents a major global health challenge, affecting hundreds of millions of people and ranking among the leading causes of premature mortality. Its systemic impact includes microvascular and macrovascular complications, chronic kidney disease, and cancer, but cardiovascular disease remains the principal cause of death in affected individuals [5, 6]. The underlying mechanisms include endothelial dysfunction, persistent inflammation, and accelerated atherosclerosis, which together markedly increase the burden of coronary artery disease, heart failure, and arrhythmias [7, 8, 9, 10]. In parallel, MASLD, formerly termed non-alcoholic fatty liver disease, has emerged as the most common chronic liver condition, affecting nearly 40% of the global adult population [11, 12]. Beyond hepatic outcomes such as cirrhosis and hepatocellular carcinoma, CVD is the leading cause of mortality in these patients [13, 14]. Shared pathophysiological features, including insulin resistance, visceral adiposity, and systemic inflammatory activity, underscore the tight interdependence between MASLD, T2D, and cardiovascular dysfunction [15, 16, 17]. The coexistence of T2D and MASLD therefore delineates a cardiovascular high-risk phenotype, where overlapping metabolic insults synergistically accelerate vascular injury, oxidative stress, and cardiac remodelling [18, 19, 20].

The coexistence of T2D and MASLD defines a cardiovascular high-risk phenotype because both conditions share and amplify pathophysiological mechanisms such as insulin resistance, visceral adiposity, chronic inflammation, and oxidative stress [13, 14, 20]. These synergistic processes are associated with accelerated endothelial dysfunction, atherosclerosis, and cardiac remodelling, leading to an excess burden of cardiovascular morbidity and mortality beyond the contribution of each disease alone.

While MASLD and T2D substantially increase cardiovascular morbidity and mortality, growing evidence indicates that cardiovascular disease itself may also accelerate the onset and progression of MASLD. Chronic heart failure and ischemic heart disease are frequently accompanied by hepatic congestion, impaired microcirculation, and systemic inflammation, which can worsen insulin resistance and promote steatosis and fibrosis [18, 21]. Experimental and clinical data suggest that myocardial dysfunction induces neurohormonal activation and altered lipid metabolism, thereby exacerbating hepatic injury [19]. Furthermore, persistent systemic hypoperfusion and increased venous pressures in advanced CVD create a milieu that fosters hepatic inflammation and fibrogenesis [20]. This bidirectional relationship highlights the need for integrated management strategies that recognize not only the hepatic contribution to cardiovascular risk but also the detrimental effect of CVD on liver health.

MASLD is the most common chronic liver disease worldwide, and insulin resistance (IR) is widely recognized as a central driver of its pathogenesis [22]. IR promotes hepatic steatosis, systemic inflammation, and vascular injury, which together accelerate both liver damage and cardiovascular disease [23, 24]. Mechanistically, IR increases free fatty acid (FFA) flux to the liver through enhanced lipolysis and de novo lipogenesis [24, 25], while impairing mitochondrial β-oxidation. This leads to toxic lipid accumulation and excessive reactive oxygen species (ROS) formation, fuelling hepatocellular inflammation and fibrosis [24]. In parallel, reduced apolipoprotein B-100 synthesis impairs very-low-density lipoprotein assembly, further favoring triglyceride retention.

From a clinical perspective, these mechanisms may help explain why patients with diabetes and MASLD often present with vascular injury and myocardial dysfunction earlier than expected for their age. Visceral adipose tissue worsens this scenario by releasing pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), along with molecules like plasminogen activator inhibitor-1 (PAI-1) and angiotensinogen, which contribute to endothelial dysfunction and vascular remodelling [26, 27]. The imbalance of adipokines adds another layer: reduced adiponectin promotes steatosis and vascular inflammation [28, 29], while elevated leptin drives hepatic fibrogenesis and vascular hypertrophy [30, 31, 32]. These maladaptive pathways illustrate how adipose dysfunction, beyond simple fat storage, becomes a mechanistic bridge linking IR, MASLD, and CVD [33, 34].

Mitochondrial dysfunction is another crucial contributor. Impaired β-oxidation and ROS accumulation sustain a state of "metaflammation" [35, 36, 37], a chronic low-grade inflammation typical of nutrient excess. Clinically, this translates into a higher incidence of endothelial dysfunction, myocardial fibrosis, and plaque instability among patients with MASLD [38, 39].

Inflammation represents a second cornerstone of the MASLD-CVD connection. Pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and c-Jun N-terminal kinase (JNK), activated by cytokines, toll-like receptors, and receptors for advanced glycation end-products, directly link obesity-related inflammation to both liver fibrosis and cardiovascular injury [40, 41]. FFAs amplify these signals by triggering endoplasmic reticulum (ER) stress and ROS production [14, 42, 43], perpetuating a cycle of hepatocellular damage.

In hepatocytes, ER stress activates NADPH oxidase (NOX) isoforms, stimulating hepatic stellate cells through TGF-β signalling and promoting fibrosis [44]. Kupffer cell activation, cytokine release (IL-6, TNF-α, interleukin-1 (IL-1)), and feedback loops with insulin signalling [45, 46, 47, 48] aggravate this process. On the cardiovascular side, similar inflammatory cascades foster endothelial dysfunction, macrophage infiltration, and plaque development [14, 38, 49].

Clinically, this systemic "spillover" is evident: MASLD patients frequently present with subclinical myocardial inflammation and fibrosis, even in the absence of overt coronary disease [50, 51, 52, 53]. This observation supports the concept of liver-heart cross-talk, whereby hepatic inflammation and fibrosis contribute to heart failure with preserved ejection fraction and arrhythmias.

Atherogenic dyslipidaemia, characterized by high triglycerides, low high-density lipoprotein cholesterol (HDL-C), and small dense low-density lipoprotein (LDL), is a hallmark of T2D and MASLD [15]. The accumulation of toxic intermediates such as diacylglycerols and ceramides further impairs insulin signalling, worsening IR [54, 55]. Mitochondrial dysfunction and oxidative stress contribute to hepatocyte apoptosis and vascular injury [15, 35, 54, 55]. In practice, this translates into patients with MASLD exhibiting not only fatty liver but also heightened thrombotic risk. Elevated fibrinogen, PAI-1, and factor VII levels establish a hypercoagulable state, predisposing to acute cardiovascular events [56, 57]. Epidemiological data suggest MASLD as an independent predictor of cardiovascular morbidity and mortality, beyond traditional risk factors [58].

Emerging research highlights the gut microbiome as a key player in metabolic disorders including obesity, diabetes, MASLD, and CVD [59]. Gut microbial composition undergoes significant alterations in metabolic disease states. In obese and diabetic individuals, dysbiosis is characterized by reduced levels of beneficial bacteria (e.g., Akkermansia, Faecalibacterium) and an increase in pathogenic taxa [60].

Sex differences and genetic predisposition play a pivotal role in modulating the onset and progression of MASLD and cardiovascular disease in diabetes [75, 76]. Estrogens exert protective metabolic effects through multiple mechanisms, including improvements in insulin sensitivity, stimulation of glucose uptake in peripheral tissues, and favorable modulation of lipid metabolism with increased high-density lipoprotein (HDL) and reduced LDL cholesterol levels [77]. These actions contribute to the lower prevalence and slower progression of MASLD observed in premenopausal women [78]. Estrogens also attenuate systemic inflammation and oxidative stress, pathways central to both hepatic steatosis and atherosclerotic disease [79]. In contrast, following menopause, the decline in circulating estrogens leads to increased visceral adiposity, impaired lipid handling, and higher inflammation, thereby accelerating the risk of advanced liver disease and cardiovascular complications [80].

In men, androgens may exert divergent effects depending on concentration and context. While physiological androgen levels are associated with improved lean body mass and metabolic efficiency, hypogonadism is frequently observed in men with diabetes and MASLD and is linked to greater visceral adiposity, insulin resistance, and CVD risk [81, 82, 83].

Beyond this hormonal influence, genetic variants such as PNPLA3 and TM6SF2, critically shape disease expression. The PNPLA3 I148M polymorphism, strongly associated with hepatic steatosis and fibrosis, also alters systemic lipid partitioning, leading to reduced hepatic very-low-density lipoprotein (VLDL) secretion and increased intrahepatic triglyceride accumulation [84, 85]. Similarly, TM6SF2 E167K variants impair hepatic lipid export, favoring steatosis but paradoxically reducing circulating LDL cholesterol. However, the net effect appears to increase susceptibility to hepatic fibrosis while not fully mitigating cardiovascular risk [84, 85]. Personalized approaches that account for these variables may help refine risk stratification and therapeutic targeting.

The recent conceptualization of the cardiovascular-kidney-metabolic (CKM) syndrome has reshaped our understanding of systemic metabolic injury, emphasizing that the heart, kidney, and metabolic organs, including the liver, function as an integrated network rather than isolated targets of disease [86]. The kidney plays a pivotal role in this continuum: chronic hyperglycaemia, insulin resistance, oxidative stress, and inflammation drive glomerular hyperfiltration, endothelial dysfunction, and albuminuria, which in turn amplify neurohormonal activation, vascular stiffness, and cardiac remodelling [87, 88]. Parallel mechanisms, such as activation of the renin-angiotensin-aldosterone system and alterations in sodium-glucose transport, further link renal dysfunction to adverse cardiovascular outcomes [89, 90]. Increasing evidence also points to a close bidirectional interaction between CKM dysfunction and MASLD [91]. Renal impairment is frequent in MASLD and independently predicts higher cardiovascular morbidity and mortality, while hepatic inflammation and altered lipid metabolism can accelerate renal microvascular injury [92]. Integrating MASLD within the CKM framework supports a unified view of multi-organ metabolic injury, where the liver acts as both a mediator and a marker of systemic cardiometabolic stress [93]. This perspective advocates for multidimensional screening, including assessment of liver stiffness, kidney function, and subclinical cardiac injury, and for the adoption of therapeutic strategies, such as sodium–glucose cotransporter-2 (SGLT2) inhibitors and GLP-1 receptor agonists, that confer simultaneous cardio-renal-hepatic protection [93, 94].

Cardiovascular disease remains the leading cause of death in individuals with T2D and is increasingly recognized as a major cause of morbidity and mortality among individuals with MASLD [95]. The overlap of these conditions amplifies the risk of coronary artery disease (CAD), heart failure (HF), and arrhythmias, beyond the contribution of classical risk factors such as hypertension, dyslipidaemia, and obesity. Patients often present with atypical or silent symptoms, which complicates timely diagnosis and risk prediction [96, 97]. CAD in diabetes frequently manifests as diffuse and severe coronary atherosclerosis. Due to autonomic neuropathy, typical anginal symptoms may be absent, increasing the likelihood of delayed diagnosis. As a result, diabetic patients carry a two- to fourfold higher risk of cardiovascular death compared with non-diabetic individuals [9, 98]. In MASLD, the prevalence of CAD is lower than in T2D but its severity may be accentuated by cirrhotic cardiomyopathy, where chronic inflammation and altered lipid handling impair cardiac performance [99, 100].

HF is another shared endpoint. In diabetes, persistent hyperglycaemia, oxidative stress, and neurohormonal activation drive myocardial fibrosis and vascular remodelling, leading to increased ventricular stiffness [101, 102]. In liver disease, cirrhotic cardiomyopathy reduces contractile reserve and blunts the haemodynamic response to stress, while a hyperdynamic circulation may conceal early manifestations [103].

Arrhythmias are also frequent. In diabetes, mechanisms include autonomic imbalance, structural remodelling, and electrolyte disturbances, particularly during decompensation or renal dysfunction [104]. In MASLD and cirrhosis, QT interval (QT) prolongation is common and linked to electrolyte shifts and impaired drug metabolism, while advanced disease predisposes to atrial fibrillation through chronic inflammation and high-output states [105].

The coexistence of MASLD and T2D is associated with a markedly worsened cardiovascular prognosis. Shared mechanisms, including systemic inflammation, insulin resistance, lipotoxicity, and oxidative stress, accelerate atherosclerosis and myocardial dysfunction [39, 120, 128]. Outcomes after acute cardiovascular events are also poorer in this population, with higher rates of hospitalization and mortality [19, 129].

Early identification of high-risk patients is essential. Combining liver fibrosis scores (e.g., FIB-4), imaging modalities (e.g., GLS, coronary calcium scoring), and biomarkers (e.g., hs-cTnI, natriuretic peptides) provides a multidimensional assessment [130]. Such integrated strategies may guide timely interventions, from lifestyle modification to the initiation of cardioprotective drugs [131, 132].

Ultimately, the dual burden of MASLD and T2D requires a multidisciplinary approach. Collaboration among hepatologists, cardiologists, and diabetologists is central to effective management and to reducing the risk of long-term complications [133, 134, 135].

Novel therapies are under investigation to target the overlapping inflammatory and fibrotic pathways of MASLD and CVD. Obeticholic acid, a FXR agonist, has improved histology in MASH and could help slow fibrosis [179]. Other anti-inflammatory and antifibrotic drugs are being developed and may become valuable for managing this dual burden [180].

Bariatric surgery is the most effective intervention for patients with severe obesity and metabolic complications. Procedures such as Roux-en-Y gastric bypass and sleeve gastrectomy produce long-term weight loss and robust improvements in insulin sensitivity [181, 182]. They can reverse hepatic steatosis and, in some cases, fibrosis, with additional benefits on cardiovascular outcomes [183, 184]. Beyond weight reduction, changes in gut hormones, bile acid signalling, and microbiota contribute to these effects. Surgery should be considered for selected patients with advanced disease who fail lifestyle and pharmacological therapy [148]. When considering metabolic/bariatric surgery in patients with T2D and MASLD, careful patient selection is essential. Current guidelines recommend surgery for individuals with a BMI ≥40 kg/m², or ≥35 kg/m² in the presence of obesity-related comorbidities such as uncontrolled T2D, advanced MASLD, or cardiovascular disease [185]. Optimal candidates are those who fail to achieve durable weight loss or metabolic control with lifestyle and pharmacological therapies, and who can adhere to long-term nutritional and medical follow-up. However, surgery is not without risk. Early postoperative complications include bleeding, anastomotic leak, and venous thromboembolism, while long-term issues may involve micronutrient deficiencies, hypoglycemia, dumping syndrome, and surgical revisions [186]. In addition, psychosocial assessment is recommended to evaluate readiness for surgery and ensure multidisciplinary support [187]. These considerations highlight the importance of balancing expected cardiometabolic and hepatic benefits against procedural risks, tailoring the approach to individual patient profiles.

All current and emerging interventions targeting MASLD and type 2 diabetes are summarized in Table 1 (Ref. [138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187]), while the most relevant clinical trials investigating SGLT2 inhibitors, GLP-1 receptor agonists, and tirzepatide in MASLD and CVD are summarized in Table 2 (Ref. [156, 157, 162, 163, 164, 167, 168, 169, 170]).

The rapid evolution of digital health technologies has significantly transformed the landscape of chronic disease management, including metabolic disorders such as type 2 diabetes and MASLD [188]. Telemedicine platforms facilitate remote consultations, enabling timely medical interventions and continuity of care, particularly for patients with limited access to healthcare facilities [189]. Digital tools such as continuous glucose monitoring systems and mobile health applications support real-time tracking of glycaemic control, dietary intake, and physical activity. Wearable devices further empower patients by providing actionable feedback and fostering greater adherence to lifestyle interventions [190, 191]. Moreover, the integration of artificial intelligence into digital health systems enhances personalized care through predictive analytics, enabling more accurate risk stratification and optimization of treatment strategies [192].

In individuals at high metabolic risk, early prevention is crucial to halt the progression toward T2D, MASLD, and CVD. Lifestyle changes remain the most effective first-line strategy. Smoking cessation markedly lowers cardiovascular risk and reduces all-cause mortality [193]. Limiting alcohol intake, increasing physical activity, and adopting a balanced dietary pattern such as the Mediterranean diet are also associated with improvements in glycaemic control, lipid profile, and systemic inflammation [194, 195, 196, 197].

Primary prevention aims to intervene before structural damage occurs [198]. Intensive dietary counseling shortly after a T2D diagnosis improves metabolic outcomes, while even modest weight reduction (≈5%) translates into lower blood pressure, improved lipid values, and better glucose control [199]. No single dietary approach is universally optimal, but low-carbohydrate and Mediterranean-style diets are among the most effective in reducing HbA1c and body weight [200, 201]. Structured exercise programs complement these effects, lowering HbA1c by about 0.6%, improving cardiovascular fitness, and enhancing psychological well-being [202, 203].

Lifestyle modification should therefore represent the foundation of early care [204]. Nevertheless, in patients with multiple risk factors or established end-organ involvement, pharmacological treatment needs to be introduced promptly to achieve comprehensive risk reduction [198].

Although the combined burden of T2D, MASLD, and CVD is increasingly recognized, several aspects remain poorly defined. The mechanistic pathways that link hepatic inflammation, metabolic dysregulation, and cardiovascular remodelling are still only partially understood [231, 232]. This is particularly evident in lean or normal-weight individuals with T2D and MASLD, in whom conventional risk factors do not fully explain disease progression [233, 234]. More translational studies are needed to clarify these interactions and to identify early drivers of risk.

The search for reliable biomarkers and non-invasive tools represents a priority. While genetic variants, circulating markers, and advanced imaging techniques have shown potential, their integration into routine practice requires broader validation across different populations and healthcare settings [235]. Precision medicine approaches, supported by large-scale "omics" studies, may allow a more individualized assessment of risk. At the same time, artificial intelligence and machine learning could facilitate the analysis of complex datasets that combine genetic, imaging, and clinical information [236]. However, these technologies must be rigorously tested in real-world scenarios before being adopted in clinical workflows.

Progress in this field is hindered by fragmented research. Large, multicenter, and interdisciplinary collaborations are needed to ensure reproducibility and generalizability [237]. The active involvement of hepatologists, endocrinologists, cardiologists, and data scientists will be essential to identify prognostic markers, refine integrated risk scores, and test innovative therapeutic strategies. Only through such coordinated efforts can we develop patient-centered models of care that address the full spectrum of cardiometabolic disease.