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.

Graphical abstract

Keywords

type 2 diabetes mellitus / metabolic dysfunction-associated steatotic liver disease / cardiovascular disease / insulin resistance / oxidative stress cardiometabolic risk

1. Introduction

1.1 Type 2 Diabetes and MASLD: A High-Risk Cardiovascular Phenotype

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].

1.2 T2D and MASLD as a Cardiovascular High-Risk Phenotype

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.

1.3 The Reverse Impact of Cardiovascular Disease on MASLD

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.

2. Pathophysiological Mechanisms Linking Diabetes, Liver Disease, and Cardiovascular Disease

2.1 Insulin Resistance and Metabolic Dysfunction

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 \beta-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-\alpha (TNF-\alpha) 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 \beta-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].

2.2 Chronic Inflammation and Fibrosis

Inflammation represents a second cornerstone of the MASLD-CVD connection. Pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-\kappaB) 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-\beta signalling and promoting fibrosis [44]. Kupffer cell activation, cytokine release (IL-6, TNF-\alpha, 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.

2.3 Dyslipidaemia and Lipotoxicity

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].

2.4 The Gut-Liver-Heart Axis

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].

2.4.1 Gut Microbiota Composition in Metabolic Disease

The gut microbiota exerts its influence on distant organs through the production and release of a wide array of metabolites that enter the systemic circulation [61]. These include short-chain fatty acids (SCFAs), bile acids, ammonia, phenols, ethanol, lipopolysaccharides (LPS), and trimethylamine (TMA), all of which can modulate key physiological and pathological pathways [61, 62]. SCFAs such as acetate, propionate, and butyrate are generated via microbial fermentation of dietary fibres, primarily by Bacteroidetes and certain members of Firmicutes. These SCFAs play an essential role in maintaining gut barrier integrity and host metabolic balance by stimulating glucagon-like peptide-1 (GLP-1) secretion, improving insulin sensitivity, and exerting anti-inflammatory effects on adipose tissue and the liver [61, 62, 63].

2.4.2 Bile Acids and Host Metabolism

Beyond SCFAs, bile acids constitute another major class of microbiota-derived metabolites with systemic effects. Secondary bile acids, including deoxycholic acid (DCA) and lithocholic acid (LCA), are formed in the colon through microbial transformation of primary bile acids. These bile acids act as ligands for nuclear receptors such as the farnesoid X receptor (FXR), pregnane X receptor (PXR), and G protein-coupled receptors (GPCRs). Activation of intestinal FXR, for instance, induces the expression of fibroblast growth factor 15 (FGF15 in mice, FGF19 in humans), which then signals to the liver to repress the rate-limiting enzyme cholesterol 7\alpha-hydroxylase (CYP7A1), thereby regulating bile acid synthesis and enterohepatic circulation [64]. Disruption of this signalling can contribute to hepatic lipid accumulation and insulin resistance, key features of MASLD.

2.4.3 Endogenous Ethanol and Endotoxemia

Ethanol, another important microbial metabolite, is produced through saccharolytic fermentation by certain gut bacteria, especially Proteobacteria and Enterobacteriaceae, which are found in elevated numbers in patients with obesity and non-alcoholic steatohepatitis (NASH) [65]. Endogenous ethanol production has been shown to disrupt intestinal epithelial tight junctions, increasing gut permeability and enabling the translocation of endotoxins such as LPS into the portal circulation [66]. This process activates inflammatory cascades in the liver, promoting hepatocellular injury, steatosis, and fibrosis [67]. The resulting low-grade endotoxemia contributes not only to liver disease but also to systemic inflammation, a key driver of atherosclerosis and CVD [68].

2.4.4 TMAO and Cardiometabolic Risk

One of the most compelling examples of gut-derived molecules linking the gut-liver-heart axis is trimethylamine N-oxide (TMAO) [69]. TMAO is produced from dietary choline and phosphatidylcholine via microbial metabolism to trimethylamine (TMA), which is subsequently oxidized in the liver by flavin-containing monooxygenases (primarily FMO3). Elevated plasma levels of TMAO have been associated with several adverse cardiometabolic outcomes, including subclinical myocardial damage, increased atherosclerotic burden, and elevated cardiovascular mortality [69, 70, 71]. Mechanistically, TMAO impairs reverse cholesterol transport, promotes foam cell formation, enhances platelet hyperreactivity, and induces vascular inflammation [72]. Additionally, TMAO exacerbates insulin resistance, promotes adipose tissue inflammation, and aggravates hepatic steatosis, thereby serving as a molecular bridge between gut dysbiosis, liver dysfunction, and cardiovascular pathology [73, 74]. Altogether, the gut-liver-heart axis underscores a complex and bidirectional interaction between gut microbial ecology and host metabolism, with gut-derived metabolites acting as key messengers in the pathogenesis of obesity-related liver disease and cardiovascular complications (Figs. 1,2). Targeting this axis, through modulation of microbiota composition, dietary interventions, or inhibition of specific microbial metabolic pathways, represents a promising avenue for therapeutic development in cardiometabolic diseases.

2.5 Sex Differences and Genetic Predisposition

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.

2.6 The Cardiovascular-Kidney-Metabolic Axis and Its Integration With MASLD

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].

3. Clinical Implications

3.1 Common Cardiovascular Manifestations

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].

3.2 Diagnostic Challenges

3.2.1 Cardiovascular Risk Scores

MASLD has emerged as an independent cardiovascular risk factor, and its coexistence with T2D defines a particularly high-risk phenotype [106]. For patients with diabetes, tools such as SCORE2-Diabetes provide more refined risk estimation by integrating traditional and diabetes-specific parameters [107]. By contrast, no validated cardiovascular risk score is currently available for MASLD alone [57]. Nonetheless, indices such as fibrosis-4 index (FIB-4) may offer indirect prognostic information, as advanced liver fibrosis correlates with systemic inflammation and a higher incidence of major adverse cardiovascular events (MACE) [57, 108].

3.2.2 Imaging

The increasing recognition of MASLD in diabetes underscores the need for early detection of subclinical cardiovascular dysfunction [109, 110]. Among available tools, speckle-tracking echocardiography and its parameter, global longitudinal strain (GLS), are particularly promising [111, 112]. GLS detects subtle myocardial impairment well before reductions in ejection fraction, and its prognostic value has been confirmed across several populations [113, 114, 115, 116]. This technique could therefore provide an accessible method for stratifying risk in patients with MASLD and/or T2D.

3.2.3 Biomarkers

High-sensitivity cardiac troponin I (hs-cTnI) is a robust biomarker with strong predictive value in diabetes and MASLD [117, 118, 119, 120]. Even within normal ranges, hs-cTnI identifies patients at increased risk of CAD, HF, and mortality, and its levels appear to decline in response to cardioprotective therapies [121]. The use of sex-specific thresholds may further refine prognostication.

3.2.4 Genetic Background

Variants such as PNPLA3 and TM6SF2 not only drive MASLD progression but also interact with systemic metabolic and inflammatory pathways [122, 123, 124]. Incorporating genetic risk into screening algorithms may, in the future, allow more personalized cardiovascular risk assessment [125, 126, 127].

3.2.5 Integration of Screening Tools in Clinical Practice

To enhance risk stratification in patients with T2D and MASLD, individual tools should not be considered in isolation but integrated into a structured diagnostic pathway. A practical approach begins with the SCORE2-Diabetes algorithm, which provides a standardized 10-year cardiovascular risk estimation tailored to patients with diabetes (SCORE2-Diabetes Working Group and the European Society of Cardiology [ESC] Cardiovascular Risk Collaboration). SCORE2-Diabetes: 10-year cardiovascular risk estimation in type 2 diabetes in Europe [107]. In parallel, the FIB-4 index can be calculated from routine laboratory data to estimate the likelihood of advanced liver fibrosis and to capture its systemic implications [108]. For patients identified as high risk by either cardiovascular or hepatic assessment, advanced imaging with GLS may detect subclinical myocardial dysfunction before overt heart failure develops [111]. In addition, circulating biomarkers such as hs-cTnI can provide incremental prognostic value, reflecting ongoing myocardial injury even in asymptomatic individuals [120].

By combining these tools into a stepwise algorithm, clinicians can move from broad population-based screening (SCORE2-Diabetes and FIB-4) to targeted advanced testing (GLS and hs-cTnI) in selected high-risk patients. This integrated strategy allows early identification of subclinical organ damage and supports the timely initiation of cardioprotective and hepatoprotective interventions.

3.3 Prognostic Implications

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].

4. Management Strategies

4.1 Lifestyle Interventions

4.1.1 Diet

Lifestyle modification is the foundation of care in both MASLD and T2D [136, 137]. Among dietary approaches, the Mediterranean diet stands out as the most effective in improving hepatic and cardiometabolic outcomes [138]. Its emphasis on plant-based foods, whole grains, and unsaturated fats supports better glycaemic control, reduced liver fat, and lower cardiovascular risk. Randomized trials confirm that adherence to this dietary pattern not only improves insulin sensitivity but also reduces hepatic steatosis, highlighting its central role in clinical practice [138, 139, 140].

4.1.2 Physical Activity

Regular physical activity is equally important. Aerobic training enhances mitochondrial function and promotes hepatic fat oxidation, while resistance training increases muscle glucose uptake and lean mass [141, 142, 143, 144]. Combining the two modalities maximizes metabolic benefits, with sustained exercise reducing cardiovascular events over time [145].

4.1.3 Weight Reduction

Weight loss is a major therapeutic target. Even modest reductions (5–10%) lead to consistent improvements in steatosis, while greater losses may reverse fibrosis [146, 147, 148]. Structured interventions integrating diet, exercise, and behavioural support are the most effective, though alternative approaches such as intermittent fasting and very-low-calorie diets are gaining interest [149, 150].

4.2 Pharmacological Interventions

4.2.1 Diabetes Drugs With Cardiovascular and Hepatic Benefits

4.2.1.1 SGLT2 Inhibitors

SGLT2 inhibitors have demonstrated robust cardiovascular protection in patients with T2D. In the EMPA-REG OUTCOME trial, empagliflozin significantly reduced cardiovascular mortality by 38%, hospitalization for heart failure by 35%, and all-cause mortality by 32% compared with placebo [151]. Similarly, the CANVAS program with canagliflozin reported a 14% relative risk reduction in major adverse cardiovascular events and a 33% reduction in hospitalization for heart failure [152]. These results have also been confirmed in both meta-analyses and real-world studies [153, 154, 155]. Beyond cardiovascular outcomes, the E-LIFT trial demonstrated that empagliflozin reduced liver fat content and improved aminotransferases in patients with T2D and MASLD [156]. Similar hepatic benefits were also observed with dapagliflozin in the EFFECT II randomized trial, which showed a significant reduction in liver fat content assessed by magnetic resonance imaging–proton density fat fraction (MRI-PDFF) and improvement in alanine aminotransferase levels after 12 weeks of treatment [157]. Nevertheless, these findings should be interpreted with caution. The available evidence is largely based on biochemical and imaging endpoints, while robust histological confirmation of fibrosis improvement with SGLT2 inhibitors is still lacking.

4.2.1.2 GLP-1 Receptor Agonists

GLP-1 receptor agonists have also proven effective in reducing cardiovascular risk [158]. The LEADER trial showed that liraglutide reduced the risk of major adverse cardiovascular events by 13% and cardiovascular death by 22% [159]. In SUSTAIN-6, semaglutide reduced MACE by 26% [160], while the REWIND trial with dulaglutide demonstrated a 12% reduction, even in a population with predominantly primary prevention [161]. In addition, the phase 2 LEAN trial showed that liraglutide promoted histological resolution of metabolic dysfunction-associated steatohepatitis (MASH) in patients with biopsy-proven disease [162]. While imaging studies and liver enzyme improvements are encouraging, histological evidence remains limited. The LEAN trial provided proof-of-concept for liraglutide [162], but large-scale outcome studies are needed before firm conclusions on fibrosis regression can be drawn. Consistent with these findings, exploratory analyses from the AWARD and REWIND programs showed that dulaglutide reduced liver fat content and aminotransferase levels, while confirming significant reductions in major adverse cardiovascular events in patients with type 2 diabetes [163]. Furthermore, in a phase 2 randomized trial, semaglutide demonstrated significant histological resolution of MASH without worsening of fibrosis, along with reductions in liver fat and aminotransferases [164].

In a global TriNetX analysis of nearly 19,000 semaglutide-treated MASLD patients reported improved one-year survival, lower cardiovascular risk, and reduced progression to advanced liver disease compared with matched controls, with benefits attributed to improvements in body mass index (BMI), lipid profile, glycated hemoglobin (HbA1c), and systemic inflammation [165]. A second TriNetX comparative study involving more than 640,000 patients with T2D and non-alcoholic fatty liver disease (NAFLD) showed that semaglutide was associated with a significantly lower risk of major adverse liver outcomes, including decompensated cirrhosis, hepatocellular carcinoma, and liver transplantation, compared with SGLT2 inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, and thiazolidinediones, and also conferred a survival advantage [166].

4.2.1.3 Tirzepatide

Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist, has shown remarkable efficacy in the SURPASS program. In SURPASS-2, tirzepatide achieved HbA1c reductions of up to –2.3% and weight loss exceeding 11 kg compared with semaglutide [167]. Pooled analyses suggest additional cardiovascular benefits through improvements in blood pressure, triglycerides, and inflammatory markers [168, 169]. The ongoing SURPASS-CVOT will provide definitive evidence regarding cardiovascular outcomes, and preliminary not peer reviewed results showed non-inferiority compared to dulaglutide [170]. Furthermore, in the SURMOUNT-1 trial, tirzepatide led to substantial weight loss (up to –21% of baseline body weight) and improvements in hepatic steatosis assessed by MRI-PDFF [171]. Although tirzepatide has shown striking metabolic and imaging-based hepatic benefits, histological data are still preliminary and experimental [172]. Results from phase 2 studies such as SYNERGY-NASH are promising but require confirmation in larger and longer-term trials [173, 174].

4.2.2 Lipid-Lowering Therapies

Statins remain first-line therapy for dyslipidaemia in patients with T2D and MASLD. Despite past concerns about hepatotoxicity, they are safe and reduce cardiovascular morbidity and mortality, with possible antifibrotic effects [175, 176]. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represent an additional option for high-risk patients, with strong low-density lipoprotein cholesterol (LDL-C) lowering efficacy and growing evidence of potential benefits on hepatic lipid injury [177, 178].

4.3 Anti-Inflammatory and Antifibrotic Agents

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].

4.4 Bariatric Surgery

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 \ge40 kg/m², or \ge35 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]).

4.5 Incorporating Telemedicine and Digital Health Tools

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].

5. Preventive Strategies

5.1 Primary Prevention

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 (\approx5%) 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].

Screening for MASLD and CVD

Given the strong interconnection between MASLD, T2D, and cardiovascular complications, systematic screening is essential. Patients with T2D should be regarded as at least at equivalent risk to those with established coronary disease. The SCORE2-Diabetes algorithm refines 10-year risk prediction by integrating traditional and diabetes-specific factors, including HbA1c and renal function [107].

In practice, CAD may be suspected even in the absence of chest pain, which is frequently absent in diabetes [98]. Dyspnoea on exertion is an important warning sign [205], particularly in the presence of multiple risk factors or abnormal electrocardiogram (ECG) findings. Stress testing in this setting can help identify patients who might benefit from revascularization [199]. For MASLD, ultrasound remains the first-line diagnostic tool owing to its accessibility and cost-effectiveness. Transient elastography (FibroScan®), particularly with the Controlled Attenuation Parameter (CAP), provides additional non-invasive information on liver stiffness and fat content [206]. Several biochemical scores, such as the Fatty Liver Index, Hepatic Steatosis Index, and NAFLD Liver Fat Score, are also useful for risk stratification and can be integrated into routine practice [207, 208].

Studies have demonstrated that participation in comprehensive cardiac rehabilitation is associated with lower rates of rehospitalization, improved cardiovascular risk factor control, and enhanced quality of life, underscoring the vital role of these programs in the continuum of care for individuals with cardiovascular disease (Table 3, Ref. [193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224]) [225, 226, 227].

5.2 Secondary and Tertiary Prevention

5.2.1 Comprehensive Care in Established Disease

For patients with diagnosed CVD, secondary and tertiary prevention strategies are essential to reduce recurrence and improve survival. This requires an integrated approach addressing all modifiable risk factors [225, 228].

•	• Lipid management. LDL-C lowering is central to prevention, with stringent targets (70 mg/dL in high-risk, 55 mg/dL in very-high-risk individuals) [209]. Statins remain first-line therapy; ezetimibe, PCSK9 inhibitors, and bempedoic acid can be added if targets are not achieved [209, 228, 229, 230].
•	• Blood pressure. In diabetes, levels 130/80 mmHg are recommended when tolerated. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) are preferred, particularly in proteinuric kidney disease [209].
•	• Glycaemic control. Most patients should aim for HbA1c 7%. For those with established CVD, agents with proven cardiovascular benefit, notably SGLT2 inhibitors and GLP-1 RAs, should be prioritized regardless of baseline glycaemia [209, 210, 211].
•	• Renal protection. Monitoring estimated glomerular filtration rate (eGFR) and albuminuria is mandatory. In addition to renin-angiotensin system (RAS) blockade, SGLT2 inhibitors and finerenone offer significant cardio-renal benefits [212, 213].
•	• Antiplatelet therapy. Low-dose aspirin remains standard for secondary prevention unless contraindicated. Dual antiplatelet therapy may be indicated after acute coronary syndrome or percutaneous coronary intervention (PCI), with duration tailored to ischemic and bleeding risks [214, 215].

5.2.2 Cardiac Rehabilitation and Lifestyle Clinics

Following a cardiovascular event, cardiac rehabilitation is a cornerstone of long-term care. Early mobilization during hospitalization shortens recovery and improves functional capacity. Subsequent structured programs combine aerobic and resistance training with education on medication adherence, nutrition, smoking cessation, and stress management [216, 217, 218, 219, 220, 221]. The benefits extend beyond physical recovery. Addressing psychological aspects, such as depression and anxiety, is critical to ensure adherence and quality of life [221]. Multidisciplinary follow-up with cardiologists, nurses, physiotherapists, dietitians, and psychologists helps maintain progress and prevent relapses. Telemedicine and digital health platforms can expand access, particularly in rural or resource-limited settings [222]. Participation in comprehensive rehabilitation has been consistently associated with reduced rehospitalizations, better risk factor control, and improved survival, underscoring its importance as part of secondary and tertiary prevention (Table 3) [223, 224].

6. Research Gaps and Future Directions

6.1 Unanswered Questions

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.

6.2 Emerging Trends

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.

6.3 Call for Collaboration

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.

7. Conclusions

The rising prevalence of T2D, MASLD, and CVD is not only a public health issue but also a daily clinical reality. Patients increasingly embody this “triad,” often presenting with overlapping risk factors and accelerated disease trajectories. While substantial progress has been made in understanding pathophysiology and testing new therapies, current practice still suffers from fragmented care.

Our perspective is that cardiologists, hepatologists, and diabetologists must move beyond traditional silos. A shared care model, built on integrated risk stratification and combined therapeutic strategies, is essential. At the same time, unanswered questions, ranging from the long-term impact of dual incretin therapies to the clinical implementation of AI-based prediction models, demand collaborative, multicenter research. Ultimately, a shift in mindset is required: these patients should not be viewed as having three separate diseases but rather as carrying a unified cardiometabolic risk that calls for unified solutions.

References

[1] Mensah GA, Roth GA, Fuster V. The Global Burden of Cardiovascular Diseases and Risk Factors: 2020 and Beyond. Journal of the American College of Cardiology. 2019; 74: 2529–2532. https://doi.org/10.1016/j.jacc.2019.10.009.

[2] Wu S, Xu W, Guan C, Lv M, Jiang S, Jinhua Z. Global burden of cardiovascular disease attributable to metabolic risk factors, 1990-2019: an analysis of observational data from a 2019 Global Burden of Disease study. BMJ Open. 2023; 13: e069397. https://doi.org/10.1136/bmjopen-2022-069397.

[3] Roth GA, Mensah GA, Johnson CO, Addolorato G, Ammirati E, Baddour LM, et al. Global Burden of Cardiovascular Diseases and Risk Factors, 1990-2019: Update From the GBD 2019 Study. Journal of the American College of Cardiology. 2020; 76: 2982–3021. https://doi.org/10.1016/j.jacc.2020.11.010.

[4] Chong B, Jayabaskaran J, Jauhari SM, Chan SP, Goh R, Kueh MTW, et al. Global burden of cardiovascular diseases: projections from 2025 to 2050. European Journal of Preventive Cardiology. 2025; 32: 1001–1015. https://doi.org/10.1093/eurjpc/zwae281.

[5] Rus M, Crisan S, Andronie-Cioara FL, Indries M, Marian P, Pobirci OL, et al. Prevalence and Risk Factors of Metabolic Syndrome: A Prospective Study on Cardiovascular Health. Medicina (Kaunas, Lithuania). 2023; 59: 1711. https://doi.org/10.3390/medicina59101711.

[6] Tune JD, Goodwill AG, Sassoon DJ, Mather KJ. Cardiovascular consequences of metabolic syndrome. Translational Research: the Journal of Laboratory and Clinical Medicine. 2017; 183: 57–70. https://doi.org/10.1016/j.trsl.2017.01.001.

[7] Lin X, Xu Y, Pan X, Xu J, Ding Y, Sun X, et al. Global, regional, and national burden and trend of diabetes in 195 countries and territories: an analysis from 1990 to 2025. Scientific Reports. 2020; 10: 14790. https://doi.org/10.1038/s41598-020-71908-9.

[8] Chen H, Chen G, Zheng X, Guo Y. Contribution of specific diseases and injuries to changes in health adjusted life expectancy in 187 countries from 1990 to 2013: retrospective observational study. BMJ (Clinical Research Ed.). 2019; 364: l969. https://doi.org/10.1136/bmj.l969.

[9] Dal Canto E, Ceriello A, Rydén L, Ferrini M, Hansen TB, Schnell O, et al. Diabetes as a cardiovascular risk factor: An overview of global trends of macro and micro vascular complications. European Journal of Preventive Cardiology. 2019; 26: 25–32. https://doi.org/10.1177/2047487319878371.

[10] GBD 2015 Risk Factors Collaborators. Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet (London, England). 2016; 388: 1659–1724. https://doi.org/10.1016/S0140-6736(16)31679-8.

[11] Bragg F, Holmes MV, Iona A, Guo Y, Du H, Chen Y, et al. Association Between Diabetes and Cause-Specific Mortality in Rural and Urban Areas of China. JAMA. 2017; 317: 280–289. https://doi.org/10.1001/jama.2016.19720.

[12] Policardo L, Seghieri G, Anichini R, De Bellis A, Franconi F, Francesconi P, et al. Effect of diabetes on hospitalization for ischemic stroke and related in-hospital mortality: a study in Tuscany, Italy, over years 2004-2011. Diabetes/metabolism Research and Reviews. 2015; 31: 280–286. https://doi.org/10.1002/dmrr.2607.

[13] Huang D, Refaat M, Mohammedi K, Jayyousi A, Al Suwaidi J, Abi Khalil C. Macrovascular Complications in Patients with Diabetes and Prediabetes. BioMed Research International. 2017; 2017: 7839101. https://doi.org/10.1155/2017/7839101.

[14] Caturano A, Rocco M, Tagliaferri G, Piacevole A, Nilo D, Di Lorenzo G, et al. Oxidative Stress and Cardiovascular Complications in Type 2 Diabetes: From Pathophysiology to Lifestyle Modifications. Antioxidants (Basel, Switzerland). 2025; 14: 72. https://doi.org/10.3390/antiox14010072.

[15] Shah MS, Brownlee M. Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes. Circulation Research. 2016; 118: 1808–1829. https://doi.org/10.1161/CIRCRESAHA.116.306923.

[16] Wang A, Green JB, Halperin JL, Piccini JP, Sr. Atrial Fibrillation and Diabetes Mellitus: JACC Review Topic of the Week. Journal of the American College of Cardiology. 2019; 74: 1107–1115. https://doi.org/10.1016/j.jacc.2019.07.020.

[17] Machado MV. MASLD treatment-a shift in the paradigm is imminent. Frontiers in Medicine. 2023; 10: 1316284. https://doi.org/10.3389/fmed.2023.1316284.

[18] Zhang H, Targher G, Byrne CD, Kim SU, Wong VWS, Valenti L, et al. A global survey on the use of the international classification of diseases codes for metabolic dysfunction-associated fatty liver disease. Hepatology International. 2024; 18: 1178–1201. https://doi.org/10.1007/s12072-024-10702-5.

[19] Riley DR, Hydes T, Hernadez G, Zhao SS, Alam U, Cuthbertson DJ. The synergistic impact of type 2 diabetes and MASLD on cardiovascular, liver, diabetes-related and cancer outcomes. Liver International: Official Journal of the International Association for the Study of the Liver. 2024; 44: 2538–2550. https://doi.org/10.1111/liv.16016.

[20] Chan WK, Chuah KH, Rajaram RB, Lim LL, Ratnasingam J, Vethakkan SR. Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A State-of-the-Art Review. Journal of Obesity & Metabolic Syndrome. 2023; 32: 197–213. https://doi.org/10.7570/jomes23052.

[21] Xie W, Gan J, Zhou X, Tian H, Pan X, Liu W, et al. Myocardial infarction accelerates the progression of MASH by triggering immunoinflammatory response and induction of periosti. Cell Metabolism. 2024; 36: 1269–1286.e9. https://doi.org/10.1016/j.cmet.2024.04.020.

[22] Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, Abdelmalek MF, Caldwell S, Barb D, et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology (Baltimore, Md.). 2023; 77: 1797–1835. https://doi.org/10.1097/HEP.0000000000000323.

[23] Lee KC, Wu PS, Lin HC. Pathogenesis and treatment of non-alcoholic steatohepatitis and its fibrosis. Clinical and Molecular Hepatology. 2023; 29: 77–98. https://doi.org/10.3350/cmh.2022.0237.

[24] Cataldo I, Sarcognato S, Sacchi D, Cacciatore M, Baciorri F, Mangia A, et al. Pathology of non-alcoholic fatty liver disease. Pathologica. 2021; 113: 194–202. https://doi.org/10.32074/1591-951X-242.

[25] Magkos F, Fabbrini E, Conte C, Patterson BW, Klein S. Relationship between adipose tissue lipolytic activity and skeletal muscle insulin resistance in nondiabetic women. The Journal of Clinical Endocrinology and Metabolism. 2012; 97: E1219–23. https://doi.org/10.1210/jc.2012-1035.

[26] Konior A, Schramm A, Czesnikiewicz-Guzik M, Guzik TJ. NADPH oxidases in vascular pathology. Antioxidants & Redox Signaling. 2014; 20: 2794–2814. https://doi.org/10.1089/ars.2013.5607.

[27] Russo V, Papa AA, Williams EA, Rago A, Palladino A, Politano L, et al. ACE inhibition to slow progression of myocardial fibrosis in muscular dystrophies. Trends in Cardiovascular Medicine. 2018; 28: 330–337. https://doi.org/10.1016/j.tcm.2017.12.006.

[28] Nguyen TMD. Adiponectin: Role in Physiology and Pathophysiology. International Journal of Preventive Medicine. 2020; 11: 136. https://doi.org/10.4103/ijpvm.IJPVM_193_20.

[29] Choi HM, Doss HM, Kim KS. Multifaceted Physiological Roles of Adiponectin in Inflammation and Diseases. International Journal of Molecular Sciences. 2020; 21: 1219. https://doi.org/10.3390/ijms21041219.

[30] Obradovic M, Sudar-Milovanovic E, Soskic S, Essack M, Arya S, Stewart AJ, et al. Leptin and Obesity: Role and Clinical Implication. Frontiers in Endocrinology. 2021; 12: 585887. https://doi.org/10.3389/fendo.2021.585887.

[31] Skoracka K, Hryhorowicz S, Schulz P, Zawada A, Ratajczak-Pawłowska AE, Rychter AM, et al. The role of leptin and ghrelin in the regulation of appetite in obesity. Peptides. 2025; 186: 171367. https://doi.org/10.1016/j.peptides.2025.171367.

[32] Karmazyn M, Gan XT. Molecular and Cellular Mechanisms Underlying the Cardiac Hypertrophic and Pro-Remodelling Effects of Leptin. International Journal of Molecular Sciences. 2024; 25: 1137. https://doi.org/10.3390/ijms25021137.

[33] Clemente-Suárez VJ, Redondo-Flórez L, Beltrán-Velasco AI, Martín-Rodríguez A, Martínez-Guardado I, Navarro-Jiménez E, et al. The Role of Adipokines in Health and Disease. Biomedicines. 2023; 11: 1290. https://doi.org/10.3390/biomedicines11051290.

[34] Burtenshaw D, Hakimjavadi R, Redmond EM, Cahill PA. Nox, Reactive Oxygen Species and Regulation of Vascular Cell Fate. Antioxidants (Basel, Switzerland). 2017; 6: 90. https://doi.org/10.3390/antiox6040090.

[35] LeFort KR, Rungratanawanich W, Song BJ. Contributing roles of mitochondrial dysfunction and hepatocyte apoptosis in liver diseases through oxidative stress, post-translational modifications, inflammation, and intestinal barrier dysfunction. Cellular and Molecular Life Sciences: CMLS. 2024; 81: 34. https://doi.org/10.1007/s00018-023-05061-7.

[36] Caso VM, Manzo V, Pecchillo Cimmino T, Conti V, Caso P, Esposito G, et al. Regulation of Inflammation and Oxidative Stress by Formyl Peptide Receptors in Cardiovascular Disease Progression. Life (Basel, Switzerland). 2021; 11: 243. https://doi.org/10.3390/life11030243.

[37] Perrone MA, Aimo A, Bernardini S, Clerico A. Inflammageing and Cardiovascular System: Focus on Cardiokines and Cardiac-Specific Biomarkers. International Journal of Molecular Sciences. 2023; 24: 844. https://doi.org/10.3390/ijms24010844.

[38] Theofilis P, Sagris M, Oikonomou E, Antonopoulos AS, Siasos G, Tsioufis C, et al. Inflammatory Mechanisms Contributing to Endothelial Dysfunction. Biomedicines. 2021; 9: 781. https://doi.org/10.3390/biomedicines9070781.

[39] Alfaddagh A, Martin SS, Leucker TM, Michos ED, Blaha MJ, Lowenstein CJ, et al. Inflammation and cardiovascular disease: From mechanisms to therapeutics. American Journal of Preventive Cardiology. 2020; 4: 100130. https://doi.org/10.1016/j.ajpc.2020.100130.

[40] Papa S, Bubici C, Zazzeroni F, Franzoso G. Mechanisms of liver disease: cross-talk between the NF-kappaB and JNK pathways. Biological Chemistry. 2009; 390: 965–976. https://doi.org/10.1515/BC.2009.111.

[41] Duncan BB, Schmidt MI, Pankow JS, Ballantyne CM, Couper D, Vigo A, et al. Low-grade systemic inflammation and the development of type 2 diabetes: the atherosclerosis risk in communities study. Diabetes. 2003; 52: 1799–1805. https://doi.org/10.2337/diabetes.52.7.1799.

[42] Bierhaus A, Humpert PM, Morcos M, Wendt T, Chavakis T, Arnold B, et al. Understanding RAGE, the receptor for advanced glycation end products. Journal of Molecular Medicine (Berlin, Germany). 2005; 83: 876–886. https://doi.org/10.1007/s00109-005-0688-7.

[43] Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and insulin resistance. Gastroenterology. 2007; 132: 2169–2180. https://doi.org/10.1053/j.gastro.2007.03.059.

[44] Zhou S, Cheng K, Peng Y, Liu Y, Hu Q, Zeng S, et al. Regulation mechanism of endoplasmic reticulum stress on metabolic enzymes in liver diseases. Pharmacological Research. 2024; 207: 107332. https://doi.org/10.1016/j.phrs.2024.107332.

[45] Ramos-Tovar E, Muriel P. Molecular Mechanisms That Link Oxidative Stress, Inflammation, and Fibrosis in the Liver. Antioxidants (Basel, Switzerland). 2020; 9: 1279. https://doi.org/10.3390/antiox9121279.

[46] Cai X, Wang J, Wang J, Zhou Q, Yang B, He Q, et al. Intercellular crosstalk of hepatic stellate cells in liver fibrosis: New insights into therapy. Pharmacological Research. 2020; 155: 104720. https://doi.org/10.1016/j.phrs.2020.104720.

[47] Kisseleva T, Brenner D. Molecular and cellular mechanisms of liver fibrosis and its regression. Nature Reviews. Gastroenterology & Hepatology. 2021; 18: 151–166. https://doi.org/10.1038/s41575-020-00372-7.

[48] Xu GX, Wei S, Yu C, Zhao SQ, Yang WJ, Feng YH, et al. Activation of Kupffer cells in NAFLD and NASH: mechanisms and therapeutic interventions. Frontiers in Cell and Developmental Biology. 2023; 11: 1199519. https://doi.org/10.3389/fcell.2023.1199519.

[49] Thomas TP, Grisanti LA. The Dynamic Interplay Between Cardiac Inflammation and Fibrosis. Frontiers in Physiology. 2020; 11: 529075. https://doi.org/10.3389/fphys.2020.529075.

[50] Tiegs G, Horst AK. TNF in the liver: targeting a central player in inflammation. Seminars in Immunopathology. 2022; 44: 445–459. https://doi.org/10.1007/s00281-022-00910-2.

[51] Matyas C, Haskó G, Liaudet L, Trojnar E, Pacher P. Interplay of cardiovascular mediators, oxidative stress and inflammation in liver disease and its complications. Nature Reviews. Cardiology. 2021; 18: 117–135. https://doi.org/10.1038/s41569-020-0433-5.

[52] Ma F, Huang X, Cai B. Linking MASLD to ACVD through Kupffer cells. Nature Cardiovascular Research. 2024; 3: 258–259. https://doi.org/10.1038/s44161-024-00442-y.

[53] Wang J, Li J, Buist-Homan M, Harmsen MC, Moshage H. Extracellular vesicle-dependent crosstalk between hepatic stellate cells and Kupffer cells promotes their mutual activation. Biochimica et Biophysica Acta. Molecular Basis of Disease. 2025; 1871: 167914. https://doi.org/10.1016/j.bbadis.2025.167914.

[54] Duran EK, Aday AW, Cook NR, Buring JE, Ridker PM, Pradhan AD. Triglyceride-Rich Lipoprotein Cholesterol, Small Dense LDL Cholesterol, and Incident Cardiovascular Disease. Journal of the American College of Cardiology. 2020; 75: 2122–2135. https://doi.org/10.1016/j.jacc.2020.02.059.

[55] Savage DB, Petersen KF, Shulman GI. Disordered lipid metabolism and the pathogenesis of insulin resistance. Physiological Reviews. 2007; 87: 507–520. https://doi.org/10.1152/physrev.00024.2006.

[56] Pezzino S, Luca T, Castorina M, Puleo S, Latteri S, Castorina S. Role of Perturbated Hemostasis in MASLD and Its Correlation with Adipokines. Life (Basel, Switzerland). 2024; 14: 93. https://doi.org/10.3390/life14010093.

[57] Zheng H, Sechi LA, Navarese EP, Casu G, Vidili G. Metabolic dysfunction-associated steatotic liver disease and cardiovascular risk: a comprehensive review. Cardiovascular Diabetology. 2024; 23: 346. https://doi.org/10.1186/s12933-024-02434-5.

[58] Targher G, Byrne CD, Tilg H. MASLD: a systemic metabolic disorder with cardiovascular and malignant complications. Gut. 2024; 73: 691–702. https://doi.org/10.1136/gutjnl-2023-330595.

[59] Wu J, Wang K, Wang X, Pang Y, Jiang C. The role of the gut microbiome and its metabolites in metabolic diseases. Protein & Cell. 2021; 12: 360–373. https://doi.org/10.1007/s13238-020-00814-7.

[60] Breton J, Galmiche M, Déchelotte P. Dysbiotic Gut Bacteria in Obesity: An Overview of the Metabolic Mechanisms and Therapeutic Perspectives of Next-Generation Probiotics. Microorganisms. 2022; 10: 452. https://doi.org/10.3390/microorganisms10020452.

[61] Schroeder BO, Bäckhed F. Signals from the gut microbiota to distant organs in physiology and disease. Nature Medicine. 2016; 22: 1079–1089. https://doi.org/10.1038/nm.4185.

[62] Collins SL, Stine JG, Bisanz JE, Okafor CD, Patterson AD. Bile acids and the gut microbiota: metabolic interactions and impacts on disease. Nature Reviews. Microbiology. 2023; 21: 236–247. https://doi.org/10.1038/s41579-022-00805-x.

[63] Fusco W, Lorenzo MB, Cintoni M, Porcari S, Rinninella E, Kaitsas F, et al. Short-Chain Fatty-Acid-Producing Bacteria: Key Components of the Human Gut Microbiota. Nutrients. 2023; 15: 2211. https://doi.org/10.3390/nu15092211.

[64] Poland JC, Flynn CR. Bile Acids, Their Receptors, and the Gut Microbiota. Physiology (Bethesda, Md.). 2021; 36: 235–245. https://doi.org/10.1152/physiol.00028.2020.

[65] Meijnikman AS, Nieuwdorp M, Schnabl B. Endogenous ethanol production in health and disease. Nature Reviews. Gastroenterology & Hepatology. 2024; 21: 556–571. https://doi.org/10.1038/s41575-024-00937-w.

[66] Elamin E, Masclee A, Dekker J, Jonkers D. Ethanol disrupts intestinal epithelial tight junction integrity through intracellular calcium-mediated Rho/ROCK activation. American Journal of Physiology. Gastrointestinal and Liver Physiology. 2014; 306: G677–85. https://doi.org/10.1152/ajpgi.00236.2013.

[67] Taru V, Szabo G, Mehal W, Reiberger T. Inflammasomes in chronic liver disease: Hepatic injury, fibrosis progression and systemic inflammation. Journal of Hepatology. 2024; 81: 895–910. https://doi.org/10.1016/j.jhep.2024.06.016.

[68] Violi F, Nocella C, Bartimoccia S, Castellani V, Carnevale R, Pignatelli P, et al. Gut dysbiosis-derived low-grade endotoxemia: A common basis for liver and cardiovascular disease. Kardiologia Polska. 2023; 81: 563–571. https://doi.org/10.33963/KP.a2023.0115.

[69] Senthong V, Li XS, Hudec T, Coughlin J, Wu Y, Levison B, et al. Plasma Trimethylamine N-Oxide, a Gut Microbe-Generated Phosphatidylcholine Metabolite, Is Associated With Atherosclerotic Burden. Journal of the American College of Cardiology. 2016; 67: 2620–2628. https://doi.org/10.1016/j.jacc.2016.03.546.

[70] Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011; 472: 57–63. https://doi.org/10.1038/nature09922.

[71] Gao X, Liu X, Xu J, Xue C, Xue Y, Wang Y. Dietary trimethylamine N-oxide exacerbates impaired glucose tolerance in mice fed a high fat diet. Journal of Bioscience and Bioengineering. 2014; 118: 476–481. https://doi.org/10.1016/j.jbiosc.2014.03.001.

[72] Oktaviono YH, Dyah Lamara A, Saputra PBT, Arnindita JN, Pasahari D, Saputra ME, et al. The roles of trimethylamine-N-oxide in atherosclerosis and its potential therapeutic aspect: A literature review. Biomolecules & Biomedicine. 2023; 23: 936–948. https://doi.org/10.17305/bb.2023.8893.

[73] Jaworska K, Kuś M, Ufnal M. TMAO and diabetes: from the gut feeling to the heart of the problem. Nutrition & Diabetes. 2025; 15: 21. https://doi.org/10.1038/s41387-025-00377-8.

[74] Kong L, Zhao Q, Jiang X, Hu J, Jiang Q, Sheng L, et al. Trimethylamine N-oxide impairs β-cell function and glucose tolerance. Nature Communications. 2024; 15: 2526. https://doi.org/10.1038/s41467-024-46829-0.

[75] Shufelt CL, Pacheco C, Tweet MS, Miller VM. Sex-Specific Physiology and Cardiovascular Disease. Advances in Experimental Medicine and Biology. 2018; 1065: 433–454. https://doi.org/10.1007/978-3-319-77932-4_27.

[76] Johnson ML, Preston JD, Rashid CS, Pearson KJ, Ham JN. Sex differences in type 2 diabetes: an opportunity for personalized medicine. Biology of Sex Differences. 2023; 14: 88. https://doi.org/10.1186/s13293-023-00571-2.

[77] Yan H, Yang W, Zhou F, Li X, Pan Q, Shen Z, et al. Estrogen Improves Insulin Sensitivity and Suppresses Gluconeogenesis via the Transcription Factor Foxo1. Diabetes. 2019; 68: 291–304. https://doi.org/10.2337/db18-0638.

[78] Lonardo A, Nascimbeni F, Ballestri S, Fairweather D, Win S, Than TA, et al. Sex Differences in Nonalcoholic Fatty Liver Disease: State of the Art and Identification of Research Gaps. Hepatology (Baltimore, Md.). 2019; 70: 1457–1469. https://doi.org/10.1002/hep.30626.

[79] Chen L, Xu T, Lou J, Zhang T, Wu S, Xie R, et al. The beneficial roles and mechanisms of estrogens in immune health and infection disease. Steroids. 2024; 207: 109426. https://doi.org/10.1016/j.steroids.2024.109426.

[80] Gulbahar A, Caglar GS, Arslanca T. Evaluation of visceral adiposity index with cardiovascular risk factors, biomarkers in postmenopausal women to predict cardiovascular disease: A 10 year study. Experimental Gerontology. 2022; 170: 111986. https://doi.org/10.1016/j.exger.2022.111986.

[81] Mouser JG, Loprinzi PD, Loenneke JP. The association between physiologic testosterone levels, lean mass, and fat mass in a nationally representative sample of men in the United States. Steroids. 2016; 115: 62–66. https://doi.org/10.1016/j.steroids.2016.08.009.

[82] Papadimitriou K, Mousiolis AC, Mintziori G, Tarenidou C, Polyzos SA, Goulis DG. Hypogonadism and nonalcoholic fatty liver disease. Endocrine. 2024; 86: 28–47. https://doi.org/10.1007/s12020-024-03878-1.

[83] Corona G, Mannucci E, Forti G, Maggi M. Hypogonadism, ED, metabolic syndrome and obesity: a pathological link supporting cardiovascular diseases. International Journal of Andrology. 2009; 32: 587–598. https://doi.org/10.1111/j.1365-2605.2008.00951.x.

[84] Seko Y, Yamaguchi K, Shima T, Iwaki M, Takahashi H, Kawanaka M, et al. Clinical Utility of Genetic Variants in PNPLA3 and TM6SF2 to Predict Liver-Related Events in Metabolic Dysfunction-Associated Steatotic Liver Disease. Liver International: Official Journal of the International Association for the Study of the Liver. 2025; 45: e16124. https://doi.org/10.1111/liv.16124.

[85] Simons N, Isaacs A, Koek GH, Kuč S, Schaper NC, Brouwers MCGJ. PNPLA3, TM6SF2, and MBOAT7 Genotypes and Coronary Artery Disease. Gastroenterology. 2017; 152: 912–913. https://doi.org/10.1053/j.gastro.2016.12.020.

[86] Zhou XD, Zheng MH. Cardiovascular-kidney-metabolic syndrome and MASLD: integrating medical perspectives. Nature Reviews. Cardiology. 2025; 22: 843. https://doi.org/10.1038/s41569-025-01199-y.

[87] Zoccali C, Agarwal R, Mallamaci F, Jager KJ, Stel V, Kanbay M, et al. Inter-organ crosstalk: The kidney’s role in systemic health and disease. Journal of Internal Medicine. 2025; 298: 368–391. https://doi.org/10.1111/joim.70015.

[88] Hartupee J, Mann DL. Neurohormonal activation in heart failure with reduced ejection fraction. Nature Reviews. Cardiology. 2017; 14: 30–38. https://doi.org/10.1038/nrcardio.2016.163.

[89] Ruan Y, Yu Y, Wu M, Jiang Y, Qiu Y, Ruan S. The renin-angiotensin-aldosterone system: An old tree sprouts new shoots. Cellular Signalling. 2024; 124: 111426. https://doi.org/10.1016/j.cellsig.2024.111426.

[90] Hsueh WA, Wyne K. Renin-Angiotensin-aldosterone system in diabetes and hypertension. Journal of Clinical Hypertension (Greenwich, Conn.). 2011; 13: 224–237. https://doi.org/10.1111/j.1751-7176.2011.00449.x.

[91] Yang T, Bu T, Yang B, Zhao Y, Wang Q. CKM: A new approach to managing metabolic comorbidities in MASLD? Journal of Hepatology. 2025; 82: e291–e292. https://doi.org/10.1016/j.jhep.2024.12.014.

[92] Bilson J, Mantovani A, Byrne CD, Targher G. Steatotic liver disease, MASLD and risk of chronic kidney disease. Diabetes & Metabolism. 2024; 50: 101506. https://doi.org/10.1016/j.diabet.2023.101506.

[93] Iacoviello M, Gori M, Grandaliano G, Minutolo R, Pitocco D, Trevisan R. A holistic approach to managing cardio-kidney metabolic syndrome: insights and recommendations from the Italian perspective. Frontiers in Cardiovascular Medicine. 2025; 12: 1583702. https://doi.org/10.3389/fcvm.2025.1583702.

[94] Theodorakis N, Nikolaou M. From Cardiovascular-Kidney-Metabolic Syndrome to Cardiovascular-Renal-Hepatic-Metabolic Syndrome: Proposing an Expanded Framework. Biomolecules. 2025; 15: 213. https://doi.org/10.3390/biom15020213.

[95] Puchner SB, Lu MT, Mayrhofer T, Liu T, Pursnani A, Ghoshhajra BB, et al. High-risk coronary plaque at coronary CT angiography is associated with nonalcoholic fatty liver disease, independent of coronary plaque and stenosis burden: results from the ROMICAT II trial. Radiology. 2015; 274: 693–701. https://doi.org/10.1148/radiol.14140933.

[96] Xanthopoulos A, Starling RC, Kitai T, Triposkiadis F. Heart Failure and Liver Disease: Cardiohepatic Interactions. JACC. Heart Failure. 2019; 7: 87–97. https://doi.org/10.1016/j.jchf.2018.10.007.

[97] Aronson D, Edelman ER. Coronary artery disease and diabetes mellitus. Cardiology Clinics. 2014; 32: 439–455. https://doi.org/10.1016/j.ccl.2014.04.001.

[98] Raghavan S, Vassy JL, Ho YL, Song RJ, Gagnon DR, Cho K, et al. Diabetes Mellitus-Related All-Cause and Cardiovascular Mortality in a National Cohort of Adults. Journal of the American Heart Association. 2019; 8: e011295. https://doi.org/10.1161/JAHA.118.011295.

[99] Ren Z, Simons PIHG, Wesselius A, Stehouwer CDA, Brouwers MCGJ. Relationship between NAFLD and coronary artery disease: A Mendelian randomization study. Hepatology (Baltimore, Md.). 2023; 77: 230–238. https://doi.org/10.1002/hep.32534.

[100] Gu C, Dong L, Chai L, Tong Z, Gao F, Ageno W, et al. Risk of Coronary Artery Disease in Patients with Liver Cirrhosis: A Systematic Review and Meta-analysis. Journal of Clinical and Translational Hepatology. 2025; 13: 93–104. https://doi.org/10.14218/JCTH.2024.00226.

[101] Jia G, Hill MA, Sowers JR. Diabetic Cardiomyopathy: An Update of Mechanisms Contributing to This Clinical Entity. Circulation Research. 2018; 122: 624–638. https://doi.org/10.1161/CIRCRESAHA.117.311586.

[102] Caturano A, Vetrano E, Galiero R, Salvatore T, Docimo G, Epifani R, et al. Cardiac Hypertrophy: From Pathophysiological Mechanisms to Heart Failure Development. Reviews in Cardiovascular Medicine. 2022; 23: 165. https://doi.org/10.31083/j.rcm2305165.

[103] Lyssy LA, Soos MP. Cirrhotic Cardiomyopathy. In: StatPearls [Internet]. StatPearls Publishing: Treasure Island (FL). 2025.

[104] Grisanti LA. Diabetes and Arrhythmias: Pathophysiology, Mechanisms and Therapeutic Outcomes. Frontiers in Physiology. 2018; 9: 1669. https://doi.org/10.3389/fphys.2018.01669.

[105] Lu X, Wang Z, Yang L, Yang C, Song M. Risk Factors of Atrial Arrhythmia in Patients With Liver Cirrhosis: A Retrospective Study. Frontiers in Cardiovascular Medicine. 2021; 8: 704073. https://doi.org/10.3389/fcvm.2021.704073.

[106] Caussy C, Aubin A, Loomba R. The Relationship Between Type 2 Diabetes, NAFLD, and Cardiovascular Risk. Current Diabetes Reports. 2021; 21: 15. https://doi.org/10.1007/s11892-021-01383-7.

[107] SCORE2-Diabetes Working Group and the ESC Cardiovascular Risk Collaboration. SCORE2-Diabetes: 10-year cardiovascular risk estimation in type 2 diabetes in Europe. European Heart Journal. 2023; 44: 2544–2556. https://doi.org/10.1093/eurheartj/ehad260.

[108] Anstee QM, Berentzen TL, Nitze LM, Jara M, Jensen AB, Kjær MS, et al. Prognostic utility of Fibrosis-4 Index for risk of subsequent liver and cardiovascular events, and all-cause mortality in individuals with obesity and/or type 2 diabetes: a longitudinal cohort study. The Lancet Regional Health. Europe. 2023; 36: 100780. https://doi.org/10.1016/j.lanepe.2023.100780.

[109] Dawod S, Brown K. Non-invasive testing in metabolic dysfunction-associated steatotic liver disease. Frontiers in Medicine. 2024; 11: 1499013. https://doi.org/10.3389/fmed.2024.1499013.

[110] Caturano A, Galiero R, Loffredo G, Vetrano E, Medicamento G, Acierno C, et al. Effects of a Combination of Empagliflozin Plus Metformin vs. Metformin Monotherapy on NAFLD Progression in Type 2 Diabetes: The IMAGIN Pilot Study. Biomedicines. 2023; 11: 322. https://doi.org/10.3390/biomedicines11020322.

[111] Collier P, Phelan D, Klein A. A Test in Context: Myocardial Strain Measured by Speckle-Tracking Echocardiography. Journal of the American College of Cardiology. 2017; 69: 1043–1056. https://doi.org/10.1016/j.jacc.2016.12.012.

[112] Russo V, Malvezzi Caracciolo D’Aquino M, Caturano A, Scognamiglio G, Pezzullo E, Fabiani D, et al. Improvement of Global Longitudinal Strain and Myocardial Work in Type 2 Diabetes Patients on Sodium-Glucose Cotransporter 2 Inhibitors Therapy. Journal of Cardiovascular Pharmacology. 2023; 82: 196–200. https://doi.org/10.1097/FJC.0000000000001450.

[113] Ferruzzi GJ, Campanile A, Visco V, Loria F, Mone P, Masarone D, et al. Subclinical left ventricular dysfunction assessed by global longitudinal strain correlates with mild cognitive impairment in hypertensive patients. Hypertension Research: Official Journal of the Japanese Society of Hypertension. 2025; 48: 1768–1778. https://doi.org/10.1038/s41440-025-02182-3.

[114] Fujikura K, Peltzer B, Tiwari N, Shim HG, Dinhofer AB, Shitole SG, et al. Reduced global longitudinal strain is associated with increased risk of cardiovascular events or death after kidney transplant. International Journal of Cardiology. 2018; 272: 323–328. https://doi.org/10.1016/j.ijcard.2018.07.088.

[115] Polomski EAS, Heemelaar JC, Krol ADG, Louwerens M, Beeres SLMA, Holman ER, et al. Impaired Global Longitudinal Strain Is Associated with Cardiovascular Events in Hodgkin Lymphoma Survivors. Cancers. 2022; 14: 2329. https://doi.org/10.3390/cancers14092329.

[116] Sonaglioni A, Cerini F, Fagiani V, Nicolosi GL, Rumi MG, Lombardo M, et al. Effect of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) on Left Ventricular Mechanics in Patients Without Overt Cardiac Disease: A Systematic Review and Meta-Analysis. Journal of Clinical Medicine. 2025; 14: 2690. https://doi.org/10.3390/jcm14082690.

[117] Lee DY. Emerging Circulating Biomarkers for Enhanced Cardiovascular Risk Prediction. Journal of Lipid and Atherosclerosis. 2024; 13: 262–279. https://doi.org/10.12997/jla.2024.13.3.262.

[118] Moore JS, Nesbit MA, Moore T. Appraisal of Cardiovascular Risk Factors, Biomarkers, and Ocular Imaging in Cardiovascular Risk Prediction. Current Cardiology Reviews. 2023; 19: 72–81. https://doi.org/10.2174/1573403X19666230727101926.

[119] Clerico A, Zaninotto M, Aimo A, Padoan A, Passino C, Fortunato A, et al. Advancements and challenges in high-sensitivity cardiac troponin assays: diagnostic, pathophysiological, and clinical perspectives. Clinical Chemistry and Laboratory Medicine. 2025; 63: 1260–1278. https://doi.org/10.1515/cclm-2024-1090.

[120] Clerico A, Zaninotto M, Aimo A, Cardinale DM, Dittadi R, Sandri MT, et al. Variability of cardiac troponin levels in normal subjects and in patients with cardiovascular diseases: analytical considerations and clinical relevance. Clinical Chemistry and Laboratory Medicine. 2023; 61: 1209–1229. https://doi.org/10.1515/cclm-2022-1285.

[121] Farmakis D, Richter D, Chronopoulou G, Goumas G, Kountouras D, Mastorakou A, et al. High-sensitivity cardiac troponin I for cardiovascular risk stratification in apparently healthy individuals. Hellenic Journal of Cardiology: HJC = Hellenike Kardiologike Epitheorese. 2024; 75: 74–81. https://doi.org/10.1016/j.hjc.2023.09.011.

[122] Verschuren L, Mak AL, van Koppen A, Özsezen S, Difrancesco S, Caspers MPM, et al. Development of a novel non-invasive biomarker panel for hepatic fibrosis in MASLD. Nature Communications. 2024; 15: 4564. https://doi.org/10.1038/s41467-024-48956-0.

[123] Samarasinghe SM, Hewage AS, Siriwardana RC, Tennekoon KH, Niriella MA, De Silva S, et al. Association between single nucleotide polymorphisms in PNPLA3, TM6SF2 and MBOAT7 genes and markers of cancer aggressiveness in a Sri Lankan NASH-related HCC cohort. BMC Gastroenterology. 2025; 25: 151. https://doi.org/10.1186/s12876-025-03738-w.

[124] Wu B, Lan X, Gao M, Wei W, Wang Y, Yang Y, et al. Elucidation of the molecular mechanism of type 2 diabetes mellitus affecting the progression of nonalcoholic steatohepatitis using bioinformatics and network pharmacology: A review. Medicine. 2024; 103: e39731. https://doi.org/10.1097/MD.0000000000039731.

[125] Weiskirchen S, Weiskirchen R. Unraveling the future: hot topics shaping molecular diagnostics today. Expert Review of Molecular Diagnostics. 2025; 25: 111–116. https://doi.org/10.1080/14737159.2025.2467969.

[126] Slunecka JL, van der Zee MD, Beck JJ, Johnson BN, Finnicum CT, Pool R, et al. Implementation and implications for polygenic risk scores in healthcare. Human Genomics. 2021; 15: 46. https://doi.org/10.1186/s40246-021-00339-y.

[127] Bustin SA, Jellinger KA. Advances in Molecular Medicine: Unravelling Disease Complexity and Pioneering Precision Healthcare. International Journal of Molecular Sciences. 2023; 24: 14168. https://doi.org/10.3390/ijms241814168.

[128] Zhou YY, Zhou XD, Wu SJ, Hu XQ, Tang B, Poucke SV, et al. Synergistic increase in cardiovascular risk in diabetes mellitus with nonalcoholic fatty liver disease: a meta-analysis. European Journal of Gastroenterology & Hepatology. 2018; 30: 631–636. https://doi.org/10.1097/MEG.0000000000001075.

[129] Babes EE, Bustea C, Behl T, Abdel-Daim MM, Nechifor AC, Stoicescu M, et al. Acute coronary syndromes in diabetic patients, outcome, revascularization, and antithrombotic therapy. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie. 2022; 148: 112772. https://doi.org/10.1016/j.biopha.2022.112772.

[130] Clayton-Chubb D, Roberts SK, Majeed A, Woods RL, Tonkin AM, Nelson MR, et al. Associations between MASLD, atrial fibrillation, cardiovascular events, mortality and aspirin use in older adults. GeroScience. 2025; 47: 1303–1318. https://doi.org/10.1007/s11357-024-01435-2.

[131] Morrison AE, Zaccardi F, Khunti K, Davies MJ. Causality between non-alcoholic fatty liver disease and risk of cardiovascular disease and type 2 diabetes: A meta-analysis with bias analysis. Liver International: Official Journal of the International Association for the Study of the Liver. 2019; 39: 557–567. https://doi.org/10.1111/liv.13994.

[132] Abeysekera KWM, Macpherson I, Glyn-Owen K, McPherson S, Parker R, Harris R, et al. Community pathways for the early detection and risk stratification of chronic liver disease: a narrative systematic review. The Lancet. Gastroenterology & Hepatology. 2022; 7: 770–780. https://doi.org/10.1016/S2468-1253(22)00020-6.

[133] Park S, Lee J, Seok JW, Park CG, Jun J. Comprehensive lifestyle modification interventions for metabolic syndrome: A systematic review and meta-analysis. Journal of Nursing Scholarship: an Official Publication of Sigma Theta Tau International Honor Society of Nursing. 2024; 56: 249–259. https://doi.org/10.1111/jnu.12946.

[134] Gries JJ, Lazarus JV, Brennan PN, Siddiqui MS, Targher G, Lang CC, et al. Interdisciplinary perspectives on the co-management of metabolic dysfunction-associated steatotic liver disease and coronary artery disease. The Lancet. Gastroenterology & Hepatology. 2025; 10: 82–94. https://doi.org/10.1016/S2468-1253(24)00310-8.

[135] Chew NWS, Mehta A, Goh RSJ, Zhang A, Chen Y, Chong B, et al. Cardiovascular-Liver-Metabolic Health: Recommendations in Screening, Diagnosis, and Management of Metabolic Dysfunction-Associated Steatotic Liver Disease in Cardiovascular Disease via Modified Delphi Approach. Circulation. 2025; 151: 98–119. https://doi.org/10.1161/CIRCULATIONAHA.124.070535.

[136] Chen MJ, Chen Y, Lin JQ, Hu R, Liu D, Chen JY, et al. Evidence summary of lifestyle interventions in adults with metabolic dysfunction-associated steatotic liver disease. Frontiers in Nutrition. 2025; 11: 1421386. https://doi.org/10.3389/fnut.2024.1421386.

[137] Saenz C, Salinas M, Rothman RL, White RO. Personalized Lifestyle Modifications for Improved Metabolic Health: The Role of Cultural Sensitivity and Health Communication in Type 2 Diabetes Management. Journal of the American Nutrition Association. 2025; 44: 198–211. https://doi.org/10.1080/27697061.2024.2413368.

[138] Ryan MC, Itsiopoulos C, Thodis T, Ward G, Trost N, Hofferberth S, et al. The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease. Journal of Hepatology. 2013; 59: 138–143. https://doi.org/10.1016/j.jhep.2013.02.012.

[139] Huo R, Du T, Xu Y, Xu W, Chen X, Sun K, et al. Effects of Mediterranean-style diet on glycemic control, weight loss and cardiovascular risk factors among type 2 diabetes individuals: a meta-analysis. European Journal of Clinical Nutrition. 2015; 69: 1200–1208. https://doi.org/10.1038/ejcn.2014.243.

[140] Della Corte C, Mosca A, Vania A, Alterio A, Iasevoli S, Nobili V. Good adherence to the Mediterranean diet reduces the risk for NASH and diabetes in pediatric patients with obesity: The results of an Italian Study. Nutrition (Burbank, Los Angeles County, Calif.). 2017; 39–40: 8–14. https://doi.org/10.1016/j.nut.2017.02.008.

[141] Zhang T, Liu Y, Yang Y, Luo J, Hao C. The Effect and Mechanism of Regular Exercise on Improving Insulin Impedance: Based on the Perspective of Cellular and Molecular Levels. International Journal of Molecular Sciences. 2025; 26: 4199. https://doi.org/10.3390/ijms26094199.

[142] Brouwers B, Hesselink MKC, Schrauwen P, Schrauwen-Hinderling VB. Effects of exercise training on intrahepatic lipid content in humans. Diabetologia. 2016; 59: 2068–2079. https://doi.org/10.1007/s00125-016-4037-x.

[143] Thyfault JP, Rector RS. Exercise Combats Hepatic Steatosis: Potential Mechanisms and Clinical Implications. Diabetes. 2020; 69: 517–524. https://doi.org/10.2337/dbi18-0043.

[144] Diniz TA, de Lima Junior EA, Teixeira AA, Biondo LA, da Rocha LAF, Valadão IC, et al. Aerobic training improves NAFLD markers and insulin resistance through AMPK-PPAR-α signaling in obese mice. Life Sciences. 2021; 266: 118868. https://doi.org/10.1016/j.lfs.2020.118868.

[145] Ormazabal V, Nair S, Elfeky O, Aguayo C, Salomon C, Zuñiga FA. Association between insulin resistance and the development of cardiovascular disease. Cardiovascular Diabetology. 2018; 17: 122. https://doi.org/10.1186/s12933-018-0762-4.

[146] Van Gaal L, Scheen A. Weight management in type 2 diabetes: current and emerging approaches to treatment. Diabetes Care. 2015; 38: 1161–1172. https://doi.org/10.2337/dc14-1630.

[147] Apovian CM, Okemah J, O’Neil PM. Body Weight Considerations in the Management of Type 2 Diabetes. Advances in Therapy. 2019; 36: 44–58. https://doi.org/10.1007/s12325-018-0824-8.

[148] European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). Journal of Hepatology. 2024; 81: 492–542. https://doi.org/10.1016/j.jhep.2024.04.031.

[149] Yin C, Li Z, Xiang Y, Peng H, Yang P, Yuan S, et al. Effect of Intermittent Fasting on Non-Alcoholic Fatty Liver Disease: Systematic Review and Meta-Analysis. Frontiers in Nutrition. 2021; 8: 709683. https://doi.org/10.3389/fnut.2021.709683.

[150] Conte C, Camajani E, Lai A, Caprio M. Not all very-low-carbohydrate diets are created equal. Diabetologia. 2023; 66: 1752–1753. https://doi.org/10.1007/s00125-023-05961-0.

[151] Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. The New England Journal of Medicine. 2015; 373: 2117–2128. https://doi.org/10.1056/NEJMoa1504720.

[152] Chen AX, Fletcher R, Neuen BL, Neal B, Arnott C. An overview of the CANVAS Program and CREDENCE trial: The primary outcomes and key clinical implications for those managing patients with type 2 diabetes. Diabetes, Obesity & Metabolism. 2024; 26: 5–13. https://doi.org/10.1111/dom.15751.

[153] Wu JHY, Foote C, Blomster J, Toyama T, Perkovic V, Sundström J, et al. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. The Lancet. Diabetes & Endocrinology. 2016; 4: 411–419. https://doi.org/10.1016/S2213-8587(16)00052-8.

[154] Palmiero G, Cesaro A, Galiero R, Loffredo G, Caturano A, Vetrano E, et al. Impact of gliflozins on cardiac remodelling in patients with type 2 diabetes mellitus & reduced ejection fraction heart failure: A pilot prospective study. GLISCAR study. Diabetes Research and Clinical Practice. 2023; 200: 110686. https://doi.org/10.1016/j.diabres.2023.110686.

[155] Nevola R, Alfano M, Pafundi PC, Brin C, Gragnano F, Calabrò P, et al. Cardiorenal Impact of SGLT-2 Inhibitors: A Conceptual Revolution in The Management of Type 2 Diabetes, Heart Failure and Chronic Kidney Disease. Reviews in Cardiovascular Medicine. 2022; 23: 106. https://doi.org/10.31083/j.rcm2303106.

[156] Kuchay MS, Krishan S, Mishra SK, Farooqui KJ, Singh MK, Wasir JS, et al. Effect of Empagliflozin on Liver Fat in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial (E-LIFT Trial). Diabetes Care. 2018; 41: 1801–1808. https://doi.org/10.2337/dc18-0165.

[157] Eriksson JW, Lundkvist P, Jansson PA, Johansson L, Kvarnström M, Moris L, et al. Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: a double-blind randomised placebo-controlled study. Diabetologia. 2018; 61: 1923–1934. https://doi.org/10.1007/s00125-018-4675-2.

[158] Bethel MA, Patel RA, Merrill P, Lokhnygina Y, Buse JB, Mentz RJ, et al. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. The Lancet. Diabetes & Endocrinology. 2018; 6: 105–113. https://doi.org/10.1016/S2213-8587(17)30412-6.

[159] Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JFE, Nauck MA, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. The New England Journal of Medicine. 2016; 375: 311–322. https://doi.org/10.1056/NEJMoa1603827.

[160] Leiter LA, Bain SC, Hramiak I, Jódar E, Madsbad S, Gondolf T, et al. Cardiovascular risk reduction with once-weekly semaglutide in subjects with type 2 diabetes: a post hoc analysis of gender, age, and baseline CV risk profile in the SUSTAIN 6 trial. Cardiovascular Diabetology. 2019; 18: 73. https://doi.org/10.1186/s12933-019-0871-8.

[161] Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet (London, England). 2019; 394: 121–130. https://doi.org/10.1016/S0140-6736(19)31149-3.

[162] Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet (London, England). 2016; 387: 679–690. https://doi.org/10.1016/S0140-6736(15)00803-X.

[163] Ludvik B, Frías JP, Tinahones FJ, Wainstein J, Jiang H, Robertson KE, et al. Dulaglutide as add-on therapy to SGLT2 inhibitors in patients with inadequately controlled type 2 diabetes (AWARD-10): a 24-week, randomised, double-blind, placebo-controlled trial. The Lancet. Diabetes & Endocrinology. 2018; 6: 370–381. https://doi.org/10.1016/S2213-8587(18)30023-8.

[164] Loomba R, Abdelmalek MF, Armstrong MJ, Jara M, Kjær MS, Krarup N, et al. Semaglutide 2·4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial. The Lancet. Gastroenterology & Hepatology. 2023; 8: 511–522. https://doi.org/10.1016/S2468-1253(23)00068-7.

[165] Suki M, Amer J, Milgrom Y, Massarwa M, Hazou W, Tiram Y, et al. Semaglutide in MASLD Patients: Improved Survival and Liver Outcomes. Pharmaceuticals (Basel, Switzerland). 2025; 18: 1075. https://doi.org/10.3390/ph18071075.

[166] Kuo CC, Chuang MH, Li CH, Huang PY, Kuo HT, Lai CC. Semaglutide and the risk of adverse liver outcomes in patients with nonalcoholic fatty liver disease and type 2 diabetes: a multi-institutional cohort study. Hepatology International. 2025; 19: 395–404. https://doi.org/10.1007/s12072-024-10752-9.

[167] Frías JP, Davies MJ, Rosenstock J, Pérez Manghi FC, Fernández Landó L, Bergman BK, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. The New England Journal of Medicine. 2021; 385: 503–515. https://doi.org/10.1056/NEJMoa2107519.

[168] Liu L, Shi H, Xie M, Sun Y, Nahata MC. The Efficacy and Safety of Tirzepatide in Patients with Diabetes and/or Obesity: Systematic Review and Meta-Analysis of Randomized Clinical Trials. Pharmaceuticals (Basel, Switzerland). 2025; 18: 668. https://doi.org/10.3390/ph18050668.

[169] Lingvay I, Mosenzon O, Brown K, Cui X, O’Neill C, Fernández Landó L, et al. Systolic blood pressure reduction with tirzepatide in patients with type 2 diabetes: insights from SURPASS clinical program. Cardiovascular Diabetology. 2023; 22: 66. https://doi.org/10.1186/s12933-023-01797-5.

[170] Eli Lilly and Company. Lilly’s Mounjaro (tirzepatide), a GIP/GLP-1 dual agonist, demonstrated cardiovascular protection in landmark head-to-head trial, reinforcing its benefit in patients with type 2 diabetes and heart disease. 2025. Available at: https://investor.lilly.com/news-releases/news-release-details/lillys-mounjaro-tirzepatide-gipglp-1-dual-agonist-demonstrated (Accessed: 17 September 2025).

[171] Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, et al. Tirzepatide Once Weekly for the Treatment of Obesity. The New England Journal of Medicine. 2022; 387: 205–216. https://doi.org/10.1056/NEJMoa2206038.

[172] Hu W, Gong W, Yang F, Cheng R, Zhang G, Gan L, et al. Dual GIP and GLP-1 receptor agonist tirzepatide alleviates hepatic steatosis and modulates gut microbiota and bile acid metabolism in diabetic mice. International Immunopharmacology. 2025; 147: 113937. https://doi.org/10.1016/j.intimp.2024.113937.

[173] Hartman ML, Loomba R, Lawitz EJ, Vuppalanchi R, Boursier J, Bugianesi E, et al. Consistent improvements in liver histology across subgroups in a post hoc analysis of the SYNERGY-NASH trial with tirzepatide. JHEP Reports. 2025; 7: 101472. https://doi.org/10.1016/j.jhepr.2025.101472.

[174] Targher G, Mantovani A, Byrne CD, Tilg H. Recent advances in incretin-based therapy for MASLD: from single to dual or triple incretin receptor agonists. Gut. 2025; 74: 487–497. https://doi.org/10.1136/gutjnl-2024-334023.

[175] Tarar ZI, Farooq U, Inayat F, Basida SD, Ibrahim F, Gandhi M, et al. Statins decrease the risk of hepatocellular carcinoma in metabolic dysfunction-associated steatotic liver disease: A systematic review and meta-analysis. World Journal of Experimental Medicine. 2024; 14: 98543. https://doi.org/10.5493/wjem.v14.i4.98543.

[176] Ciardullo S, Perseghin G. Statin use is associated with lower prevalence of advanced liver fibrosis in patients with type 2 diabetes. Metabolism: Clinical and Experimental. 2021; 121: 154752. https://doi.org/10.1016/j.metabol.2021.154752.

[177] Schmidt AF, Pearce LS, Wilkins JT, Overington JP, Hingorani AD, Casas JP. PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease. The Cochrane Database of Systematic Reviews. 2017; 4: CD011748. https://doi.org/10.1002/14651858.CD011748.pub2.

[178] Castellano-Castillo D, Núñez-Sánchez MÁ Balaguer-Román A, Martínez-Sánchez MA, Fernández-Ruiz VE, Ferrer-Gómez M, et al. The role of PCSK9 in metabolic dysfunction-associated steatotic liver disease and its impact on bariatric surgery outcomes. Surgery for Obesity and Related Diseases: Official Journal of the American Society for Bariatric Surgery. 2024; 20: 652–659. https://doi.org/10.1016/j.soard.2024.01.017.

[179] Sanyal AJ, Ratziu V, Loomba R, Anstee QM, Kowdley KV, Rinella ME, et al. Results from a new efficacy and safety analysis of the REGENERATE trial of obeticholic acid for treatment of pre-cirrhotic fibrosis due to non-alcoholic steatohepatitis. Journal of Hepatology. 2023; 79: 1110–1120. https://doi.org/10.1016/j.jhep.2023.07.014.

[180] Hardy T, Anstee QM, Day CP. Nonalcoholic fatty liver disease: new treatments. Current Opinion in Gastroenterology. 2015; 31: 175–183. https://doi.org/10.1097/MOG.0000000000000175.

[181] Conte C, Lapeyre-Mestre M, Hanaire H, Ritz P. Diabetes Remission and Relapse After Bariatric Surgery: a Nationwide Population-Based Study. Obesity Surgery. 2020; 30: 4810–4820. https://doi.org/10.1007/s11695-020-04924-3.

[182] Aderinto N, Olatunji G, Kokori E, Olaniyi P, Isarinade T, Yusuf IA. Recent advances in bariatric surgery: a narrative review of weight loss procedures. Annals of Medicine and Surgery (2012). 2023; 85: 6091–6104. https://doi.org/10.1097/MS9.0000000000001472.

[183] Schneck AS, Anty R, Patouraux S, Bonnafous S, Rousseau D, Lebeaupin C, et al. Roux-En Y Gastric Bypass Results in Long-Term Remission of Hepatocyte Apoptosis and Hepatic Histological Features of Non-alcoholic Steatohepatitis. Frontiers in Physiology. 2016; 7: 344. https://doi.org/10.3389/fphys.2016.00344.

[184] Kroh A, Schmitz S, Köhne S, Andruszkow J, Nolting J, Preisinger C, et al. Sleeve-gastrectomy results in improved metabolism and a massive stress response of the liver proteome in a mouse model of metabolic dysfunction-associated steatohepatitis. Heliyon. 2024; 10: e38678. https://doi.org/10.1016/j.heliyon.2024.e38678.

[185] Rubino F, Nathan DM, Eckel RH, Schauer PR, Alberti KGMM, Zimmet PZ, et al. Metabolic Surgery in the Treatment Algorithm for Type 2 Diabetes: A Joint Statement by International Diabetes Organizations. Diabetes Care. 2016; 39: 861–877. https://doi.org/10.2337/dc16-0236.

[186] Mechanick JI, Apovian C, Brethauer S, Garvey WT, Joffe AM, Kim J, et al. Clinical Practice Guidelines For The Perioperative Nutrition, Metabolic, and Nonsurgical Support of Patients Undergoing Bariatric Procedures – 2019 Update: Cosponsored By American Association of Clinical Endocrinologists/American College of Endocrinology, The Obesity Society, American Society For Metabolic & Bariatric Surgery, Obesity Medicine Association, and American Society of Anesthesiologists. Endocrine Practice. 2019; 25: 1–75. https://doi.org/10.4158/GL-2019-0406.

[187] Flores CA. Psychological assessment for bariatric surgery: current practices. Arquivos Brasileiros De Cirurgia Digestiva: ABCD = Brazilian Archives of Digestive Surgery. 2014; 27 Suppl 1: 59–62. https://doi.org/10.1590/s0102-6720201400s100015.

[188] Veluvali A, Dehghani Zahedani A, Hosseinian A, Aghaeepour N, McLaughlin T, Woodward M, et al. Impact of digital health interventions on glycemic control and weight management. NPJ Digital Medicine. 2025; 8: 20. https://doi.org/10.1038/s41746-025-01430-7.

[189] Haleem A, Javaid M, Singh RP, Suman R. Telemedicine for healthcare: Capabilities, features, barriers, and applications. Sensors International. 2021; 2: 100117. https://doi.org/10.1016/j.sintl.2021.100117.

[190] Joseph JJ, Deedwania P, Acharya T, Aguilar D, Bhatt DL, Chyun DA, et al. Comprehensive Management of Cardiovascular Risk Factors for Adults With Type 2 Diabetes: A Scientific Statement From the American Heart Association. Circulation. 2022; 145: e722–e759. https://doi.org/10.1161/CIR.0000000000001040.

[191] Johnston CA, Moreno JP, Foreyt JP. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. Current Atherosclerosis Reports. 2014; 16: 457. https://doi.org/10.1007/s11883-014-0457-6.

[192] Li YH, Li YL, Wei MY, Li GY. Innovation and challenges of artificial intelligence technology in personalized healthcare. Scientific Reports. 2024; 14: 18994. https://doi.org/10.1038/s41598-024-70073-7.

[193] Pan A, Wang Y, Talaei M, Hu FB. Relation of Smoking With Total Mortality and Cardiovascular Events Among Patients With Diabetes Mellitus: A Meta-Analysis and Systematic Review. Circulation. 2015; 132: 1795–1804. https://doi.org/10.1161/CIRCULATIONAHA.115.017926.

[194] Schellenberg ES, Dryden DM, Vandermeer B, Ha C, Korownyk C. Lifestyle interventions for patients with and at risk for type 2 diabetes: a systematic review and meta-analysis. Annals of Internal Medicine. 2013; 159: 543–551. https://doi.org/10.7326/0003-4819-159-8-201310150-00007.

[195] Pafundi PC, Garofalo C, Galiero R, Borrelli S, Caturano A, Rinaldi L, et al. Role of Albuminuria in Detecting Cardio-Renal Risk and Outcome in Diabetic Subjects. Diagnostics (Basel, Switzerland). 2021; 11: 290. https://doi.org/10.3390/diagnostics11020290.

[196] Messner B, Bernhard D. Smoking and cardiovascular disease: mechanisms of endothelial dysfunction and early atherogenesis. Arteriosclerosis, Thrombosis, and Vascular Biology. 2014; 34: 509–515. https://doi.org/10.1161/ATVBAHA.113.300156.

[197] O’Keefe JH, Bhatti SK, Bajwa A, DiNicolantonio JJ, Lavie CJ. Alcohol and cardiovascular health: the dose makes the poison…or the remedy. Mayo Clinic Proceedings. 2014; 89: 382–393. https://doi.org/10.1016/j.mayocp.2013.11.005.

[198] Micha R, Peñalvo JL, Cudhea F, Imamura F, Rehm CD, Mozaffarian D. Association Between Dietary Factors and Mortality From Heart Disease, Stroke, and Type 2 Diabetes in the United States. JAMA. 2017; 317: 912–924. https://doi.org/10.1001/jama.2017.0947.

[199] Visseren FLJ, Mach F, Smulders YM, Carballo D, Koskinas KC, Bäck M, et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. European Heart Journal. 2021; 42: 3227–3337. https://doi.org/10.1093/eurheartj/ehab484.

[200] Andrews RC, Cooper AR, Montgomery AA, Norcross AJ, Peters TJ, Sharp DJ, et al. Diet or diet plus physical activity versus usual care in patients with newly diagnosed type 2 diabetes: the Early ACTID randomised controlled trial. Lancet (London, England). 2011; 378: 129–139. https://doi.org/10.1016/S0140-6736(11)60442-X.

[201] Schwingshackl L, Chaimani A, Hoffmann G, Schwedhelm C, Boeing H. A network meta-analysis on the comparative efficacy of different dietary approaches on glycaemic control in patients with type 2 diabetes mellitus. European Journal of Epidemiology. 2018; 33: 157–170. https://doi.org/10.1007/s10654-017-0352-x.

[202] Garcia SP, Cureau FV, Iorra FDQ, Bottino LG, R C Monteiro LE, Leivas G, et al. Effects of exercise training and physical activity advice on HbA1c in people with type 2 diabetes: A network meta-analysis of randomized controlled trials. Diabetes Research and Clinical Practice. 2025; 221: 112027. https://doi.org/10.1016/j.diabres.2025.112027.

[203] Çolak TK, Acar G, Dereli EE, Özgül B, Demirbüken İ Alkaç Ç et al. Association between the physical activity level and the quality of life of patients with type 2 diabetes mellitus. Journal of Physical Therapy Science. 2016; 28: 142–147. https://doi.org/10.1589/jpts.28.142.

[204] Lambrinou E, Hansen TB, Beulens JW. Lifestyle factors, self-management and patient empowerment in diabetes care. European Journal of Preventive Cardiology. 2019; 26: 55–63. https://doi.org/10.1177/2047487319885455.

[205] Zellweger MJ, Hachamovitch R, Kang X, Hayes SW, Friedman JD, Germano G, et al. Prognostic relevance of symptoms versus objective evidence of coronary artery disease in diabetic patients. European Heart Journal. 2004; 25: 543–550. https://doi.org/10.1016/j.ehj.2004.02.013.

[206] Miele L, Zocco MA, Pizzolante F, De Matthaeis N, Ainora ME, Liguori A, et al. Use of imaging techniques for non-invasive assessment in the diagnosis and staging of non-alcoholic fatty liver disease. Metabolism: Clinical and Experimental. 2020; 112: 154355. https://doi.org/10.1016/j.metabol.2020.154355.

[207] Caturano A, Albanese G, Di Martino A, Coppola C, Russo V, Galiero R, et al. Predictive Value of Fatty Liver Index for Long-Term Cardiovascular Events in Patients Receiving Liver Transplantation: The COLT Study. Biomedicines. 2023; 11: 2866. https://doi.org/10.3390/biomedicines11102866.

[208] Petroff D, Blank V, Newsome PN, Shalimar, Voican CS, Thiele M, et al. Assessment of hepatic steatosis by controlled attenuation parameter using the M and XL probes: an individual patient data meta-analysis. The Lancet. Gastroenterology & Hepatology. 2021; 6: 185–198. https://doi.org/10.1016/S2468-1253(20)30357-5.

[209] Marx N, Federici M, Schütt K, Müller-Wieland D, Ajjan RA, Antunes MJ, et al. 2023 ESC Guidelines for the management of cardiovascular disease in patients with diabetes. European Heart Journal. 2023; 44: 4043–4140. https://doi.org/10.1093/eurheartj/ehad192.

[210] Rolek B, Haber M, Gajewska M, Rogula S, Pietrasik A, Gąsecka A. SGLT2 Inhibitors vs. GLP-1 Agonists to Treat the Heart, the Kidneys and the Brain. Journal of Cardiovascular Development and Disease. 2023; 10: 322. https://doi.org/10.3390/jcdd10080322.

[211] Akunjee MM, Khosla SG, Nylen ES, Sen S. SGLT2 inhibitors use in kidney disease: what did we learn? American Journal of Physiology. Endocrinology and Metabolism. 2025; 328: E856–E868. https://doi.org/10.1152/ajpendo.00034.2025.

[212] Deferrari G, Cipriani A, La Porta E. Renal dysfunction in cardiovascular diseases and its consequences. Journal of Nephrology. 2021; 34: 137–153. https://doi.org/10.1007/s40620-020-00842-w.

[213] Bellos I, Marinaki S, Lagiou P, Benetou V. Comparative Efficacy and Safety of Cardio-Renoprotective Pharmacological Interventions in Chronic Kidney Disease: An Umbrella Review of Network Meta-Analyses and a Multicriteria Decision Analysis. Biomolecules. 2024; 15: 39. https://doi.org/10.3390/biom15010039.

[214] Greco A, Occhipinti G, Giacoppo D, Agnello F, Laudani C, Spagnolo M, et al. Antithrombotic Therapy for Primary and Secondary Prevention of Ischemic Stroke: JACC State-of-the-Art Review. Journal of the American College of Cardiology. 2023; 82: 1538–1557. https://doi.org/10.1016/j.jacc.2023.07.025.

[215] Joseph M, Krishna MM, Ezenna C, Pereira V, Ismayl M, Nanna MG, et al. Short Versus One-Year Dual Antiplatelet Therapy After Percutaneous Coronary Intervention: an Updated Meta-Analysis. The American Journal of Cardiology. 2025; 237: 17–28. https://doi.org/10.1016/j.amjcard.2024.10.038.

[216] Taylor RS, Dalal HM, McDonagh STJ. The role of cardiac rehabilitation in improving cardiovascular outcomes. Nature Reviews. Cardiology. 2022; 19: 180–194. https://doi.org/10.1038/s41569-021-00611-7.

[217] Tessler J, Ahmed I, Bordoni B. Cardiac Rehabilitation. In: StatPearls [Internet]. StatPearls Publishing: Treasure Island (FL). 2025.

[218] Milani JGPO, Milani M, Verboven K, Cipriano G, Jr, Hansen D. Exercise intensity prescription in cardiovascular rehabilitation: bridging the gap between best evidence and clinical practice. Frontiers in Cardiovascular Medicine. 2024; 11: 1380639. https://doi.org/10.3389/fcvm.2024.1380639.

[219] McMahon SR, Ades PA, Thompson PD. The role of cardiac rehabilitation in patients with heart disease. Trends in Cardiovascular Medicine. 2017; 27: 420–425. https://doi.org/10.1016/j.tcm.2017.02.005.

[220] Bäck M, Caldenius V, Svensson L, Lundberg M. Perceptions of Kinesiophobia in Relation to Physical Activity and Exercise After Myocardial Infarction: A Qualitative Study. Physical Therapy. 2020; 100: 2110–2119. https://doi.org/10.1093/ptj/pzaa159.

[221] Hughes JW, Serber ER, Kuhn T. Psychosocial management in cardiac rehabilitation: Current practices, recommendations, and opportunities. Progress in Cardiovascular Diseases. 2022; 73: 76–83. https://doi.org/10.1016/j.pcad.2021.12.006.

[222] Wongvibulsin S, Habeos EE, Huynh PP, Xun H, Shan R, Porosnicu Rodriguez KA, et al. Digital Health Interventions for Cardiac Rehabilitation: Systematic Literature Review. Journal of Medical Internet Research. 2021; 23: e18773. https://doi.org/10.2196/18773.

[223] Kanemitsu K, Hassan BD, Mdivnishvili M, Abbas N. The Impact of Lifestyle Intervention Programs on Long-Term Cardiac Event-Free Survival in Patients With Established Coronary Artery Disease. Cureus. 2024; 16: e76585. https://doi.org/10.7759/cureus.76585.

[224] Sári C, Heesch CM, Kovács JA, Simon A, Andréka P. Participation in a comprehensive cardiac rehabilitation program improves mid- and long-term prognosis in survivors of acute coronary syndrome. American Journal of Preventive Cardiology. 2025; 23: 101042. https://doi.org/10.1016/j.ajpc.2025.101042.

[225] Prasad K. Current Status of Primary, Secondary, and Tertiary Prevention of Coronary Artery Disease. The International Journal of Angiology: Official Publication of the International College of Angiology, Inc. 2021; 30: 177–186. https://doi.org/10.1055/s-0041-1731273.

[226] Caturano A, Galiero R, Rocco M, Tagliaferri G, Piacevole A, Nilo D, et al. The Dual Burden: Exploring Cardiovascular Complications in Chronic Kidney Disease. Biomolecules. 2024; 14: 1393. https://doi.org/10.3390/biom14111393.

[227] Angermayr L, Melchart D, Linde K. Multifactorial lifestyle interventions in the primary and secondary prevention of cardiovascular disease and type 2 diabetes mellitus–a systematic review of randomized controlled trials. Annals of Behavioral Medicine: a Publication of the Society of Behavioral Medicine. 2010; 40: 49–64. https://doi.org/10.1007/s12160-010-9206-4.

[228] Hirano T. Pathophysiology of Diabetic Dyslipidemia. Journal of Atherosclerosis and Thrombosis. 2018; 25: 771–782. https://doi.org/10.5551/jat.RV17023.

[229] Russo V, Ratti G, Parrella A, De Falco A, Crisci M, Franco R, et al. Clinical Utilization and Performance of Bempedoic Acid in an Italian Real-World Setting: Insight from Campania Region. Journal of Clinical Medicine. 2025; 14: 1839. https://doi.org/10.3390/jcm14061839.

[230] Mormone A, Tortorella G, Esposito F, Caturano A, Marrone A, Cozzolino D, et al. Advances in Pharmacological Approaches for Managing Hypercholesterolemia: A Comprehensive Overview of Novel Treatments. Biomedicines. 2024; 12: 432. https://doi.org/10.3390/biomedicines12020432.

[231] Michalopoulou E, Thymis J, Lampsas S, Pavlidis G, Katogiannis K, Vlachomitros D, et al. The Triad of Risk: Linking MASLD, Cardiovascular Disease and Type 2 Diabetes; From Pathophysiology to Treatment. Journal of Clinical Medicine. 2025; 14: 428. https://doi.org/10.3390/jcm14020428.

[232] Caturano A, di Martino A, Albanese G, Coppola C, Russo V, Koudelková K, et al. The impact of new onset diabetes on cardiovascular risks in orthotopic liver transplant recipients: findings from the COLT study. Acta Diabetologica. 2025; 62: 891–901. https://doi.org/10.1007/s00592-024-02406-x.

[233] Matsubayashi Y, Fujihara K, Khin L, Ferreira ED, Takabayashi S, Yamashita Y, et al. Association of changes in the type 2 diabetes and MASLD/related SLD status with risk of developing cardiovascular disease. Diabetes, Obesity & Metabolism. 2025; 27: 2035–2043. https://doi.org/10.1111/dom.16196.

[234] Sun W, Lv Y, Wang L, Yu H, Yi H, Wang Y, et al. Comparison of Risk Factors Between Lean and Nonlean Metabolic Dysfunction-Associated Steatotic Liver Disease in Individuals With Type 2 Diabetes: A Multicenter Study. Endocrine Practice: Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2024; 30: 1171–1179. https://doi.org/10.1016/j.eprac.2024.09.012.

[235] Nameghi SM. Exploring the recent advancements and future prospects of personalized medicine in type 2 diabetes. Endocrine and Metabolic Science. 2024; 16: 100193. https://doi.org/10.1016/j.endmts.2024.100193.

[236] Dixon D, Sattar H, Moros N, Kesireddy SR, Ahsan H, Lakkimsetti M, et al. Unveiling the Influence of AI Predictive Analytics on Patient Outcomes: A Comprehensive Narrative Review. Cureus. 2024; 16: e59954. https://doi.org/10.7759/cureus.59954.

[237] Gantayet-Mathur A, Chan K, Kalluri M. Patient-centered care and interprofessional collaboration in medical resident education: Where we stand and where we need to go. Humanities and Social Sciences Communications. 2022; 9: 206. https://doi.org/10.1057/s41599-022-01221-5.