Integrating liver and heart health: Cardiovascular risk reduction in patients with metabolic-associated steatotic liver disease

Abstract

Metabolic-associated steatotic liver disease (MASLD) is a global health burden intricately linked to cardiovascular disease (CVD) through shared pathways-insulin resistance, dyslipidemia, and chronic inflammation. CVD has become the leading cause of mortality in MASLD, necessitating integrated management strategies. This review synthesizes evidence on bidirectional MASLD-CVD interactions and evaluates therapeutic approaches: Lifestyle modifications, pharmacotherapy (e.g., GLP-1 receptor agonists, SGLT2 inhibitors, statins), and metabolic interventions. Despite progress, critical gaps persist in risk stratification tools, personalized treatment algorithms, and long-term outcomes of novel agents like resmetirom. A multidisciplinary care model, bridging hepatology and cardiology, is essential to address these challenges and improve patient outcomes.

Core Tip: Metabolic-associated steatotic liver disease (MASLD), a leading global liver disorder, is strongly linked to cardiovascular disease (CVD) through shared pathways including insulin resistance, dyslipidemia, and systemic inflammation. This review examines the bidirectional relationship between MASLD and CVD, highlighting CVD as the primary cause of morbidity and mortality in this population. We evaluate evidence-based management strategies including lifestyle modifications, pharmacotherapy and metabolic interventions, while emphasizing the need for multidisciplinary care. Critical gaps in risk stratification, treatment personalization, and long-term outcomes of emerging therapies are discussed, underscoring the necessity for integrated approaches to improve patient outcomes.

INTRODUCTION

Metabolic-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease (NAFLD), is now recognized as a distinct clinical entity within the broader category of steatotic liver disease. According to a multisociety Delphi consensus, MASLD is defined as hepatic steatosis in the presence of at least one cardiometabolic risk factor (CMRF) and the absence of harmful alcohol consumption[1]. The diagnosis of metabolic syndrome-closely associated with MASLD-requires the presence of at least three out of five CMRFs: (1) Overweight or obese; (2) Dysglycemia or type 2 diabetes mellitus (T2DM); (3) Triglycerides ≥ 1.7 mmol/L; (4) High-density lipoprotein (HDL)-cholesterol ≤ 1.0 mmol/L; and (5) Blood pressure ≥ 130/85 mmHg[2]. The spectrum of MASLD encompasses simple steatosis, metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH), progressive fibrosis, cirrhosis, and MASH-related hepatocellular carcinoma (HCC).

MASLD affects approximately 25%-30% of the adult population worldwide and is increasing in parallel with the increasing prevalence of obesity and T2DM[3-5]. Among its systemic consequences, cardiovascular disease (CVD) has emerged as the leading cause of morbidity and mortality in MASLD patients, surpassing liver-related complications[6,7]. Shared pathophysiological mechanisms, including chronic inflammation, insulin resistance, dyslipidemia, and endothelial dysfunction, create a bidirectional interplay in which MASLD and CVD mutually exacerbate disease progression, increasing the risk of myocardial infarction, heart failure, and stroke[7,8].

Despite this well-established connection, cardiovascular risk assessment and management remain inadequately addressed in many MASLD patients[9]. Although current guidelines emphasize integrated care models that consider both hepatic and cardiovascular endpoints, MASLD is still often managed in isolation from broader cardiometabolic care[2].

This review aims to bridge that gap by providing an evidence-based overview of cardiovascular risk in MASLD, highlighting both pharmacologic and nonpharmacologic strategies for risk reduction. Additionally, it addresses the key challenges in cardiovascular management specific to MASLD and emphasizes the need for a multidisciplinary, integrated approach. Through this framework, we aim to inform future strategies to improve long-term cardiometabolic outcomes in this increasingly prevalent population.

LINKING MASLD AND CVD

Pathophysiological mechanisms linking MASLD and CVD

In addition to its hepatic manifestations, MASLD is a systemic disease intricately linked to cardiometabolic disorders, especially CVD[10]. The high burden of CVD observed in MASLD patients underscores a shared pathophysiology between the two conditions, prompting mechanistic investigations into how metabolic dysfunction drives both hepatic and cardiovascular injury.

The elevated burden of CVD among patients with MASH strongly suggests that the two conditions share overlapping pathophysiological foundations. MASLD and CVD are linked through common CMRFs such as obesity, insulin resistance, T2DM, hypertension, and dyslipidemia. These shared drivers create a self-perpetuating cycle, where each condition exacerbates the other.

The mechanistic basis connecting MASLD and CVD is well established and includes endothelial dysfunction, dysregulated lipid metabolism, systemic inflammation, oxidative stress, insulin resistance, and the formation of unstable atherosclerotic plaques[11]. These disturbances contribute to structural and functional changes in the cardiovascular system, increasing susceptibility to complications such as hypertension, atherosclerosis, arrhythmias, myocardial dysfunction, valvular abnormalities, and thrombosis.

Insulin resistance in MASLD often leads to atherogenic dyslipidemia, characterized by elevated levels of triglycerides, increased concentrations of small dense low-density lipoprotein (LDL) particles, and reduced HDL cholesterol[12,13]. Together with systemic inflammation, these lipid abnormalities contribute to accelerated atherogenesis and impaired endothelial function[14].

When MASLD coexists with atherosclerosis, particularly in the context of MASH, the combined disease burden is greater than that of atherosclerosis alone. A systemetic review have demonstrated a robust association between MASH and early atherosclerotic changes, such as carotid artery thickening and subclinical atherosclerosis, regardless of diabetes status[15]. These include increased carotid intima-media thickness, arterial stiffness, impaired left ventricular function, endothelial dysfunction, reduced flow-mediated dilation, and coronary artery calcification[16].

In individuals with coexisting MASLD and T2DM, insulin resistance serves as a critical amplifier of cardiovascular risk, further increasing the incidence of adverse cardiovascular events[14]. Identifying MASLD in these patients may help clinicians identify a subgroup with elevated cardiovascular risk that could benefit from more intensive and targeted management[17].

Spectrum of cardiovascular complications in MASLD

The interplay between MASLD and CVD gives rise to a broad spectrum of clinically relevant cardiac complications. These include major adverse cardiovascular events (MACEs), heart failure, arrhythmias, valvular heart disease, neuro-circulatory disturbances, and peripheral arterial disease (Figure 1).

Figure 1.

Cardiovascular complications associated with metabolic dysfunction-associated steatotic liver disease.

Major adverse cardiac events: Recent evidence has demonstrated a robust association between MASLD and MACEs. In a comprehensive synthesis of data from 16 observational studies, individuals with MASLD presented a 64% greater likelihood of experiencing fatal or nonfatal cardiovascular outcomes-defined as cardiovascular death, acute myocardial infarction, angina, ischemic stroke, or the need for coronary revascularization-than did those without MASLD[18,19]. Notably, this elevated cardiovascular risk persists independently of conventional metabolic risk factors such as visceral adiposity or insulin resistance and is closely linked to subclinical atherosclerosis, as reflected by increased carotid intima-media thickness[18,19].

The extent of hepatic fibrosis appears to stratify cardiovascular risk further. A multinational study involving 458 patients with advanced MASLD revealed that those with bridging fibrosis had a markedly higher incidence of cardiovascular events, whereas cirrhotic individuals were more prone to liver-related complications[20].

In addition, coronary artery disease (CAD) represents a key pathophysiological intersection between MASLD and cardiovascular morbidity. A large-scale cross-sectional study by Chang et al[21] revealed a significant correlation between MASLD and the presence of coronary artery calcium (CAC), an established marker of subclinical atherosclerosis. Particularly in nondiabetic MASLD patients, increased CAC burden has been linked to multivessel coronary involvement and heightened susceptibility to myocardial ischemia, including ST-segment elevation myocardial infarction[22].

Taken together, these data reinforce the concept of MASLD as an independent determinant of cardiovascular risk, highlighting the importance of integrating hepatic evaluation into the cardiovascular risk assessment paradigm, particularly in patients with metabolic dysfunction.

Heart failure: MASLD has been increasingly recognized for its strong association with the risk of new-onset heart failure. A comprehensive meta-analysis involving over 11 million individuals demonstrated that patients with MASLD face a 1.5-fold increased risk of developing heart failure. This risk escalates in direct correlation with the degree of cirrhosis, as reflected by the fibrosis-4 (FIB-4) index, alongside a higher incidence of hospitalization due to heart failure[23,24]. The study conducted by Fudim et al[25] demonstrates a stronger association between MASLD and heart failure with preserved ejection fraction (HFpEF) as compared to heart failure with reduced ejection fraction (HFrEF)[26]. The underlying pathophysiological mechanisms of this association are multifactorial, encompassing liver fibrosis, low-grade chronic inflammation, and metabolic dysfunction, which collectively drive left ventricular remodeling. This remodeling is characterized by myocardial hypertrophy and diastolic dysfunction[27,28], impairing the left ventricle's ability to relax and adequately fill, while systolic function is typically preserved, consistent with the pathophysiology of HFpEF. Although MASLD is a chronic, progressive condition, with the theoretical possibility that prolonged left ventricular hypertrophy may eventually lead to systolic dysfunction (progressing from HFpEF to HFrEF), current clinical data indicate that the majority of MASLD patients remain predominantly in the HFpEF stage for much of their disease progression[29,30]. This phenomenon, as previously discussed in the pathophysiological mechanisms section, can be explained by the disease’s pathogenesis, which is characterized by liver fibrosis, chronic low-grade inflammation, and metabolic disturbances. These factors favor left ventricular remodeling through wall thickening rather than dilation of the ventricular chamber, thus predisposing the development of HFpEF over HFrEF[27,30].

These findings reinforce the hypothesis that heart failure, particularly HFpEF, is not simply an associated comorbidity of MASLD, but may also be a direct consequence of the disease, driven by histological changes and subsequent cardiovascular hemodynamic alterations[2,26,31].

Arrhythmia: Cardiac arrhythmias, particularly atrial fibrillation (AF), are increasingly recognized as significant cardiovascular complications in patients with MASLD, with epidemiological data indicating a twofold increase in AF incidence and a 1.6-fold higher risk of new-onset AF compared to the general population[32]. Several interrelated pathophysiological mechanisms have been proposed to explain this association. MASLD is characterized by chronic low-grade systemic inflammation and oxidative stress, impairing cardiac ion channel function and electrophysiological stability, thereby contributing to QTc prolongation, a known risk factor for ventricular tachyarrhythmias and sudden cardiac death[1,33]. Concurrent activation of inflammatory pathways, including elevated serum CRP levels and the NLRP3 inflammasome, has been implicated in atrial structural remodeling and electrical instability, fostering a substrate for AF initiation and maintenance[34-37]. Insulin resistance, a hallmark of MASLD, promotes ectopic lipid deposition in atrial and myocardial tissues, leading to interstitial fibrosis, diastolic dysfunction, and left atrial enlargement, which are key contributors to AF pathogenesis[27,38,39]. Increased interatrial septal fat thickness and left atrial stiffness have also been independently associated with AF development in MASLD[39]. Additionally, autonomic dysfunction characterized by reduced vagal tone and heightened sympathetic activity further exacerbates arrhythmogenic potential by altering cardiac conduction and refractoriness[40], while conduction abnormalities such as atrioventricular blocks and bundle branch blocks occur up to three times more frequently in MASLD patients[41]. Moreover, metabolic derangements including impaired glycogen synthesis and excessive release of free fatty acids, ceramides, and pro-inflammatory cytokines can adversely affect myocardial energy metabolism, exacerbating structural and electrical remodeling[42]. Collectively, these mechanisms not only explain the increased prevalence of AF and ventricular arrhythmias in MASLD but also highlight the broader impact of hepatic metabolic dysfunction on cardiovascular electrophysiology and adverse outcomes.

Cardiac valvular complications: MASLD has been associated with a higher incidence of aortic valve sclerosis, as shown in a meta-analysis of over 2600 patients[43]. Recent findings from the MESA study also linked MASLD to an increased risk of aortic valve calcification and incident aortic stenosis, independent of genetic predisposition[44]. These associations suggest a possible role of MASLD in valvular heart disease, warranting further investigation.

Peripheral artery complications: Peripheral artery complications are increasingly recognized in patients with MASLD and are likely associated with progressive atherosclerosis, endothelial dysfunction, and arterial stiffness[45,46]. Patients with MASLD, including those without T2DM, often exhibit a low ankle-brachial index (< 0.9), indicating an elevated cardiovascular risk[47]. Measures of arterial stiffness, such as brachial–ankle pulse wave velocity and cardio-ankle vascular index, have also been found to be significantly higher in these patients[47]. The underlying pathophysiological mechanisms include chronic low-grade inflammation and oxidative stress, leading to endothelial injury and reduced nitric oxide production, thereby promoting vasoconstriction and atherosclerosis[48]. Insulin resistance and dyslipidemia in MASLD contribute to extracellular matrix accumulation and arterial wall fibrosis, reducing vascular elasticity[49]. Furthermore, increased levels of pro-inflammatory cytokines such as TNF-α and IL-6 activate endothelial cells, upregulate adhesion molecules, recruit leukocytes, and promote atheroma formation[50]. In addition, lipid metabolism disorders lead to lipid deposition in peripheral arterial walls, and impaired endothelial progenitor cell function limits vascular repair capacity[51,52]. Given the strong association with metabolic syndrome, MASLD substantially increases the risk of peripheral artery disease even in patients without T2DM[53].

CHALLENGES IN MANAGING MASLD AND CVD

Managing MASLD and its cardiovascular complications presents several challenges that hinder optimal patient care, as illustrated in Figure 2. Addressing these barriers is essential to improving outcomes.

Figure 2.

Key challenges in managing cardiovascular risk in patients with metabolic-associated steatotic liver disease.

Lack of specialized risk assessment tools

The most recent guidelines of the ESC, ACC/AHA, AASLD and EASL have shown that patients with MASLD are at increased risk of developing cardiovascular problems, including atherosclerosis, hypertension, and CAD[2,54,55]. This may be due to the chronic inflammation, insulin resistance, and metabolic factors associated with MASLD, which increase the burden on the cardiovascular system.

Current cardiovascular risk assessment tools, such as the Framingham Risk Score or ASCVD Risk Calculator, are not specifically designed for MASLD patients. These tools often underestimate cardiovascular risk in this population because they do not account for liver-specific factors, such as hepatic fibrosis, which is a strong predictor of adverse outcomes[56-58].

However, there is still a need for validated, MASLD-specific risk assessment tools that integrate hepatic and cardiovascular parameters. Given that MASLD is inherently linked to cardiometabolic dysfunction and often considered the hepatic manifestation of metabolic syndrome, it is not surprising that patients with MASLD consistently exhibit a higher burden of CVD, morbidity, and mortality[2,59-62]. While several studies suggest MASLD may independently predict CVD even after adjusting for traditional risk factors[63,64], the overlapping pathophysiology with metabolic syndrome poses a challenge in clearly delineating its independent contribution to cardiovascular risk. This ambiguity is reflected in divergent clinical guidelines. The 2021 ESC Guidelines argue that MASLD does not increase cardiovascular risk beyond established risk factors, yet still recommend cardiovascular risk assessment and diabetes screening in these patients[65]. In contrast, a scientific statement from the AHA supports MASLD as an independent risk factor for atherosclerotic CVD[66]. This perspective is further supported by evidence showing that individuals with steatotic liver disease—even in the absence of obesity or overt metabolic dysfunction—may experience disproportionately severe hepatic fibrosis, higher rates of chronic kidney disease, and increased all-cause mortality, underscoring the systemic nature of the disease and its impact beyond traditional cardiometabolic pathways[67]. Despite differing viewpoints, there is consensus across major societies-including ESC, ACC/AHA, AASLD, and EASL-that routine cardiovascular risk assessment is essential in patients with MASLD, particularly those with comorbid T2DM[2,55,68,69]. However, no risk assessment tool is specifically designed for MASLD, and widely used models like the Framingham Risk Score, ASCVD score, SCORE2, and SCORE-OP have only been validated in limited MASLD cohorts, highlighting a significant gap in personalized risk prediction[9,56,57].

Lack of consensus on treatment algorithms

There is no universally accepted treatment algorithm for managing cardiovascular risk in MASLD patients. While guidelines exist for individual conditions like T2DM, hypertension, and dyslipidemia, they do not provide clear, integrated recommendations for MASLD patients with comorbid CVD.

As it is unclear if MASLD independently increases the CVD risk, neither EASL, the European Association for the Study of Diabetes and Obesity[70,71], the AACE[72], AASLD[69], ESC[68], or ACC/AHA[55] recommend any specific treatment of CVD risk factors in the setting of MASLD.

The current treatment of MASLD/MASH is hampered by the lack of uniform standards, which leads to differences in clinical practice and complicates physician decision-making and international collaboration. In addition, the genetic, metabolic, and lifestyle diversity of patients means that a treatment may work for some but not others, requiring the development of individualized strategies. Although some therapies are effective in the short term, their long-term effectiveness-particularly with medications and lifestyle interventions-requires further investigation, where patient adherence is a major challenge[73].

This lack of consensus leads to variability in clinical practice and highlights the need for evidence-based, multidisciplinary guidelines tailored to this high-risk population.

Challenges in treatment adherence

Long-term adherence to lifestyle modifications and pharmacotherapy remains a significant challenge in MASLD patients. Many patients struggle to maintain dietary changes, regular exercise, and medication regimens due to socioeconomic barriers, lack of motivation, or inadequate education about the disease. Improving adherence requires a patient-centered approach that includes education, behavioral support, and regular follow-up.

The primary objective of lifestyle care is to provide the education, resources and motivation for people with MASLD to adopt and adhere to lifestyle behaviors that will improve and sustain health and wellbeing. Improving diet quality, increasing physical activity, decreasing or abstinence from alcohol consumption, and smoking cessation can have multifactorial benefits for hepatic and extra-hepatic outcomes[74]. Lifestyle interventions can halt the progression of MASLD, prevent severe hepatic injury and reverse histological features of MASLD, and reduce the incidence of HCC. They can also improve cardiometabolic disease risk factors to reduce cardiovascular morbidity and mortality and lifestyle-related cancers, which are the leading causes of death in people with MASLD[74,75]. From a patient-centred perspective, improving health-related quality of life and patient-important outcomes such as fatigue, energy, mental health, gastrointestinal symptoms and physical function should be key objectives of lifestyle intervention. Lifestyle therapy should be integrated into holistic management of MASLD by the multidisciplinary care team including physicians, dieticians, exercise professionals, psychologists, nursing and other allied health professionals.

STRATEGIES FOR CARDIOVASCULAR RISK MANAGEMENT IN MASLD PATIENTS

Given the predominance of cardiovascular mortality in patients with MASLD, current guidelines consistently emphasize the importance of early risk assessment and aggressive management of cardiometabolic comorbidities. Rather than addressing MASLD in isolation, an integrated strategy should target the overlapping metabolic and inflammatory mechanisms that drive both hepatic and cardiovascular complications. This comprehensive approach encompasses sustained lifestyle modification, optimized control of metabolic risk factors, selection of pharmacologic agents with dual cardio-hepatic benefits, and, when appropriate, bariatric or endoscopic interventions. Furthermore, individualized and multidisciplinary care planning is essential to tailoring interventions to each patient’s fibrosis stage, cardiovascular risk level, and comorbid burden. A visual representation of these interlinked strategies is provided in Figure 3.

Figure 3.

Strategic approaches to cardiovascular risk management in metabolic dysfunction-associated steatotic liver disease. This figure illustrates a comprehensive framework for managing cardiometabolic risk in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD). The approach is grounded in four synergistic pillars: (1) Lifestyle interventions, including dietary modifications and regular physical activity, serving as the foundation of care; (2) Pharmacological management with agents such as GLP-1 receptor agonists, SGLT2 inhibitors, metformin, and statins, aimed at optimizing metabolic control and reducing hepatic and cardiovascular burden; (3) Surgical and endoscopic interventions like bariatric surgery, reserved for eligible patients with obesity-related complications; and (4) Multidisciplinary approaches, encompassing patient-centered care models and educational strategies to personalize treatment and promote long-term adherence. This holistic strategy integrates hepatology, cardiology, and metabolic medicine to address the overlapping risks and therapeutic opportunities in MASLD.

Lifestyle interventions

Lifestyle modifications remain the cornerstone of MASLD management, with proven benefits for both hepatic and cardiovascular health. These interventions target the root causes of metabolic dysfunction and are supported by robust clinical evidence.

Dietary modifications: A reduction of 7%-10% in body weight can significantly improve hepatic steatosis, inflammation, and fibrosis[76]. Furthermore, sustained weight loss helps reverse hepatic steatosis, improve insulin sensitivity, and reduce systemic inflammation, thereby lowering cardiovascular risk, a major comorbidity in patients with MASLD[55]. Therefore, dietary modification plays a central role in comprehensive cardiovascular risk management strategies in MASLD patients.

Diets should be individualized according to the patient’s nutritional and metabolic status, while ensuring energy control-typically reducing 500-1000 kcal/day in overweight or obese patients-to achieve a ≥ 7%-10% reduction in initial body weight, which significantly improves hepatic steatosis and related cardiovascular risks[55,77]. Meal composition should prioritize: Complex carbohydrates from whole grains (45%-50% of total energy intake), protein from fish, soy, and lean white meat (20%-25%), and unsaturated fats from olive oil, nuts, and fatty fish like salmon and mackerel (25-30%)[76,78]. Elimination or drastic reduction of simple sugars, trans fats, and ultra-processed foods is essential[77].

Healthcare professionals should actively encourage smoking cessation and the adoption of healthy dietary patterns focused on vegetables, fruits, nuts, and minimally processed whole grains. Increased consumption of leafy greens, lean animal protein, and fish is recommended, while intake of trans fats, red and processed meats, refined carbohydrates, sucrose, fructose, and sugar-sweetened beverages should be limited[55].

Among dietary models, the Mediterranean diet has been shown to be the most effective for patients with MASLD. This diet, rich in leafy vegetables, fruits, legumes, fish, and olive oil, has demonstrated benefits in improving hepatic steatosis, insulin resistance, and cardiovascular risk factors[77,79]. Additionally, the DASH diet is suitable for patients with coexisting hypertension or metabolic syndrome[55]. Notably, the Mediterranean diet is effective in reducing liver fat and improving metabolic markers even in the absence of significant weight loss[79]. Meanwhile, low-carbohydrate and high-protein dietary patterns have shown potential in reducing liver fat in several trials; however, the observed effects are often confounded by concurrent weight loss or reduced caloric intake, making it difficult to isolate the independent benefits of macronutrient manipulation. Therefore, more high-quality randomized controlled trials are needed to validate their specific roles in MASLD management[78]. Lastly, structured dietary frameworks that emphasize antioxidant-rich foods, such as the Nutrient Hazard Analysis and Critical Control Point approach, may offer additional value in mitigating oxidative stress-a key contributor to liver and cardiovascular damage[79]. Dietary interventions can help modulate these mechanisms, thereby improving disease progression.

Beyond diet, the role of alcohol remains controversial. While some studies suggest that light daily alcohol intake may offer cardiovascular benefits, current data indicate that even light to moderate alcohol consumption can increase the risk of liver disease progression in MASLD patients[77]. Systems biology analyses suggest a synergistic interaction between alcohol consumption and metabolic syndrome that exacerbates the pathogenic pathways of hepatic steatosis[77]. Therefore, regardless of any potential cardiovascular benefits, patients with MASLD should be advised to completely abstain from alcohol to preserve liver function.

In addition, intermittent fasting-including time-restricted eating or alternate-day fasting-has emerged as a promising adjunct strategy. This approach may reduce hepatic triglycerides, improve insulin sensitivity, and regulate blood lipids, thereby enhancing the effectiveness of nutritional interventions[2,77]. Dietary plans should be regularly monitored and adjusted based on clinical and laboratory markers such as weight, waist circumference, liver enzymes [aspartate aminotransferase (AST), alanine aminotransferase (ALT)], blood glucose, lipid profile, and glycated hemoglobin (HbA1c). Patient education on maintaining consistent and long-term healthy eating behaviors is crucial to the effective management of MASLD.

Physical activity: Physical activity is one of the key strategies with comprehensive effects in managing cardiovascular risk in patients with MASLD. A growing body of evidence indicates that regular physical activity not only supports weight loss but also confers direct metabolic benefits independent of weight reduction.

Regular exercise reduces cardiovascular risk by lowering blood pressure and improving lipid profiles[55]. In patients with type 2 diabetes and NAFLD, it also reduces liver fat content and visceral adiposity, improves body composition, and enhances insulin sensitivity[80]. Additionally, in patients with type 2 diabetes, structured physical activity has been shown to significantly reduce HbA1c levels, further supporting its role in metabolic control[81].

In terms of exercise modalities, both aerobic training (such as brisk walking, running, cycling) and resistance training (such as weightlifting or muscle-strengthening exercises) have demonstrated effectiveness in reducing hepatic fat and improving metabolic parameters. In the RAED2 study, aerobic or resistance training performed three times per week for four months significantly reduced liver fat in patients with T2DM and NAFLD, even in the absence of significant weight loss[80]. According to current ACC/AHA guidelines, adults should engage in at least 150 minutes of moderate-intensity aerobic activity or 75 minutes of vigorous-intensity activity per week, along with at least two sessions of muscle-strengthening activities per week to optimally prevent CVD[55]. This level of physical activity is also recommended for patients with MASLD, especially when accompanied by risk factors such as diabetes, obesity, or hypertension.

In MASLD patients, physical activity offers specific benefits, including reduction of hepatic fat accumulation, slowing progression to steatohepatitis (MASH) and liver fibrosis, and improvement in overall cardiovascular function, largely through enhanced endothelial function and reduced vascular inflammation[80,81]. Moreover, maintaining regular physical activity helps enhance weight loss outcomes and boost the effectiveness of dietary interventions and/or pharmacologic therapy. In lifestyle intervention programs such as the LOOK-AHEAD trial, or in studies combining nutrition and exercise, patients achieved better outcomes in terms of weight reduction, glycemic control, and liver fat reduction than those who received diet modification alone[82,83].

Finally, physical activity plans must be individualized based on each patient's functional capacity and comorbid conditions. For individuals with CVD, musculoskeletal disorders, or metabolic complications, pre-exercise assessment may be required, and consultation with a physician or rehabilitation specialist may be necessary to ensure safety and long-term adherence[55].

Pharmacological management

Pharmacological therapies play a critical role in managing MASLD and reducing cardiovascular risk, particularly in patients with comorbidities such as T2DM, hypertension, and dyslipidemia.

GLP-1 receptor agonists: GLP-1 receptor agonists (GLP-1RAs) have evolved beyond their original role in glucose regulation to become a cornerstone in the management of cardiometabolic diseases, including MASLD. Since the introduction of exenatide nearly two decades ago, agents such as liraglutide and semaglutide have shown significant benefits in improving glycemic control, promoting weight loss, and reducing cardiovascular events in patients with T2DM or obesity[84-88]. In particular, semaglutide has been associated with a reduction in MACEs, even in obese individuals without diabetes[88].

Emerging dual- and multiagonist therapies, such as tirzepatide (GLP-1/GIP agonist) and survodutide (GLP-1/glucagon coagonist), have demonstrated greater efficacy in weight reduction and improvement in liver histology in patients with MASH, further supporting the cardiometabolic relevance of this class[89-94]. Although histological endpoints remain under investigation in ongoing phase III trials, the cardiovascular benefits of GLP-1RAs are already well established in high-risk populations[2,69].

Interestingly, recent data suggest that GLP-1RAs may also exert their benefits through modulation of the gut-liver axis. These agents appear to influence the gut microbiota composition, thereby improving metabolic health and reducing hepatic inflammation-an effect particularly relevant given the role of intestinal dysbiosis in the pathogenesis of MASLD[95].

Reflecting this evolving evidence base, the EASL–EASD-EASO 2024 Clinical Practice Guidelines recommend GLP-1RAs for patients with MASLD who have comorbid T2DM or obesity. These guidelines highlight the safety of GLP-1RAs even in patients with MASH and compensated cirrhosis and emphasize their positive impact on cardiometabolic outcomes, which is a key therapeutic goal in MASLD management[2].

In summary, GLP-1 receptor agonists offer a unique opportunity to address both hepatic and cardiovascular risks in MASLD through a combination of metabolic regulation, anti-inflammatory effects, cardiovascular protection, and gut–liver axis modulation. The use of these agents should be strongly considered in patients with MASLD who meet standard indications for these agents.

SGLT2 inhibitors: SGLT2 inhibitors are widely recommended for the treatment of T2DM, heart failure, and chronic kidney disease owing to their proven cardiovascular and renal benefits[54,76,96,97]. Specifically, agents such as empagliflozin and dapagliflozin have significantly reduced hospitalizations for heart failure and MACEs in both diabetic and nondiabetic populations[98], making them particularly valuable for patients with MASLD, who often present with overlapping CMRFs.

In addition to their cardiovascular benefits, SGLT2 inhibitors have also demonstrated potential hepatic effects. Several studies have reported reductions in liver fat content and improvements in aminotransferase levels in T2DM patients treated with empagliflozin, dapagliflozin, and licogliflozin[98-102]. Furthermore, in a large Korean cohort involving over 80000 individuals with T2DM and MASLD, SGLT2 inhibitor use was associated with a lower incidence of liver-related events and MASLD regression[103].

However, as no randomized controlled trials (RCTs) with histological liver endpoints are currently available, the EASL-EASD-EASO Clinical Practice Guidelines (2024) do not recommend SGLT2 inhibitors as MASH-specific therapies. Nevertheless, these findings confirm that these agents are safe for use in MASLD patients within their approved indications, given their robust cardiometabolic benefits[2].

Emerging evidence supports the combined use of GLP-1 receptor agonists and SGLT2 inhibitors as a complementary strategy for managing type 2 diabetes with coexisting NAFLD or NASH and elevated cardiovascular risk[104,105]. The SUSTAIN-8 trial further showed that semaglutide and canagliflozin both improved body composition, including reductions in total and visceral fat mass, in patients with uncontrolled type 2 diabetes on metformin[106]. Building on this rationale, several clinical trials such as DURATION-8, AWARD-10, and SUSTAIN-9 have demonstrated that this combination achieves greater reductions in HbA1c and body weight than either monotherapy does[107-109], which may translate into improved hepatic and cardiovascular outcomes in MASLD. Reflecting this, recent ADA-EASD guidelines now advocate for personalized treatment strategies that incorporate such dual therapy in patients with T2DM and coexisting metabolic or liver disease[110].

In summary, while SGLT2 inhibitors are not currently indicated as liver-directed therapies, they-especially when used in combination with GLP-1 receptor agonists-offer substantial promise in addressing both cardiovascular and hepatic risk in MASLD.

Metformin: Metformin remains the first-line pharmacologic agent for patients with T2DM, many of whom have coexisting MASLD. Its cardiometabolic benefits are particularly relevant in this population, where insulin resistance, hepatic steatosis, and atherosclerosis often coexist. Metformin exerts its effects through the activation of adenosine monophosphate-activated protein kinase, resulting in suppressed hepatic gluconeogenesis, increased peripheral glucose uptake, and improved lipid oxidation. These actions not only improve glycemic control but also reduce visceral fat and hepatic lipid accumulation, which are central to the pathogenesis of MASLD[111].

Several studies have demonstrated that metformin can lower liver fat content and improve liver enzyme levels in patients with MASLD and T2DM[112,113]. However, its effects on reversing fibrosis remain limited. Importantly, metformin has demonstrated cardiovascular protective effects, as supported by major trials such as UKPDS and HOME, which reported significant reductions in cardiovascular events and all-cause mortality in overweight patients with T2DM[114,115]. These benefits are attributed to the ability of metformin to reduce systemic inflammation, improve endothelial function, and lower atherogenic risk factors-mechanisms that are highly relevant in MASLD, where CVD is the leading cause of mortality[114,116].

While current guidelines such as those from the AASLD do not recommend metformin as a treatment for MASLD itself[69], its widespread use in patients with T2DM and metabolic syndrome makes it a pragmatic therapeutic option in MASLD patients with elevated cardiovascular risk. Thus, metformin remains a valuable cornerstone therapy in this population, as it targets both metabolic and vascular pathways that contribute to disease burden.

Statins: Statins play a pivotal role in cardiovascular risk reduction for patients with MASLD, who frequently present with an atherogenic lipid profile and other CMRFs. Clinical guidelines recommend moderate- to high-intensity statin therapy in MASLD patients with dyslipidemia or elevated cardiovascular risk, regardless of liver disease severity-except in cases of decompensated cirrhosis or acute liver failure[2,69,117,118].

Despite these recommendations, statins remain significantly underutilized in clinical practice. Observational studies across multiple healthcare systems report that up to 50% of eligible MASLD patients do not receive statin therapy, often owing to concerns over hepatotoxicity in the setting of elevated transaminases[119-121]. However, these enzyme elevations are more commonly a reflection of the underlying liver disease than is statin-induced liver injury. Notably, multiple studies have confirmed that statins not only are safe but also may improve liver biochemistry in MASLD[122-124].

The GREACE study demonstrated that patients with elevated baseline transaminases-presumed secondary to MASLD-who received statins experienced significant improvements in liver function tests and reduced cardiovascular events, with < 1% discontinuing therapy owing to hepatotoxicity[123]. A meta-analysis of 13 studies further revealed that statin therapy improved liver enzymes and histological features without worsening fibrosis[125].

In addition to cardiovascular protection, recent evidence supports a potential hepatoprotective role for statins. In a large cohort study by Choi et al[126] involving over 16500 patients with chronic liver disease, statin use was significantly associated with slower progression of liver fibrosis-measured via longitudinal FIB-4 scores-as well as a reduced risk of hepatic decompensation and HCC. These benefits were independent of baseline fibrosis stage and persisted after adjustment for multiple confounders. This real-world evidence highlights the dual benefit of statins in preventing both cardiovascular and liver-related complications in MASLD patients. In support of this, a meta-analysis of over 2 million individuals reported a 46% lower incidence of HCC among statin users, likely attributed to the anti-inflammatory and pleiotropic effects of statins[126].

Although RCTs with histological endpoints are still lacking, accumulating data from real-world studies and meta-analyses consistently support the efficacy and safety of statins in MASLD populations. In cases where LDL-C targets are not met with statin monotherapy, adjunctive agents such as ezetimibe or PCSK9 inhibitors may be considered, although dedicated data in MASLD remain limited[2,69,125].

Emerging therapies

Proprotein convertase subtilisin/kexin type 9 inhibitors: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are recommended for patients at very high cardiovascular risk who either fail to achieve LDL-C targets despite statin-ezetimibe therapy or are intolerant to statins[127]. Major trials such as FOURIER and ODYSSEY OUTCOMES demonstrated significant reductions in MACE with PCSK9i therapy[128,129]. Although evidence in MASLD remains limited, emerging studies suggest potential hepatic benefits. A randomized trial in 40 patients with familial hyperlipidemia showed complete resolution of MASLD after one year of PCSK9i treatment[130]. Similarly, a retrospective review found that 8 of 11 MASLD patients achieved radiologic resolution alongside significant ALT reduction following PCSK9i therapy[131]. These findings suggest a promising, albeit preliminary, role for PCSK9 inhibitors in addressing both hepatic and cardiovascular risks in MASLD.

Peroxisome proliferator-activated receptor agonists: Peroxisome proliferator-activated receptor (PPAR) agonists, including pioglitazone, lanifibranor, and elafibranor, have been explored for their dual benefits on liver and cardiovascular outcomes in MASLD. Pioglitazone, a PPAR-γ agonist, improves insulin sensitivity and lipid metabolism and has been demonstrated to provide cardiovascular protection in patients with T2DM and atherosclerotic disease, as evidenced by the PROactive trial, which revealed a reduction in MACE[132]. Despite its benefits, concerns remain regarding side effects such as weight gain and fluid retention.

Among newer agents, lanifibranor, a pan-PPAR agonist, has shown promising results in a phase IIb trial, with improvements in liver fibrosis and cardiometabolic markers[133,134]. In contrast, elafibranor, another pan-PPAR agonist, failed to demonstrate significant histological benefits in a RESOLVE-IT (NCT02704403) study-a phase III trial[135].

Current EASL-EASD-EASO guidelines consider pioglitazone safe in noncirrhotic MASH and acknowledge the potential of PPAR agonists but do not endorse them as liver-specific therapies owing to the lack of large-scale phase III evidence[2]. Further research is needed to clarify their role in cardiovascular risk reduction within the MASLD population.

Liver-directed thyroid hormone receptor agonists: Resmetirom, a selective thyroid hormone receptor-β (THR-β) agonist, has emerged as a major breakthrough in the treatment of MASLD. It is the first and currently only agent to demonstrate positive results in a registrational phase III clinical trial (MAESTRO-NASH trial), showing significant histological improvements in non-cirrhotic patients with significant fibrosis (F2-F3)[136].

Based on these robust findings, the United States Food and Drug Administration granted accelerated approval to resmetirom in 2024 for the treatment of non-cirrhotic MASLD patients with fibrosis stages F2–F3[137]. Current EASL-EASD-EASO guidelines also acknowledge resmetirom as an important therapeutic option in appropriately selected patients[2].

Beyond its histological benefits in the liver, resmetirom has also demonstrated favorable effects on cardiovascular risk markers. In the MAESTRO-NAFLD trial, resmetirom significantly reduced atherogenic lipoproteins, including apoCIII, lipoprotein(a), and VLDL-cholesterol, compared to placebo[138]. These improvements in lipid profiles were consistently observed in the MAESTRO-NASH trial as well[136]. This dual impact-targeting both hepatic pathology and CMRFs-highlights resmetirom’s potential not only to slow liver disease progression but also to improve cardiovascular outcomes in MASLD patients. Although long-term cardiovascular endpoint data are still awaited, current evidence positions resmetirom as a key therapeutic advance in the integrated management of MASLD.

Gut microbiota modulation

Modulating the gut microbiota is an emerging strategy to improve metabolic health and reduce cardiovascular risk in MASLD. Prebiotics can promote the growth of beneficial bacteria and increase the production of short-chain fatty acids, which help reduce inflammation, improve insulin sensitivity, and lower hepatic lipid accumulation[139]. Additionally, rifaximin-a nonabsorbable antibiotic-has shown beneficial effects on MASLD by reducing AST, ALT, LDL cholesterol, and body mass index (BMI), suggesting systemic cardiometabolic improvements[140,141]. While further studies are needed, gut-targeted therapies may represent a supportive approach for reducing cardiovascular risk in MASLD patients.

The differential hepatocardiac effects of major pharmacologic agents are systematically compared in Table 1, highlighting the need for therapy personalization based on dominant disease manifestations.

Table 1.

Comparative hepatocardiac effects of pharmacologic therapies in metabolic dysfunction–associated steatotic liver disease

Drug class	Hepatic effects	Cardiovascular effects	Clinical notes
GLP-1 receptor agonists	Improves liver histology, reduces inflammation; supports weight loss	Reduces major adverse cardiovascular events	First-line in MASLD with type 2 diabetes mellitus or obesity; safe in compensated cirrhosis
SGLT2 inhibitors	Reduces hepatic steatosis, improves liver enzymes	Decreases heart failure hospitalizations, cardiorenal protection	Superior cardiovascular benefits; potential synergy with GLP-1RAs
Statins	Safe, may improve liver enzymes	Significantly reduces cardiovascular events	Preferred in MASLD with CV risk; avoid in decompensated cirrhosis
THR-β agonists	Markedly improves liver fibrosis	Limited cardiovascular data available	Promising but requires further research
PPAR agonists	Improves hepatic inflammation	Variable effects depending on specific agent	Pioglitazone beneficial in diabetic patients
Metformin	No improvement in liver histology	Beneficial for diabetic patients	Not recommended for MASLD alone

MASLD: Metabolic dysfunction-associated steatotic liver disease; THR-β: Thyroid hormone receptor-β; PPAR: Peroxisome proliferator-activated receptor.

Surgical and endoscopic interventions

Bariatric (metabolic) surgery is increasingly recognized as an effective strategy for improving both hepatic and cardiovascular outcomes in patients with MASLD and obesity. Procedures such as Roux-en-Y gastric bypass and sleeve gastrectomy not only promote sustained weight loss and resolution of T2DM but also significantly reduce MACE, all-cause mortality, and liver-related outcomes[142-144]. In the SPLENDOR study and other meta-analyses, bariatric surgery was associated with improvements in liver histology and a 30%-40% reduction in fibrosis in MASLD patients[144,145]. Notably, randomized trials have demonstrated MASH resolution in more than half of surgical patients and improved blood pressure and lipid profiles, making these procedures particularly beneficial for individuals with high cardiometabolic risk[146].

Current guidelines recommend considering bariatric surgery in noncirrhotic MASLD patients with a BMI ≥ 40 kg/m² or ≥ 35 kg/m² with comorbidities and even in patients with a BMI ≥ 30 kg/m² with poorly controlled T2DM or hypertension[147]. For patients with compensated cirrhosis, surgery may still be considered with careful multidisciplinary evaluation[69].

In contrast, endoscopic bariatric therapies-such as intragastric balloon placement, endoscopic sleeve gastroplasty, or duodenal mucosal resurfacing-offer a minimally invasive alternative for patients who are not surgical candidates or prefer nonsurgical options. These procedures have resulted in moderate improvements in hepatic steatosis, insulin resistance, and cardiovascular risk markers[148,149]. However, owing to limited long-term and histology-based data, they are not yet recommended as standard therapies for MASLD, and further studies are warranted.

In summary, bariatric and emerging endoscopic interventions offer promising cardiometabolic benefits in MASLD and should be considered in appropriately selected patients to reduce cardiovascular risk and liver disease progression.

Integrated and multidisciplinary approaches

To effectively manage MASLD and its cardiovascular complications, an integrated and multidisciplinary approach is essential. This strategy ensures that both hepatic and cardiovascular health are addressed simultaneously, optimizing patient outcomes.

The need for multidisciplinary collaboration: Effective management of MASLD and CVD requires close collaboration between hepatologists, cardiologists, endocrinologists, and primary care providers. A multidisciplinary team can develop comprehensive care plans that address the full spectrum of metabolic, hepatic, and cardiovascular risks. For example, hepatologists can monitor liver health and fibrosis progression, whereas cardiologists focus on reducing cardiovascular risk through targeted therapies.

The link between MASLD and cardiometabolic disease is gaining attention through articles, research groups, and awareness campaigns aimed at improving multidisciplinary care for patients. This raises questions about the co-occurrence of MASLD and atherosclerotic CVD, its causes, and the need for screening and mutual care. Moreover, MASLD is highlighted as an important health care task, requiring close collaboration between specialties such as hepatology, general medicine, diabetes, and cardiology, with increasing support from international guidelines for a multidisciplinary approach[128].

Patient-centered care: A patient-centered approach is essential for improving outcomes in MASLD management. This begins with a comprehensive assessment that not only evaluates liver and cardiovascular health but also considers psychosocial factors such as mental well-being, social support, and lifestyle constraints-all of which can influence treatment adherence.

Personalized treatment plans should be developed on the basis of the individual’s specific clinical profile, preferences, and comorbidities. For example, patients with advanced fibrosis may benefit from more aggressive monitoring and therapy than patients with simple steatosis. Tailoring the approach in this way ensures that interventions are both clinically appropriate and aligned with the patient’s goals.

Equally important is shared decision-making. Engaging patients in discussions about their treatment options and expected outcomes empowers them to take an active role in managing their condition, which is linked to improved satisfaction and long-term adherence.

The evidence supports the role of behavioral therapy in helping patients modify their dietary habits, increase their physical activity, and strengthen their self-management skills. These strategies are effective in achieving sustainable weight loss and improving the histological features of MASH. Moreover, addressing psychosocial barriers—such as anxiety, depression, or lack of support-can further enhance motivation and treatment success[73,150,151].

The role of education and awareness: Educating patients about the interconnection between MASLD and CVD is essential to promote self-management, improve treatment adherence, and empower individuals to take an active role in reducing their cardiometabolic risk. Rather than offering generic advice to lose weight, healthcare providers should support patients in adopting sustainable lifestyles and behavioral changes-starting with the early identification of barriers to effective weight management[152].

Dietary and physical activity recommendations should be personalized to align with each patient’s medical condition, preferences, and socioeconomic context, thereby increasing the likelihood of long-term adherence[152]. Patients should be clearly informed that lifestyle modifications and appropriate pharmacotherapy can yield dual benefits-ameliorating liver steatosis while also improving cardiovascular health. Equally important is ensuring that healthcare professionals are equipped with up-to-date knowledge and clinical guidelines to provide consistent, evidence-based care.

FUTURE RESEARCH OPPORTUNITIES

Closing the gaps in MASLD and CVD management requires ongoing research to address unanswered questions and develop innovative solutions, with several areas identified as key opportunities for advancing care and improving patient outcomes.

Development of specialized risk assessment tools

Future research should focus on creating MASLD-specific risk assessment tools that incorporate liver-specific markers (e.g., the FIB-4 index and liver stiffness measurements) and metabolic parameters. These tools will enable more accurate risk stratification and personalized treatment plans.

New noninvasive prediction methods, such as high-resolution computed tomography, magnetic resonance imaging, and biomarkers (FIB-4, FAST), are opening new opportunities for the early detection of MASLD and the assessment of complications such as osteoporosis, cirrhosis, and hepatitis[153-156]. However, the effectiveness and stability of these technologies need to be further validated through large-scale studies.

Evaluating the long-term efficacy of emerging therapies

While several emerging pharmacologic agents-such as GLP-1 receptor agonists, SGLT2 inhibitors, PPAR agonists, and THR-β agonists-have demonstrated promising dual benefits in terms of liver histology and cardiometabolic parameters, their long-term efficacy in reducing cardiovascular events in patients with MASLD remains uncertain. Most available data are derived from short- to midterm studies, surrogate markers, or extrapolated cardiovascular outcomes in broader diabetic or obese populations.

Currently, there is a critical lack of large-scale RCTs that directly evaluate the impact of these therapies on cardiovascular endpoints, especially in MASLD cohorts. Moreover, while improvements in liver enzymes, steatosis, and fibrosis have been documented, the translation of these hepatic benefits into meaningful cardiovascular risk reductions has yet to be firmly established.

Future research must prioritize well-designed, long-term outcome trials that include both hepatic and cardiovascular end points. This is essential not only for confirming the dual-organ efficacy of emerging treatments but also for guiding integrated therapeutic strategies for MASLD patients, who remain at high residual cardiovascular risk despite advances in pharmacotherapy.

Optimizing lifestyle intervention programs

Research is needed to identify the most effective lifestyle interventions for MASLD patients. A "one-size-fits-all" approach to lifestyle interventions is unlikely to be effective. Lifestyle intervention for MAFLD should be based on a comprehensive 24-hour strategy that simultaneously integrates diet, physical activity and exercise; reducing sedentary time; smoking; alcohol restriction; and improved sleep[157]. Research should explore the role of culturally tailored interventions and behavioral support programs in promoting long-term adherence to dietary and exercise recommendations.

Harnessing the potential of digital health

Digital health technologies present promising opportunities to transform the management of MASLD by supporting behavior change, facilitating risk stratification, and enabling continuous care. Mobile applications and wearable devices allow real-time tracking of dietary intake, physical activity, and medication adherence, thereby offering patients personalized feedback and motivation. Systematic reviews and meta-analyses have demonstrated the effectiveness of these digital interventions in improving weight-related outcomes and promoting lifestyle modification[158-160].

In addition, artificial intelligence (AI) has potential for developing risk prediction models by integrating clinical, genetic, and behavioral data to identify high-risk individuals and personalize treatment strategies. Such AI-based tools may support earlier diagnosis and tailored interventions, improving both hepatic and cardiovascular outcomes. Furthermore, the use of telemedicine and remote monitoring platforms enables timely clinical decision-making while reducing the burden of in-person visits. These technologies are particularly valuable in managing chronic conditions such as MASLD, where sustained engagement and monitoring are essential for long-term success.

CONCLUSION

MASLD has emerged as a pivotal metabolic disorder with far-reaching cardiovascular implications, necessitating a fundamental rethinking of its clinical management. The recognition of shared pathophysiological pathways has catalyzed the development of dual-purpose therapies, from established agents like GLP-1RAs and SGLT2 inhibitors to groundbreaking liver-targeted treatments such as resmetirom. However, the field continues to grapple with significant challenges-particularly the absence of validated cardiovascular risk stratification tools specific to MASLD populations and insufficient long-term outcome data for emerging pharmacotherapies. These knowledge gaps underscore the urgent need for collaborative, multidisciplinary frameworks that integrate hepatology and cardiology perspectives. Moving forward, the research and clinical communities must prioritize the development of precision risk assessment methodologies, rigorous evaluation of therapeutic interventions through prospective trials, and implementation of integrated care pathways. By addressing these priorities, we can transform the current fragmented approach into a cohesive strategy that effectively mitigates the substantial cardiovascular burden borne by MASLD patients worldwide.

ACKNOWLEDGEMENTS

We would like to express our sincere gratitude to all the authors for their dedication and efforts in completing this study. We are especially thankful to Duong Hung Tran for his valuable support in formatting and editing the manuscript. We also extend our appreciation to the Heart and Metabolic Innovations Research Team (HAMIRT) for their collaborative spirit and meaningful contributions to this research.