Metabolic dysfunction-associated steatotic liver disease and diabetes: Together against the heart

Abstract

Cardiovascular events are the main cause of mortality in individuals with type 2 diabetes mellitus (T2DM) and also in those with metabolic dysfunction-associated steatotic liver disease (MASLD). In this editorial, we comment on the results of a meta-analysis published by Shetty et al that shows an addictive risk for cardiovascular events when both pathologies are together. Patients with MASLD and T2DM have the worst prognosis related to liver disease since they have a higher risk for metabolic dysfunction-associated steatohepatitis, disease progression, and hepatocarcinoma. The meta-analysis included 370013 participants and showed that, although with high heterogeneity, there is a higher prevalence of cardiovascular events in patients with T2DM when MASLD is diagnosed compared to those without MASLD. Hence, MASLD and T2DM may have a new interplay regarding cardiovascular outcomes in addition to the already known liver-related outcomes.

Key Words: Meta-analysis; Cardiovascular outcomes; Liver outcomes; Type 2 diabetes mellitus; Liver steatosis; Metabolic dysfunction; Interplay

Core Tip: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease, affecting about 38% of adults worldwide. MASLD is closely associated with the growing obesity epidemic and the increasing burden of type 2 diabetes mellitus. These diseases pose a substantial threat to public health, with repercussions ranging from social to economic burden worldwide. Although the conclusion of this meta-analysis has already been displayed in individual articles, this present analysis included 370013 participants and corroborates the interplay between these two epidemic diseases and highlights the importance of adequate screening for cardiovascular and liver disease in this population.

INTRODUCTION

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease, affecting approximately 38% of adults worldwide[1,2]. MASLD is closely associated with the growing obesity epidemic and the increasing burden of type 2 diabetes mellitus (T2DM)[2-4]. Together, these diseases pose substantial threat to public health, with repercussions ranging from social to economic[5]. T2DM is a major risk factor for the onset and progression of MASLD[6,7]. It disrupts glucose and lipid metabolism, leading to systemic metabolic disorders and organ dysfunction; the two conditions overlap in approximately 65% of patients with T2DM[4], encompassing a subgroup at increased risk for liver fibrosis progression, hepatic decompensation, and hepatocellular carcinoma[7,8].

In this issue of World Journal of Hepatology, Shetty et al[9] conducted a systematic review and meta-analysis of 14 studies with 370013 participants to examine the impact of MASLD coexistence on cardiovascular risk in patients with T2DM. In studies with a follow-up period ranging between 5-6 years, they found that patients with T2DM and MASLD had a higher risk of cardiovascular events (defined as a composite outcome of cardiovascular death, nonfatal myocardial infarction, late coronary revascularization, nonfatal stroke, or hospitalization for heart failure) compared to those without MASLD[9]. The study also demonstrated that the MASLD-T2DM group had a significantly higher prevalence of cardiovascular disease[9]. Notably, as acknowledged by the authors, this study has important limitations, including a lack of adjustment for recognized confounders (e.g., age, sex, duration of diabetes, obesity and use of background medications), which may have biased the magnitude of the observed associations. Additionally, the predominance of cross-sectional data in several included studies limits causal inference. The analysis also showed considerable between-study heterogeneity in terms of design, population, MASLD diagnosis/definition, and outcome ascertainment, as reflected by high I² values. There was also potential selection bias, which might restrict the generalizability of the findings. Overall, these limitations call for a cautious interpretation of the findings of the study by Shetty et al[9]. Nevertheless, the observed associations highlight the important role of MASLD on cardiovascular outcomes in T2DM and have clinical implications for the management of patients with MASLD-T2DM.

Screening for MASLD and liver fibrosis should be considered in T2DM population. Most patients with T2DM have comorbid MASLD, a subgroup of which approximately 35% have clinically significant fibrosis (i.e., F2-F4)[4]. Shetty et al’s reinforces MASLD[9] as an additive in the risk of cardiovascular events, considered the leading cause of mortality in this liver disease[10]. Identifying high-risk patients early could help guide treatment and an opportunity to reduce the risk of cardiovascular complications. While there is no consensus on screening these patients, most guidelines recommend using the fibrosis-4 score–a simple, blood-based biomarker that includes age, aspartate aminotransferase, alanine aminotransferase, and platelet count–as an initial, non-invasive approach to identifying higher-risk patients; these patients can then undergo further evaluation using more accurate methods, such as elastography[11]. In addition, glucose monitoring can be a helpful tool for assessing the course of MASLD beyond T2DM diagnosis[11]. Glycated hemoglobin (HbA1c) is a valuable indicator of MASLD severity[12]; specifically, a 1% increase in mean HbA1c is associated with a 15% higher likelihood of an increased fibrosis stage[13]. Changes in liver disease severity over time can be reflected by continuous glucose monitoring[12,13], and glycemic control should be a key treatment target for patients with MASLD-T2DM.

It is essential to co-manage MASLD and T2DM to reduce the associated cardiovascular risk. MASLD is a multisystemic disease requiring a multidisciplinary approach[10]. The emerging concept of "cardio-liver-metabolic health" reflects this idea, emphasizing the coexistence of metabolic diseases and the need for comprehensive care[14,15]. Lifestyle intervention remains the cornerstone of managing T2DM and MASLD. In the setting of pharmacological treatment, there is compelling evidence demonstrating the efficacy of antidiabetic medications, particularly glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors, in reducing cardiovascular events in patients with T2DM[16-20]. These medications have also been repurposed to treat MASLD and have shown promising long-term results in population-based cohorts[21-23] and liver histology improvements in early-phase trials[24-26]. More recently, the landmark phase 3 ESSENCE trial showed that semaglutide resolved steatohepatitis and improved fibrosis, and approval of this medication for treating liver disease is expected soon[27-29]. Other drugs, such as the dual agonist of glucose-dependent insulinotropic polypeptide and GLP-1R, which was originally developed for T2DM, are also being tested for the treatment of MASLD[28,30].

DIRECTIONS FOR FUTURE RESEARCH

Important questions remain to be answered in future studies. Currently, many patients with T2DM are not routinely checked for liver health[31]. This indicates that some healthcare providers still lack awareness, in part due to the misconception that MASLD is strictly a liver disease and the suboptimal understanding of its silent, yet harmful, nature.

CONCLUSION

More efforts are needed to educate and train professionals across different specialties. For example, integrating liver health assessments into clinical guidelines for endocrinologists, diabetologists, and cardiologists could increase awareness and promote interdisciplinary research. Prospective cohort data are needed to confirm the findings of this meta-analysis and to evaluate the long-term impact of MASLD comorbidity on the risk of microvascular complications and extrahepatic cancers in patients with T2DM. Additionally, identifying the impact of social determinants of health on MASLD progression in T2DM is important.