The Triad of Risk: Linking MASLD, Cardiovascular Disease and Type 2 Diabetes; From Pathophysiology to Treatment

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging global health concern, and it is not only the keystone precursor of eventual liver-related morbidity, but it also places patients at considerably higher cardiovascular risk, which is still a leading cause of death in these patients. The most important common underlying pathophysiological mechanisms in these diseases are primarily related to insulin resistance, chronic inflammation and oxidative stress. The presence of MASLD with cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) elevates the risk for poor outcomes, thus this review highlights a method to the therapeutic approaches. Given the intertwined nature of MASLD, T2DM, and CVD, there is an urgent need for therapeutic strategies that address all three conditions. Although lifestyle changes are important as treatment, medication plays a crucial role in managing hyperglycemia, enhancing liver function and lowering cardiovascular risk. The onset and progression of MASLD should be addressed through a multifaceted therapeutic approach, targeting inflammatory, immune, metabolic, oxidative stress, hormonal and gutaxis pathways, alongside the treatment strategies for T2DM. In this review, we discuss the effects of antidiabetic drugs with an impact on both liver outcomes and cardiovascular risk in patients affected by MASLD, T2DM and CDV.

Keywords: antidiabetic drugs; cardiovascular disease; diabetes mellitus; metabolic dysfunction-associated fatty liver disease; pathophysiology; treatment.

Figure 1

The triad of risk: Metabolic dysfunction-associated steatotic liver disease fatty liver disease (MASLD), diabetes mellitus, and cardiovascular disease (common CVD like atherosclerosis, myocardial infarction, heart failure, arrhythmias which are associated with diabetes mellitus and MASLD), metabolic-associated steatotic liver disease steatohepatitis (MASH). The red arrow shows that the metabolic syndrome and insulin resistance are main causes for the strong interaction and association of MASLD and Diabetes (big black arrows). The thin single black arrows show the path-effect while the double ones black arrows the interaction between the conditions.

Figure 2

The pathophysiological link between metabolic dysfunction-associated steatotic liver disease (MASLD) (previously known as NAFLD: Nonalcoholic fatty liver disease), diabetes mellitus and cardiovascular disease (CVD). Tg: triglycerides; LDL: low-density lipoprotein; HDL: high-density lipoproteins. Insulin resistance is associated with an increase infree fatty acids that contributes to increased TG production that stimulates secretion of LDL in hepatocytes. Fat accumulation in the liver is associated with oxidative stress and lipid peroxidation. Additionally, an increased secretion of inflammatory markers and plasma glucose and a decrease in HDL concentration have been observed in MASLD patients. The result of this physiological dysfunction is increased risk for the development of diabetes and atherosclerosis and increased risk for coronary artery disease. The single arrows regardless of color and thickness mean “leads to”, the double thin black arrows indicate the interaction.

Figure 3

Algorithm of monitoring based on FIB-4 (FIB-4: fibrosis-4).

Figure 4

General management of MASLD (MASLD: Metabolic dysfunction-associated steatotic liver disease, MASH: Metabolic Dysfunction-Associated Steatohepatitis and BMI: body mass index).