This historical cohort study aimed to clarify the association between the presence of MetS and MAFLD, which share the common pathophysiological background of IR, and the risk of developing cardiovascular disease. Results showed that, overall, MetS had slightly superior predictive ability for the development of cardiovascular disease than MAFLD. However, the results differed greatly depending on sex and the presence or absence of type 2 diabetes as well as between CAD and CVD.
One reason for the superiority of the MetS diagnosis over the MAFLD diagnosis in predicting future cardiovascular disease in the analysis of non-type 2 diabetes participants is that MetS may be more closely associated with atherosclerosis due a broader range of pathological conditions not limited to IR. Results suggested that MAFLD was associated with more severe IR indicated by higher values for VAI, BMI, WC, and FLI than for MetS only. Although the MetS-only group had values that indicated a milder IR than the MAFLD-only group, that group was older, had higher pulse pressure, a greater proportion of hypertensive and diabetic patients, and higher use of statins, suggesting that the atherosclerosis in these individuals may be more advanced as indicated by advanced vascular calcification [25, 26]. As in our previous report, MetS as a predictor of cardiovascular disease was reduced in type 2 diabetes patients who were already at high risk for atherosclerotic disease . However, in predicting the development of CAD but not CVD, MAFLD was shown to be useful even in patients with type 2 diabetes, which is associated with more severe IR than MetS. This result can be interpreted as indicating that the presence of more severe hyperinsulinemia is an additional risk factor for CAD, even in those with type 2 diabetes.
Neither the presence of MetS only or MAFLD only was useful in predicting the development of CVD in persons with type 2 diabetes. Unlike CAD, the association between IR and CVD development has not been clarified [27, 28]. The results of this study may be related to the difference in the impact of IR on the development of both CAD and CVD. It is also of interest that even in patients with type 2 diabetes MetS-only and MAFLD-only did not increase CVD risk but if both were present, the CAD risk increased. The severity of fatty liver and the progression of liver fibrosis have been significantly correlated with the risk of stroke . In this study, the FLI was significantly higher in the group with both MAFLD and MetS compared with the other groups, even in groups with diabetic patients. Increased FLI has been reported to reflect the progression of liver fibrosis to some extent . It is possible that individuals having both MetS and MAFLD had more severe fatty liver and more advanced liver fibrosis than the other study groups, which may have influenced our results.
As to sex differences in the impact of MetS and MAFLD on the development of cardiovascular disease, results showed that MetS had a strong impact on the development of CAD in women. Even when women have risk factors for CAD, premenopausal women are less likely to develop fatty liver. Estrogen has been reported to have a strong protective effect against fatty liver in premenopausal women [15, 31, 32]. Unfortunately, information on menopause was not available for this study, but considering that 72% of female participants were younger than 50 years it can be inferred that the majority of female participants were premenopausal.
On the other hand, MAFLD only was not associated with a significantly increased risk of developing CAD in females. We hypothesized that this is because the MAFLD-only group of female participants were younger than the group with MetS and included a lower percentage of those with hypertension, type 2 diabetes, and statin use.
MAFLD did have a strong impact on the development of CAD in men. In men, unlike in women, MetS was almost always combined with MAFLD, and a MetS diagnosis captured only a small proportion of those having concomitant MAFLD. Thus, many patients with MAFLD are overlooked only by a diagnosis of MetS. Thus, for assessment of risk of CAD, in men it is more appropriate to use a diagnosis of MAFLD. In addition to the influence of sex hormones, a wide variety of mechanisms were reported to be responsible for these sex differences in both men and women, [33, 34]. Further research is expected to elucidate these mechanisms.
A strength of the current study is that it is the first large-scale clinical study to directly compare the impact of MetS and MAFLD on the risk of developing cardiovascular disease, stratified by the presence or absence of type 2 diabetes and by sex, using real-world data. It is known that the impact of MetS and MAFLD on cardiovascular events is strongly influenced by the presence or absence of type 2 diabetes and by sex [15, 35], but there are insufficient detailed studies stratified by these factors . The combination of DPC, ICD-10 codes, contents of prescribed medications, and medical procedures performed enabled accurate identification of CAD and CVD events [23, 24].
This study had the following limitations. First, since the database used is for Japanese company employees and their dependents, it included few elderly people. Also, no information on menopause was available, which may have played a role in the results. Second, in the identification of fatty liver, the FLI was used because no imaging or histopathological information was available. However, the FLI has been considered appropriate and is widely used to identify fatty liver in large-scale clinical studies [11, 13]. In addition, the currently proposed diagnostic criteria for MAFLD allowed the use of a biomarker-based index such as the FLI to identify fatty liver . Third, the diagnostic definition of MAFLD, unlike NAFLD, includes either the presence or absence of liver diseases, and the impact of liver diseases such as viral hepatitis could not be considered due to lack of information. Fourth, data on high-sensitivity CRP, HOMA-IR, and the glucose tolerance test, which are diagnostic criteria for MAFLD, were not available in this database, making it possible that MAFLD was underdiagnosed. However, we calculated and used VAI as an alternative index for HOMA-IR, which is considered to reflect IR without being inferior to HOMA-IR. Fifth, liver fibrosis is associated with the development of cardiovascular disease , but the database had no information on liver fibrosis. Finally, although we considered a large number of risk factors that might have influenced the development of cardiovascular disease, we did not have information on renal function, atrial fibrillation, etc., that may present a risk of cardiovascular disease.