The descriptive characteristics of the study participants are shown in Table 1. There were 179,437 men (53.8%) and 153,952 women (46.2%) with a median age of 57 (IQR, 51-64), a total follow-up period of 1,850,704 PY, and a total CVD event of 32,411 cases. The median BMI and WC were 23.9 kg/m2 (IQR, 22.0-25.8) and 82 cm (IQR, 76-87), respectively. Among entire study population, 46,319 participants (13.9%) had HS. Compared to the participants with no HS (n=287,070), the participants with HS (n=46,319) revealed significantly higher proportion of men, smoking, alcohol consumption, chronic viral hepatitis, hypertension, type 2 DM, dyslipidemia, and CCI≥2, indicating that the HS group had a higher cardiometabolic risk than the non-HS group (Supplementary Table 2).
Associations of HS, MD, and MAFLD with CVD risk
We first examined the association of HS with CVD using the HSS and FLI (Supplementary Table 3). HS was in direct proportion to CVD risk since both 4th quartile groups of HSS and FLI showed highly increased CVD risk compared to 1st quartile groups. The discriminative performance of the HSS in the prediction of CVD was more effective than that of the FLI in terms of the CVD incidence rates. Subsequently, the study population was stratified into 4 groups, including very low, low, moderate, and high HSS. The median HSS of the participants with no ruled in nor ruled out for HS were −1.690, which was set as the cut-off for stratification into low and moderate HSS groups. The incidence rate of CVD was lowest in very low HSS, followed by low, moderate, and high HSS (Table 2). Among participants with no MD, the aHRs were 1.30 (95% CI, 1.17-1.44), 1.24 (95% CI, 1.01-1.52), and 1.27 (95% CI, 0.78-2.06) for low, moderate, and high HSS, respectively. In addition, HS was found to significantly increase CVD risk (aHR, 1.17; 95% CI, 1.08-1.27) only among participants with ≥2 MDs, who corresponded to the MAFLD group, suggesting that significantly increased CVD risk in overall population might be highly attributed to participants with ≥2 MDs. Subgroup analysis of the effect of HS on incident CVD among subjects with MD showed that a significant trend of increased CVD risk by HS severity was observed in all subgroups except for CCI=0 (Table 3). To confirm whether the prognostic impact of MAFLD on incident CVD is consistent across various cardiovascular risk factors, subgroup analyses were carried out after stratifying the study population into MAFLD and non-MAFLD (Fig. 2). Differing from the effect of HS on incident CVD shown in Table 3, MAFLD significantly increased CVD risk only in the age≥65 years, male, past or current smoker, BMI<25 kg/m2, and CCI≥1 subgroups.
When examining the combined effect of the HSS and MD on CVD risk, both the HSS and MD additively increased the risk of CVD (Fig. 3). aHR of the HSS>0.884 and ≥2 MDs group (i.e., the MAFLD group), was 2.22 (95% CI, 2.07-2.38) compared to the HSS<−3.285 and no MD group (i.e., the reference group) (Supplementary Table 4). Considering the validity of the FLI in the reflection of HS, we stratified the participants according to the IQR of the FLI. In accordance with the HSS, the 4th quartile of the FLI with ≥2 MDs had the highest aHR of 2.23.
Sensitivity analyses on the associations of HS and MAFLD with CVD risk
To support the aforementioned effects of HS and MAFLD on incident CVD, 1-2 years of latent periods were washed out to exclude potentially uncontrolled factors. After 1-year wash out, HS lost its significant association with the risk of incident CVD, whereas the association of MAFLD with incident CVD risk remained significant (aHR 1.05; 95% CI, 1.00-1.10; Supplementary Table 5). After washing out 2 years of latent period, similar results were found for HS and MAFLD, supporting that MAFLD is an independent predictor of incident CVD. We also adopted the HSI as a proxy for HS and NAFLD and reaffirmed that MAFLD was significantly associated with increased CVD risk (aHR, 1.15; 95% CI, 1.11-1.19) in agreement with the findings based on the HSS and FLI (Supplementary Table 6).
Comparison of NAFLD and HS with and without MD in the prediction of CVD risk
According to the different probability levels of NAFLD ranged by the HSS cutoffs, the incidence rates of CVD were 20.0, 20.5, and 25.2 in the very low, low-to-moderate, and high probability NAFLD subgroups, respectively. (Table 4) In terms of the different probability levels of HS, the incidence rates of CVD were 12.0, 18.6, and 22.1 in the very low, low-to-moderate, and high probability HS subgroups, respectively. Furthermore, stratification of the participants with HS into MD=0, =1, and ≥2 revealed that the no MD group had the lowest incidence rate (9.0) despite the presence of HS. Of the HS subgroups, the 1 MD group also showed a relatively lower incidence rate (14.9) compared to NAFLD with low-to-moderate probability (20.5) or HS with low-to-moderate probability (18.6), suggesting that the presence of MD may be more effective in the prediction of CVD risk compared to the presence of NAFLD or HS. Moreover, MAFLD was more predictive of overall CVD incidence in the receiver operating characteristic contrast estimation compared to NAFLD without statistical significance (P=0.060; Supplementary Table 7).
Associations of the different MAFLD subphenotypes with CVD risk
When stratifying MAFLD into three subphenotypes, DM-negative overweight/obese, DM-negative normal weight, and DM-positive subphenotypes showed significantly increased CVD risk in all unadjusted and adjusted models (Table 5). However, after further adjusting for the number of MD, only DM-MAFLD subtype significantly showed an increased risk of CVD despite the attenuation of statistical significance (aHR, 1.18; 95% CI, 1.10-1.26), but both DM-negative overweight/obese and DM-negative normal weight subphenotypes lost their statistical significance (Table 5).