Background
The prevalence of type 2 diabetes mellitus (T2DM) has been increasing rapidly worldwide [
1]. T2DM is associated with a two- to four-fold increased risk of cardiovascular events compared with non-T2DM subjects [
2,
3]. The prevention of cardiovascular events in T2DM patients has thus become a major concern. Although several clinical risk scores for predicting cardiovascular events have been proposed, there is currently no widely used risk stratification for T2DM patients. Previous studies showed that coronary artery calcium score (CACS) determined by coronary computed tomography (CT) provided additional information on cardiovascular events in T2DM patients beyond that provided by the commonly used Framingham risk score (FRS) [
4,
5]. The latest American Heart Association and American College of Cardiology (AHA/ACC) guidelines for the primary prevention of atherosclerotic cardiovascular disease allowed the use of CACS in intermediate-risk patients if the risk level was uncertain [
6]. Thus, CACS could be a useful factor for determining cardiovascular risk in patients with T2DM.
Growing evidence suggests that non-alcoholic fatty liver disease (NAFLD) is associated with cardiovascular events independently of established cardiovascular risk factors [
7‐
9]. NAFLD is a frequent comorbidity of metabolic syndrome and T2DM [
10]. Previous studies showed that metabolic syndrome and T2DM might be predictors of vascular damage [
11,
12], and complex and bidirectional associations have been demonstrated between NAFLD and metabolic syndrome and T2DM [
13]. We recently reported on the prognostic value of NAFLD assessed by non-enhanced CT in patients with suspected coronary artery disease who underwent coronary CT angiography [
14], highlighting the benefits of concomitant assessment of liver fat content during the acquisition of coronary CT angiography to detect patients at higher risk of cardiovascular events.
We therefore hypothesized that the assessment of NAFLD using non-enhanced CT, in addition to CACS and FRS, might improve risk stratification for cardiovascular events in T2DM patients. We tested this hypothesis in a cohort of patients with suspected coronary artery disease who underwent CACS measurement, with the aim of evaluating the additional prognostic value of NAFLD compared with CACS and FRS in T2DM patients.
Discussion
This study demonstrated that the presence of NAFLD in non-enhanced CT images, in addition to CACS and FRS, improved the risk classification of cardiovascular events in T2DM patients. However, this study was conducted in a cohort of T2DM patients with suspected coronary artery disease, and further studies are needed to determine if the results apply to all T2DM patients.
Several lines of evidence have shown that NAFLD is associated with an increased risk of cardiovascular events in T2DM patients. Lee et al. showed that NAFLD was independently associated with progression of carotid intima-media thickness, as a well-established surrogate marker of subclinical atherosclerosis, in T2DM patients [
21]. In an observational study of 2103 T2DM patients, NAFLD was associated with an increased incidence of cardiovascular events after adjustment for multiple risk factors (HR 1.96, 95% CI 1.4–2.7) [
22]. However, the mechanisms by which NAFLD increases the risk of cardiovascular events are complex and not fully understood. A previous study showed that the histological severity of NAFLD was associated with increased arterial stiffness and endothelial dysfunction [
23]. In addition, inflammatory cytokines increased in line with the severity of liver disease in NAFLD patients [
24]. The presence of systemic inflammation promoted by cytokines secreted from the liver leads to endothelial dysfunction, altering vascular tone and enhancing vascular plaque formation. This mechanism was supported by a clinical study that found a significant association between the severity of NAFLD and both surrogate markers of atherosclerosis and an increased risk of cardiovascular mortality in NAFLD patients [
25‐
28].
CACS is a well-established surrogate marker of subclinical coronary artery atherosclerotic plaque burden, which can predict risk beyond the established cardiovascular risk score. Budoff et al. reported that CACS was independently and strongly associated with cardiovascular events, and CACS > 100 signified at least a 7.5% 10-year risk of cardiovascular events regardless of age, sex, or ethnicity among 6814 subjects from the general population [
29]. CACS is also used to predict cardiovascular risk in T2DM patients, with elevated CACS in T2DM compared with non-T2DM subjects [
30]. The Diabetes Heart Study comprising 1123 T2DM patients demonstrated that CACS predicted cardiovascular events more accurately than FRS [
4]. In addition, the 2019 AHA/ACC guidelines for the primary prevention of atherosclerotic cardiovascular disease included the measurement of CACS for patients in intermediate-risk groups [
6]. These data support the possible use of CACS as a means of assessing risk for cardiovascular outcomes in T2DM patients.
Hepatic steatosis has been reportedly associated with the presence of coronary artery calcium in some studies [
31‐
33]. In addition, Sung et al. reported that hepatic steatosis was independently associated with coronary artery calcium progression [
34]. However, the association between NAFLD and CACS has been inconsistent across studies, especially in T2DM patients. In a study of 213 participants with T2DM, NAFLD was not associated with CACS in patients with glycated hemoglobin A1c (HbA1c) < 7%, but was significantly associated with CACS in patients with HbA1c ≥ 7% [
35]. In contrast, McKimme et al. reported no significant association between hepatic steatosis and CACS in T2DM patients [
36]. Kim et al. reported an association between NAFLD and the prevalence of CACS, but this association was attenuated and was no longer significant after adjusting for insulin resistance [
37]. The current study also found no association between NAFLD and higher CACS. Given that our results indicated that NAFLD and CACS were independent factors, the combination of NAFLD and CACS might improve the identification of T2DM patients at higher risk of cardiovascular events.
Ultrasonography is commonly used to assess liver fat infiltration in clinical practice; however, non-enhanced CT can also be useful for diagnosing liver fat. Previous studies showed that a liver:spleen ratio < 1.0 could be used effectively to diagnose the presence of liver fat with high reproducibility [
18,
38,
39]. However, the prevalence of NAFLD in T2DM in this study was lower than that reported in other studies [
40], in which NAFLD was mostly diagnosed by ultrasonography and magnetic resonance imaging. On the other hand however, our study applied CT, which was reported to have a lower sensitivity for diagnosing hepatic steatosis compared with ultrasonography and magnetic resonance imaging, especially in cases with mild steatosis (< 30% steatosis) [
41]. The present study may thus have included patients with moderate to severe hepatic steatosis.
NAFLD is closely associated with obesity [
22], and the prevalence of NAFLD has been reported to increase in parallel with increasing severity of obesity [
42]. Recently, severe obesity among children and adolescents has recently become a significant public health concern [
43]. Furthermore, pediatric fatty liver disease clustered with cardiometabolic risk factors, associated with an increase in subsequent adult cardiovascular mortality among adolescents with severe obesity [
44]. A healthier diet and physical activity should thus be promoted among adolescents with obesity to mitigate the cardiometabolic risk.
This study had several limitations that need to be addressed. First, the number of patients and cardiovascular events were relatively small. In addition, our study population only consisted of Japanese patients with suspected coronary artery disease, and the results therefore cannot be applied directly to the T2DM population or to other ethnic groups. Second, the histological severity of liver damage was not confirmed in this study. However, CT is a useful tool for diagnosing NAFLD, without the complications associated with invasive methods. The association between CACS and histologic findings of NAFLD, such as ballooning grade, need to be evaluated in future studies. Third, we have no data about the duration of T2DM, which has been reported to increase the risk of cardiovascular events [
45]. Fourth, longitudinal information on changes in medications, risk factor control, and changes in body mass index and lifestyle during the follow-up period was not available. Finally, FRS was originally developed in Western societies and is therefore not accurate in Asians. The Suita score has been proposed and validated as an alternative score for predicting coronary heart disease in Japanese populations [
46]. The application of the Suita score instead of FRS did not affect the findings of this study (data not shown).
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