In the present study, we proposed a composite indicator of blood glucose homeostasis and dyslipidemia, the HbA1c/HDL-C ratio, and demonstrated the relationship between this ratio and subclinical carotid atherosclerosis. We observed a positive correlation between HbA1c/HDL-C levels and abnormal mean/maximum cIMT as well as carotid artery plaque burden in patients with a high risk of CVD, independent of traditional clinical risk factors. More importantly, the relationship between HbA1c/HDL-C and abnormal cIMT remained in a subsample of patients with and without DM. HbA1c/HDL-C may be an important biomarker for clinical evaluation of atherosclerosis progression.
Atherosclerosis is a slow, gradually progressing disease that begins in childhood, but there are potential risk factors that can accelerate its development such as poor glycemic control and low HDL-C [14, 28]. Patients with DM are four times more likely to develop CVD than individuals who do not have DM, and DM is also related to poor clinical prognosis of CVD events [29]. Hyperglycemia is the predominant feature of DM. Many studies have shown that the extent of glycemic control, sensitively reflected by HbA1c, is related to CVD complications in patients with DM [30, 31]. A cross-sectional study involving 541 Chinese people suggested that HbA1c levels are significantly associated with cIMT and the presence of carotid artery plaque [10]. In addition, a multi-detector coronary computed tomography data analysis based on an observational cohort study on the clinical outcomes in asymptomatic patients with type 2 DM showed that long-term stable HbA1c levels may be of great importance in preventing subclinical coronary atherosclerosis in patients with DM [32]. Moreover, a clinical trial, the UK Prospective Diabetes Study (UKPDS), indicated that well-controlled blood glucose and HbA1c could reduce the progression of CVD in DM [33]. Low HDL-C is an important manifestations of dyslipidemia. Clinical studies have consistently shown that low HDL-C is an independent risk factor for atherosclerotic CVD [14, 34]. A meta-analysis involving 21,000 people concluded that elevated cIMT is associated with low HDL-C levels, independent of LDL-C levels. Even in patients who are treated aggressively with statins to decrease LDL-C, HDL-C is still a major predictor of CVD development [35]. In addition, a study synthesizing the data of three cohorts, namely, the European Prospective Investigation into Cancer (EPIC) Norfolk Study, the Atherosclerosis Risk In Communities Study (ARIC), and the Women’s Health Study, verified that ApoA levels cannot provide additional predictive information over HDL-C for CVD [36]. Therefore, levels of HbA1c and HDL-C are useful indicators that reflect DM and dyslipidemia, respectively, which are closely related to the progression of atherosclerosis. Our study puts forth a new marker, the HbA1c/HDL-C ratio, which was found to be significantly associated with abnormal cIMT and carotid artery plaque after adjustment for other relevant clinical covariates. The present findings were consistent with those of previous studies on HbA1c and HDL-C [32–35]. Furthermore, the HbA1c/HDL-C ratio takes into account the relative state of blood glucose control and lipid levels. In recent years, studies have found that blood glucose homeostasis has an impact on blood lipid metabolism and vice versa. Kinochi et al. proposed that the existence of DM eliminates the vascular protective effects of both HDL-C on endothelial function and the progression of atherosclerosis [19]. In a post-hoc analysis of the SANDS study, it was found that levels of HbA1c were negatively correlated with the ability to achieve blood lipid targets with lipid-lowering treatment among patients with DM [17]. In contrast, HDL-C has potent antidiabetic properties via increasing insulin sensitivity and β-cell function, reflecting its role in regulating blood glucose homeostasis [20–22]. In this study, the HbA1c/HDL-C ratio marker could comprehensively reflect blood glucose homeostasis and dyslipidemia, which can be used to monitor progression of atherosclerosis.
The deterioration of blood glucose homeostasis and dyslipidemia can lead to atherosclerosis by impairing endothelial function, increasing inflammation, reducing cholesterol outflow, and promoting platelet aggregation [6, 37]. Metabolic abnormalities of DM, such as hyperglycemia, increased free fatty acids, and insulin resistance, directly result in vascular dysfunction. The molecular mechanisms include the reduction of nitric oxide bioavailability, the increase of oxidative stress, and the interference with intracellular signal transduction [38]. A reduction in HDL-C activates local inflammation and endothelial thrombosis, increases endothelial cell apoptosis, and slows down vascular repair [37]. With the double attack of increasing HbA1c and decreasing HDL-C, the progression of atherosclerosis will rapidly accelerate. From this point of view, the HbA1c/HDL-C ratio could reflect the relative status of blood glucose and serum lipids as well as the extent of damage to the arterial endothelium, which in turn can explain the rationality of the HbA1c/HDL-C ratio as a marker of atherosclerosis progression through the above pathophysiological mechanism.
Another finding of our study was that in a subsample with and without DM, the HbA1c/HDL-C ratio was still associated with abnormal cIMT. Blood glucose homeostasis as reflected by HbA1c is not only applicable in the population with DM but also useful in those without diabetes. A recent cohort study showed that the use of HbA1c can better identify subclinical atherosclerosis in individuals without DM, on the top of traditional CVD prediction models [9]. Bobbert et al. found that in patients without DM, HbA1c had a stronger correlation with cIMT than fasting or 2-h glucose levels [39]. Because blood glucose homeostasis in people without DM will also affect subclinical atherosclerosis, HbA1c levels also require attention. Therefore, the application of the proposed new marker, the HbA1c/HDL-C ratio, for individuals without DM may have an important role in primary prevention among this population.
The present research has several limitations. First, this was a single-center study; our findings should be extrapolated carefully to other populations with different demographic characteristics. Second, the cross-sectional study design prevented us prospectively identifying a causal relationship between the long-term HbA1c/HDL-C ratio and development of atherosclerosis. Third, in patients with DM, the dose–response relationship between the HbA1c/HDL-C ratio and carotid plaque score showed that with increased HbA1c/HDL-C ratio, total carotid plaque thickness was increased. Although there was no significant correlation between the HbA1c/HDL-C ratio and presence of carotid plaque when the HbA1c/HDL-C ratio was at high level, these still tended to be positively correlated. The reason may be an insufficient sample size in both the DM subsample and quartile groups.