Even though TG/HDL-C ratio has been regarded as a marker of plasma atherogenicity and an independent predictor of cardiovascular events, the potential role of TG/HDL-C ratio in predicting mortality risk in patients with DM and CAD who are treated with statin has not been determined. As far as our knowledge, the present study is the first study to investigate the prognostic value of TG/HDL-C ratio in patients with DM and CAD in the era of statin therapy. In this study, we demonstrated that higher TG/HDL-C ratio was associated with increased risk of all-cause and cardiovascular mortality. After adjusting for both established risk factors for CV disease and other prognostic biomarkers, TG/HDL-C ratio remained an independent predictor of all-cause and cardiovascular mortality. The significant association of TG/HDL-C ratio with mortality was further confirmed by sensitivity analysis. Furthermore, adding TG/HDL-C ratio to the established model exhibited a significant enhancement on the performance of predicting mortality. TG/HDL-C ratio predicted an increased risk of all-cause and cardiovascular mortality across a wide range of subgroups of patients with DM and CAD. These results are important in that they provide important information about the unique association between TG/HDL-C ratio and mortality in diabetic patients with CAD treated with statin. All these suggested that TG/HDL-C ratio is a marker for poor prognosis even in the era of statin treatment that contribute to early identification of high-risk patients with DM and CAD. Furthermore, routine TG/HDL-C ratio calculation may further improve risk stratification for mortality risk.
It has been demonstrated that LDL-C plays a key role in the development and progression of atherosclerotic cardiovascular disease (ASCVD) and statin is the first-line therapy for lowering LDL-C levels to reduce ASCVD risk. However, patients with DM and CAD remain suffer from ongoing cardiovascular risk even if LDL-C achieves the targeted goals, which indicates that there are residual cardiovascular risk factors other than LDL-C. Therefore, the classic lipid-metabolic indicator (LDL-C) cannot completely explain the poor prognosis in diabetic patients. There is evidence that statin-treated patients with DM have a high prevalence of persistent atherogenic dyslipidemia[13]. Elevated TG levels and reduced HDL-C levels, as typic lipid feature of diabetes, have been considered as potently atherogenic dyslipidemia in patients with DM[52, 53]. However, because TG and HDL-C are mutually independent risk factors, their levels alone do not reflect the actual status of plasma atherogenicity and CVD risk in the absence of IR[13]. The most relevant cases which has with potent atherogenic effect are those with concurrent elevated TG levels and reduced HDL-C levels. Thus, TG/HDL-C ratio, as an indicator reflecting TG and HDL-C simultaneously, has been regarded as a good marker for CVD in primary and secondary prevention[34, 39]. Moreover, recent findings suggested that the combination of TG and HDL-C in the form of a ratio has better predictive value for mortality than individual cholesterol risk factors[54]. It is well established that TG/HDL-C ratio is positively associated with the risk of T2DM risk[44–48]. Elevated TG/HDL-C ratios is also associated with increased risk of CAD in patients with T2DM independent of the baseline LDL-C levels[49]. Furthermore, high TG/HDL-C ratio may strongly predict the extent of coronary lesion[55, 56]. In statin-treated diabetic patients, TG/HDL-C ratio, as opposed to LDL-C levels, is associated with vulnerable plaque features evaluated by frequency-domain optical coherence tomography (FD-OCT)[57]. While diabetes is a major risk factor for CAD, not all patients with diabetes and CAD have an equal cardiovascular risk. Routine lipid examinations do not reflect the actual compositional changes of lipid parameters in patients with DM and CAD. Therefore, evaluation of TG/HDL-C ratio may have great clinical significance on risk stratification for patients with T2DM and CAD on statin treatment.
Previous studies have addressed the prognostic role of TG/HDL-C ration in patients with CAD. Studies from wan et al .and Dai et al. demonstrated that elevated TG/HDL-C ratio was associated with an increased risk of all-cause mortality in CAD patients after PCI[37, 42]. Findings from Matsumoto et al revealed that in statin-treated patients, nonfasting TG/HDL-C ratio was a valuable predictor for cardiovascular events after PCI[39]. Sultani et al revealed that elevated TG/HDL-C ratio may predict long-term all-cause mortality and major adverse cardiac event (MACE) in high-risk patients undergoing coronary angiography[40]. Bitter et al. found that after adjusting for conventional cardiovascular risk factors and coronary disease severity, TG/HDL-C ratio was a powerful independent predictor of all-cause mortality and cardiovascular events in women with suspected ischemia, but without obstructive plaque on angiography[36]. Prasad et al. reported that TG/HDL-C predicts adverse cardiovascular events in women with non-obstructive CAD[41]. All these findings suggest that using TG/HDL-C ratio may help predict poor cardiovascular outcomes in patients with CAD regardless of the severity of coronary artery stenosis and potential sex-specific difference in the prognostic value of TG/HDL-C ratio may exist. Calculation TG/HDL-C ratio is useful for identification of those at high future cardiovascular risk in CAD patients. However, there are significant limitations in few studies that assess the association between TG/HDL-C ratio and cardiovascular events given the small sample size, gender-specific and pre-selected CAD patients. Furthermore, the incremental prognostic value of TG/HDL-C ratio beyond traditional risk factors was not well investigated.
Besides, it is controversial whether TG/HDL ratio is able to predict cardiovascular risk in patients with established DM. In the Swedish National Diabetes Register (NDR) study of 54,061 patients with 4.8 years follow-up, obese T2DM patients with elevated TG/HDL-C ratio significantly increased the risk of CVD independent of LDL-C levels[58]. In a Chinese cohort of 1,447 type 2diabetic patients with angiographic-proven stable CAD with an average of 20.3 months follow-up, Yang et al. found that TG/HDL-C ratio was a significant predictor of cardiovascular events defined as the composite of cardiac death, stroke, nonfatal MI and post-discharge revascularization in patients with diabetes and stable CAD after adjustment for multiple traditional risk factors of CVD[50]. Contrary to these studies, a few other studies failed to demonstrated the association between TG/HDL-C ratio and adverse cardiovascular events in patients with diabetes. A study of 1021 diabetic patients who were followed up for 8.6 years showed that the value of TG/HDL-C ratio was significantly higher in patients with cardiovascular events than those without cardiovascular events. However, the association between TG/HDL-C ratio and cardiovascular events was not significant after multivariate cox hazard regression analysis[59]. In congruent with this study, the sub analysis of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) study including 668 patients with DM and without history of CVD could not demonstrate the independent association between TG/HDL ration and cardiovascular events over a mean follow-up period of 5.3 years[51]. Discrepancies among the aforementioned studies might due to differences in population studied, event definition and length of follow-up. It is important to note that none of the previous studies considered whether the use of statin modify the prognostic value of TG/HDL-C ratio in patients with DM.
To the best of our knowledge, the present study is the first to focus on patients with T2DM and angiography-proven CAD on statin treatment. Compared with previous studies focusing on CAD patients, our large cohort study included higher risk of patients who had a higher percentage of history of CVD. Moreover, patients in our study underwent non-invasive or invasive treatment. It is important to assess data from patients who underwent non-invasive and invasive treatment because this reflects the reality of our clinical practice. Except for the CVD risk factors, the severity of CAD, the cardiac function, the kidney function, blood glucose levels and medication use in the present study were also adjusted in the multivariable analysis. Consistent with previous studies, our study demonstrated that elevated TG/HDL-C ratio was associated with poor prognosis in patients with T2DM and CAD. After adjustment for relevant clinical and laboratory covariates, elevated TG/HDL-C remained a significant and independent predictor of all-cause and cardiovascular mortality. Moreover, TG/HDL-C ratio predicted an increased risk of all-cause and cardiovascular mortality across all subsets of patients. Even in patients with LDL-C levels ≤ 1.80mmol/L, elevated TG/HDL-C ratio was still associated with the increased risk of mortality, suggesting TG/HDL-C ratio may explain part of residual risk and TG/HDL-C ratio may show predictive value for adverse prognosis regardless of level of LDL-C. The TG/HDL-C ratio also showed predictive values for mortality in patients with HbA1c > 7.0 and ≤ 7.0, which indicated that there is no significant interaction between glycometabolic status and TG/HDL-C ratio on risk prediction. There were also no significant interactions between TG/HDL-C ratio and other variables including sex, smoking, BMI, ACS, duration of DM, insulin treatment and revascularization. Therefore, our study extended the positive association between TG/HDL-C ratio and cardiovascular risk in patients with DM. The use of statin has less impact on the prognostic value of TG/HDL-C ratio in patients with established DM.
Meanwhile, we assessed the incremental value of TG/HDL-C ratio into a risk prediction model for mortality in terms of C-statistic value, NRI and IDI. The TG/HDL-C ratio showed significant improvement in risk prediction and risk reclassification for all-cause and cardiovascular mortality. To the best of our knowledge, the present study demonstrated, for the first time, that TG/HDL-C ratio may refine risk stratification for mortality. Routinely calculated the TG/HDL-C ratio might be useful for identification of those with higher future cardiovascular risk. Our results add new evidence for the predictive value of TG/HDL-C ratio for patients with CAD. Although previous studies revealed that elevated TG/HDL-C ratio increased CVD risk, the cut-off value of TG/HDL-C ratio to predict CVD risk in secondary prevention has not been well established. We identified 1.77 and 1.57 as the optimal cut-off points of TG/HDL-C ratio to predict the risk of all-cause and cardiovascular mortality. This indicated that it is desirable to ensure the TG/HDL-C ratio is not higher than the optimal cut-off points to improve prognosis. More attention should be given to the management of cardiovascular risk in patients with higher TG/HDL-C ratios. Our results provide novel evidence for the prognostic utility of elevated TG/HDL-C ratio in patients with DM treated with statin.
Several potential mechanisms may account for the association TG/HDL-C ratio with all-cause and CV mortality in patients with T2DM and CAD. First, TG/HDL-C ratio, as a proxy for atherogenic dyslipidemia, reflects the complex interaction between atherogenic and protective lipoprotein. Elevated TG level and decreased HDL-C content may directly contribute to endothelial dysfunction and atherosclerosis. Furthermore, elevated TG/HDL-C ratio is positively associated with other atherogenic lipid phenotype, characterized by higher small dense LDL particles [14, 60]along with higher remnant particle cholesterol and non-HDL-C [61]which contribute to progression of atherosclerosis. Second, elevated TG/HDL-C ratio is associated with worsening IR in patients with diabetes[15, 16]. It is well known that IR is related to the development and accelerated progression of atherosclerosis, vulnerability of coronary plaques and risk of adverse outcomes in patients with CAD. Moreover, elevated TG/HDL-C ratio is associated with poor glycemic control in diabetic patients[62]. A hyperglycemic environment may contribute to the development of macrovascular and microvascular disease in patients with T2DM, such as diabetic nephropathy, CAD, cerebrovascular disease and peripheral artery disease, all of the conditions known to increase the risk of mortality. Although the exact mechanism needs to be further elucidated, the association between TG/HDL-C ratio and mortality has practical implications in patients with T2DM and CAD treated with statin.
Nonetheless, there are some limitations in the present study. Firstly, owing to the retrospective and observational nature of the present study, it is difficult to exclude influence from some unmeasured factors. Unmeasured factors such as diabetes complication may have exaggerated the results of this study. Secondly, lipid levels and other parameters were only examined at admission, therefore, it is not known whether time-varying TG/HDL-C ratio could predict mortality. Thirdly, data of follow-up statin use and other non-statin lipid-lowering agents were not available that could potentially impact the association between TG/HDL-C ratio and mortality. Future prospective studies are required to verify our conclusions. Last but not least, TG/HDL-C ratios are known to vary with ethnicity, which may limit the generalization of these results. Despite these limitations, the present study has important clinical significance because it is the first study to investigate the association between TG/HDL-C ratio and mortality in patients with T2DM and CAD treated with statin.