The performance of lipid profiles and ratios as a predictor of arterial stiffness measured by brachial-ankle pulse wave velocity in type 2 diabetic patients

Introduction

Type 2 diabetes mellitus (T2DM) is a major health concern and prevalence is increasing worldwide. More than 460 million people are already affected, or 9.3% of the global population, and there are projected to be around 578 million cases by 2030. Indonesia is among the top ten countries with the most prevalent occurrence of diabetes, estimated to be around 10.7 million cases in 2019 and projected to increase to 13.7 million in 2030 and to 16.6 million in 2045.^1,2 The consequence of the growing rates of T2DM is the increase in diabetes-related complications, especially macrovascular and microvascular. The prevalence of macrovascular and microvascular complications was estimated to be 27.2% and 53.5%, respectively.³ However, cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in T2DM patients.⁴ The economic impact of T2DM regarding the medical care costs and the indirect costs due to decreased productivity associated with diabetes-related morbidity is also significant.⁵

Coronary artery disease, peripheral artery disease (PAD), heart failure, and cerebral infarction are the typical manifestations of atherosclerotic CVD (ASCVD) in T2DM. Abnormal lipid metabolism (dyslipidemia) is the main pathogenesis for the development of ASCVD; meanwhile dyslipidemia is common in T2DM patients, affecting 60–70% of T2DM.⁶ The association between cholesterol and the cardiovascular outcome is well established. Recently, many risk factors for CVD have been published in international studies, implying more complex lipoprotein disorders in atherosclerosis development. Lipid ratios (TC/HDL-C, TG/HDL-C, and LDL-C/HDL-C) application, in terms of cardiovascular risk stratification and lipid-lowering therapy efficacy assessment, are promising options. Besides the advantage of being practical in clinical settings, changes in these ratios have indicated better measures of the reduction in cardiovascular risk compared with the conventional lipid parameters.⁷

Arterial stiffening depicts degenerative changes of the extracellular matrix (ECM) in the arterial media layer, marked with collagen deposition, cross-linking, and elastin fatigue fracture. From a pathological perspective, arterial stiffening is different from atherosclerosis. However, both processes commonly occur in the same vascular area, are part of the vascular aging process, and share the same risk factors. Moreover, several clinical studies have reported a significant association between arterial stiffness and the degree of atherosclerosis and also with the risk of cardiovascular event incidents.⁸ Early recognition of arterial stiffness in the high-risk population, such as T2DM, before the manifestation of clinical ASCVD, is substantially beneficial.⁹ Carotid-femoral pulse wave velocity (cf-PWV) represents primarily the aortic stiffness and is considered the gold standard for arterial stiffness measurement.¹⁰ Nowadays, ba-PWV has been widely used in clinical settings and it has strong positive association with cf-PWV. Because ba-PWV is easier to obtain and more convenient for patients, it could serve as an alternative to cf-PWV measurement.^11,12

Serum HDL-C, in the middle-aged and elderly population, has been associated with protection against arterial stiffness. Previous studies have also investigated the degree of association between a single atherogenic lipid parameter or ratio (the LDL-C, TG/HDL-C, and non HDL-C) with arterial stiffness. However, each of those studies claimed some lipid parameters or ratios superior to one another.⁹ Furthermore, the data regarding the use of those lipid ratios as a predictive biochemical marker for arterial stiffness in T2DM are lacking, especially in the Indonesian population.

Objectives

Therefore, this study aimed to explore the correlation of lipid profiles and ratios with arterial stiffness, construct a predictive model for arterial stiffness in T2DM patients, and ultimately analyze the performance (sensitivity and specificity) of the lipid ratios to detect arterial stiffness in T2DM patients.

Methods

Results

Model of lipid ratios as predictive markers for arterial stiffness in type 2 diabetes mellitus

An ROC analysis was applied for lipid ratios to arterial stiffness as the outcome of this study (Figure 1). Overall lipid ratios TC/HDL-C, TG/HDL-C, and non-HDL-C had a good performance to be used as predictive models (AUC > 0.7), except for LDL-C/HDL-C. Non-HDL-C had a sensitivity of 96.8% for arterial stiffness; however, the specificity was 52.9% with cut-off value 150 mg/dL. TG/HDL-C ratio had a specificity of 81.0% and sensitivity of 74.2% with cut-off value 4.51. The characteristics of the lipid ratios are presented in Table 3.

Figure 1. Receiver operator characteristics curve analysis of lipid ratios as a predictor of arterial stiffness in type 2 diabetes mellitus.

Table 3. Characteristics of lipid ratios using the optimal cut-off value to detect the presence of arterial stiffness in type 2 diabetes mellitus.

Parameter	AUC	95% CI	Cut-off value	Sensitivity	Specificity	p
TC/HDL-C	0.769	0.682–0.856	4.63	77.4%	68.6%	0.000*
TG/HDL-C	0.776	0.688–0.863	4.51	74.2%	81.0%	0.000*
LDL-C/HDL-C	0.644	0.544–0.744	2.71	83.9%	46.4%	0.012*
Non HDL-C	0.753	0.679–0.827	150	96.8	52.9%	0.000*

* Significant (p < 0.05).

Discussion

To our knowledge, our present study is the first to evaluate not only the correlation of lipid ratios with arterial stiffness in T2DM patients but also define the cut-off value of lipid ratios which might contribute new insight in managing dyslipidemia and CVD risk in T2DM. The main findings of our study were: 1) the lipid ratios were correlated with arterial stiffness; 2) the lipid ratios, especially TG/HDL-C ratio and non-HDL-C, had good sensitivity to detect arterial stiffness; 3) elevated TG/HDL-C ratio and non HDL-C levels increased the risk of having arterial stiffness in T2DM. These findings indicate that lipid ratios are independently associated with the risk of arterial stiffness in the T2DM population.

Atherosclerosis is the main pathogenesis of CVD; however, early atherosclerosis is asymptomatic, therefore the majority goes undetected in the early stages. Arterial stiffness is involved in these early stages of atherosclerosis. Even though the relationship between arterial stiffness and atherosclerosis is still unclear, the interaction between the two may involve several complex hemodynamic, mechanical, metabolic, and enzymatic pathways. The increase in arterial stiffness results in increased blood pressure which promotes arterial remodeling leading to atherosclerosis.¹⁸ The increase in intra-luminal pressure also promotes atheroma formation and deposition of excessive collagen in arterial walls.⁸ These mechanisms are even more pronounced in T2DM in which endothelial dysfunction, a pivotal event in the initiation of atherosclerosis, is accelerated by the presence of hyperglycemia and advanced glycation end products (AGEs).¹⁹ Moreover, T2DM is characterized by abnormal metabolism of lipoprotein which contributes to the pathomechanism of atherosclerosis. Therefore, the detection of arterial stiffness in T2DM before the development of clinical ASCVD is crucial.

Dyslipidemia and DM commonly occur together, affecting 60–70% of people with T2DM. The pathophysiology of dyslipidemia in T2DM is complex, involving a different number of abnormalities. The key abnormality is the increased production of very low-density lipoprotein (VLDL) by the liver, which is commonly found as elevated TG levels. Elevated TG-rich lipoproteins will affect other lipoproteins and result in lower Apo A-I and HDL-C levels. Increased LDL-C association with CVD is well established in T2DM patients, as in the non-diabetic population. However, a significantly reduced LDL-C still carries residual CVD risk in T2DM.²⁰ Therefore, a new CVD risk predictor is needed, and lipoprotein ratios can provide a better picture of the complex metabolic and clinical interactions between conventional lipid profile parameters. This is consistent with our findings in which lipid ratios showed a higher correlation with ba-PWV compared to conventional lipid profile parameters alone.

In our study, a significant correlation between TG/HDL-C ratio and arterial stiffness were observed (ρ = 0.326). Moreover, the TG/HDL-C ratio of > 4.51 predicts arterial stiffness with a sensitivity of 74.2% and specificity of 81.0%. An elevated TG/HDL-C ratio also increased the risk for arterial stiffness (OR: 12.293; 95% CI: 4.996–30.247). These findings are consistent with the study conducted by Chen & Dai²¹ and Zhao et al.⁹ which found that TG/HDL-C ratio is positively correlated with ba-PWV, but the participants of those studies were not limited to T2DM patients. Elevated TG/HDL-C ratio is a feature of metabolic syndrome which is associated with insulin resistance and cardiometabolic risk. Insulin resistance states and chronic hyperinsulinemia induce the local activity of the renin-angiotensin-aldosterone system, followed by the expression of angiotensin II receptors in vascular tissue, resulting in vessel wall hypertrophy, fibrosis, and reduced arterial elasticity. Furthermore, insulin resistance is strongly associated with endothelial dysfunction, marked with an imbalance between nitric oxide (NO) and endothelin-1, two important determinants of arterial stiffness.^8,22

Our present study found that non-HDL-C positively correlated with arterial stiffness, and non-HDL-C levels of >150 mg/dL predict arterial stiffness with a sensitivity of 96.8% and specificity of 52.9%. An elevated non-HDL-C level also increased the risk for arterial stiffness (OR: 16.312; 95% CI: 3.760–70.780). These findings are similar to previous studies by Bando et al.²³ and de Oliveira et al.²⁴ which reported that elevated non-HDL-C levels are associated with an increased risk of arterial stiffness. The latest evidence indicated that HDL-C determination alone has no predictive role; therefore, replacing the criteria of metabolic syndrome with that of non-HDL-C is more relevant.¹³ Unlike LDL-C, the non-HDL-C represents the cholesterol content in all the atherogenic lipoproteins, namely: VLDL-C, intermediate-density lipoprotein cholesterol (IDL-C), and lipoprotein (a) cholesterol.²⁵ In T2DM patients, non-HDL-C levels emphasize the role of the TG-rich lipoproteins in the development of arterial stiffness. The TG-rich lipoproteins through the TG hydrolysis process by lipoprotein lipase (LPL) contribute to low-grade inflammation of the arterial wall.²⁶ Inflammation has a pivotal role in both arterial stiffening and atherosclerosis.²⁷ In an in vitro study, C-reactive protein (CRP) decreased endothelial NO synthase (NOS) secretion and activity, resulting in “functional” arterial stiffening. Furthermore, inflammation may result in dysregulation between elastin breakdown and production. Some elastolytic enzyme expressions i.e. matrix metalloproteinase-9, are induced by pro-inflammatory cytokines.⁸

Conclusions

Lipid profiles and lipid ratios, especially TG/HDL-C ratio and non-HDL-C, are potential biochemical markers for arterial stiffness in T2DM patients. Type 2 DM patients with arterial stiffness were likely to have elevated lipid profiles and lipid ratios. We recommend further research with a better design (cohort) and larger scale before applying these parameters in clinical practice.