The main findings of the present study are fourfold. Firstly, we observed a high prevalence of AD in T2DM females, with 35% affected, similar to that observed in T2DM males. Secondly, the AD ratio log(TG)/HDL-C is an easy means to estimate IR, and was strongly related to a cardiometabolic phenotype characterized by IR, MetS, hyperinsulinemia, central fat accretion, sarcopenia, liver steatosis and sedentary lifestyle. Thirdly, this ratio was linked to a stepwise gradient for residual risk of future CAD. Lastly, this ratio was related to decreased insulin secretion, β-cell function loss, poorer glycemic control and higher frequency of microangiopathies. The AD ratio may therefore allow to easily identifying a comprehensive modifiable component of non-LDL, lipid-related residual vascular risk, as well as pinpoint worsening in glucose homeostasis determinants[5–7].
The hallmark of AD is decreased HDL-C level together with raised TG, with LDL-C often only marginally elevated[2–5, 33–40]. Computing a ratio from fasting TG (numerator) and fasting HDL-C (denominator) allows not only for grading AD severity as a continuous variable, but also for incorporating the effect of mutually-reinforcing or diverging confounders affecting both fraction’s components and that of one variable on the variance of the other. An analysis of isolated TG or HDL-C, both indispensable determinants to define AD, as standard continuous variables would not be able to incorporate a measure of AD. Using consensual MetS cutoffs for defining decreased HDL-C and elevated TG, we observed a high prevalence of AD in T2DM females (more than one-third). In comparison with log(TG)/HDL-C values from non-diabetic female controls, the mean AD ratio in T2DM females was well above normal values, from the fourth AD quintile onwards. This demonstrates that >40% of this population may present with AD of varying severity. This finding was expected, as raised TG and low HDL-C levels are used to define MetS phenotype, and as the latter is highly prevalent (86%) in T2DM[17, 18].
To rule out any confounding effect of LLD, we used baseline TG and HDL-C to compute the AD ratio, prior to anti-dyslipidemic drug(s). This proved appropriate, as the mean difference between baseline and current TG levels in this study averaged 46 mg.dL-1. This approach allowed thus to precisely establishing the true, underlying magnitude and frequency of AD in T2DM females[5, 7]. There is a known gender difference in HDL-C and TG levels in the general population, also observed in this diabetic sample, with T2DM females exhibiting higher mean HDL-C and lower TG values than their T2DM males, by an average 6 and 12 mg/dl, respectively (data not shown)[12–14]. As for lifestyle-related confounders of AD prevalence/severity, our data showed a significant decreasing trend across AD quintiles for alcohol intake, the inverse association being expected due to ethanol’s HDL-C-raising effects. On the other hand, we observed a trend for lower educational level. This may promote less healthy behaviours, and result in adverse (i.e. less cardioprotective) anthropometrics and body composition.
The AD ratio was associated, in a stepwise gradation, with higher levels of numerous non-lipid cardiometabolic markers: fasting insulinemia; hsCRP; fibrinogen; Big ET-1; uric acid, and cystatin C. Compensatory hyperinsulinemia is likely to represent a major underlying driver for both AD and for the proatherogenic changes observed in non-LDL lipids and non-lipid CV markers. Endothelin-1 upregulation and/or nitric oxide release imbalance by endothelial cells is another putative pathway linking IR to macroangiopathy. Thus, insulin stimulates endothelin-1 production and action through MAP-kinase-dependent pathways, while ET-1 induces IR and reactive hyperinsulinemia. Such a feed-back loop may contribute to the pathogenesis of macrovascular disease in cardiometabolic states. Expectedly, SHBG levels significantly decreased across quintiles, since IR/portal hyperinsulinemia are associated with decreased liver production and lower levels of this androgen transporter[4, 5, 24, 25, 32, 39].
Accumulating evidence links AD in T2DM not only to residual macrovascular risk, but also to residual risk for new-onset or progression of microangiopathy. In this study, log(TG)/HDL-C was associated with lesser residual insulin secretion, as well as with more severe hyperbolic product (BxS) loss over time, and heralded poorer glycemic control and earlier or more intensive need for stepping-up glucose-lowering therapies, as we previously reported in T2DM males[7, 22, 23, 29, 41, 42]. The AD ratio was associated with predicted CAD risk and prevalent overall microangiopathy. When patients were analyzed according to quitiles of non-HDL-C, another variable which rises alongside the severity of AD, we found no association between the latter and the frequency of microangiopathy. This, together with the independence from diabetes control comforts the relevance of resorting to the log(TG)/HDL-C ratio to estimate a modifiable lipid-related component of residual vascular risk linked to AD. Noteworthy, treatment with fenofibrate, a PPAR-α agonist that specifically targets AD, exerts beneficial effects on macrovascular disease in T2DM patients with AD, but also confers vascular protection against retinal, renal and lower-limb microangiopathies[3, 4, 9–11].
The present study has several limitations. Firstly, as a cross-sectional hypothesis-generating study, it does not allow for inferring causality relationships. Secondly, as we used routine measurement of HDL-C, without HDL subclass assessment, we cannot discriminate between atheroprotective vs. dysfunctional, less atheroprotective or even atherogenic particles. As the latter often concur with decreased HDL-C, a low HDL-C level in the ratio may nevertheless capture to some extent these qualitative defects. Finally, the population under study was mostly of European Caucasian ancestry, and the present findings require replication in other racial/ethnic subgroups. Moreover, the observed associations were documented from females patients with established T2DM, and may not necessarily exist in newly-diagnosed T2DM females, nor in other types of diabetes or in women with normal glucose homeostasis[43–45].
In conclusion, log(TG)/HDL-C allows for grading AD and estimating non-LDL-related residual vascular risk in T2DM females. This AD ratio negatively associates with the two major determinants of glucose homeostasis. This means that patients with more severe AD will have poorer metabolic control in addition to higher predicted CAD risk. The ratio log(TG)/HDL-C appears a simple, cheap noninvasive means to better precise gender-specific assessment and care of the female patient with diabetes. Identifying patients with abnormal AD ratio should allow improving selection and follow-up of those most at risk, more likely to benefit from available or newer therapies targeting hypertriglyceridemia and/or hypo-HDL-cholesterolemia.