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18 May 2015

Do we need new lipid biomarkers for residual cardiovascular risk?

Prof. Jean Charles Fruchart, Prof. Jean Davignon, Prof. Michel Hermans, Prof. Pierre Amarenco

An Editorial from the R3i Trustees
Prof. Jean Charles Fruchart, Prof. Jean Davignon, Prof. Michel Hermans, Prof. Pierre Amarenco Cardiovascular disease burden continues to escalate, despite advances in diagnosis, management and pharmacotherapy over the last few decades. The latest news from the Global Burden of Disease 2013,1 shows that worldwide cardiovascular death rates are increasing, driven by both increasingly aging populations (accounting for more than half of this increase), together with population growth. Western and Central Europe stands alone in that, despite an aging population, decreases in age-specific cardiovascular mortality rates have culminated in a decline in the number of cardiovascular deaths. In part this decrease may relate to reduction in the prevalence of cardiovascular risk factors, such as smoking, as well as improved medical and surgical treatments. However, evidence from surveys such as EUROASPIRE IV2 shows that even with increased prescription of efficacious treatments, attainment of lipid targets continues to be suboptimal.

Improvement in guideline implementation is clearly indicated. As recommended by expert groups, non-high-density lipoprotein cholesterol (non-HDL-C), which represents the sum of cholesterol in atherogenic apolipoprotein B-containing lipoproteins, is a simple, pragmatic lipid risk marker and treatment target. Indeed, in the 2013 Position Paper,3 the Residual Risk Reduction Initiative (R3i) called for non-HDL-C to be recognised as the key target for treatment decisions relating to lipid-related residual cardiovascular risk.

However, is there also a case to consider other lipid biomarkers that may be especially relevant to lipid-related residual cardiovascular risk. Triglycerides and HDL-C are components of atherogenic dyslipidaemia, a critical contributor to lipid-related residual cardiovascular risk. The ratio of triglycerides/HDL-C (TG/HDL-C), which takes account of these measures and grades atherogenic dyslipidemia as a continuous variable, is not only an acknowledged marker of insulin resistance/hyperinsulinemia but also an independent predictor of cardiovascular risk, as well as all-cause mortality.4-6 Recent reports add to the evidence for this biomarker. In this month’s Focus article,7 Wan and colleagues show that the TG/HDL-C ratio is a powerful independent predictor of all-cause mortality in acute coronary syndrome patients. A high TG/HDL-C ratio was also shown to be predictive of poor cardiovascular outcome in patients with chronic kidney disease.8 This latter finding is highly relevant, given that traditional lipid measures are often inadequate predictors of cardiovascular outcome in this group.9,10

Both practical considerations and clinical evidence inform the decision to consider a novel biomarker.11 The biomarker should offer new information of a strong, consistent association with the disease in question in numerous studies in a range of populations. The TG/HDL-C ratio is a simple, inexpensive, and reproducible marker of cardiovascular risk, demonstrated in patients with cardiometabolic disease, including diabetes mellitus, hypertension, nonalcoholic fatty liver disease,12-14 as well as in patients at high cardiovascular risk, including those with chronic kidney disease (as discussed above).

The key question is whether this marker adds new information beyond the use of non-HDL-C. Some have suggested that the TG/HDL-C ratio may be a better discriminator of cardiometabolic risk than non-HDL-C.15 Additionally, the use of the TG/HDL-C ratio may help to identify young individuals with early atherosclerotic changes, who may require monitoring to prevent cardiovascular disease in adulthood.16 In the context of an escalating obesity pandemic, these findings may offer support for the use of the TG/HDL-C ratio, although further study is merited.

Residual cardiovascular risk is clearly a global public health issue. While improved guideline implementation in practice is indicated, there may also be the need to consider other lipid biomarkers, especially those specific to atherogenic dyslipidaemia, a critical contributor to residual cardiovascular risk.


1. Roth GA, Forouzanfar MH, Moran AE et al. Demographic and epidemiologic drivers of global cardiovascular mortality. N Engl J Med 2015;372:1333-41.
2. Kotseva K, Wood D, De Bacquer D et al. EUROASPIRE IV: A European Society of Cardiology survey on the lifestyle, risk factor and therapeutic management of coronary patients from 24 European countries. Eur J Prev Cardiol 2015 [Epub ahead of print].
3. Fruchart JC, Davignon J, Hermans MP et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol 2014;13:26.
4. McLaughlin T, Reaven G, Abbasi F et al. Is there a simple way to identify insulin-resistant individuals at increased risk of cardiovascular disease? Am J Cardiol 2005;96:399–404.
5. Bittner V, Johnson BD, Zineh I et al. The triglyceride/high-density lipoprotein cholesterol ratio predicts all-cause mortality in women with suspected myocardial ischemia: a report from the Women's Ischemia Syndrome Evaluation (WISE). Am Heart J. 2009; 157: 548–555.
6. Eeg-Olofsson K, Gudbjörnsdottir S, Eliasson B et al. The triglycerides-to-HDL-cholesterol ratio and cardiovascular disease risk in obese patients with type 2 diabetes: an observational study from the Swedish National Diabetes Register (NDR). Diabetes Res Clin Pract 2014;106:136-44.
7. Wan K, Zhao J, Huang H, et al. The association between triglyceride/high-density lipoprotein cholesterol ratio and all-cause mortality in acute coronary syndrome after coronary revascularization. PLoS ONE 10(4): e0123521.
8. Sonmez A, Yilmaz MI, Saglam M et al. The role of plasma triglyceride/high-density lipoprotein cholesterol ratio to predict cardiovascular outcomes in chronic kidney disease. Lipids in Health and Disease 2015;14:29.
9. Tonelli M, Muntner P, Lloyd A et al. Association between LDL-C and risk of myocardial infarction in CKD. Alberta Kidney Disease Network. J Am Soc Nephrol 2013;24:979–86.
10. Holzmann MJ, Jungner I, Walldius G et al. Dyslipidemia is a strong predictor of myocardial infarction in subjects with chronic kidney disease. Ann Med 2012;44:262–70.
11. Morrow DA, de Lemos JA. Benchmarks for the assessment of novel cardiovascular biomarkers. Circulation 2007;115,949–52.
12. Vega GL, Barlow CE, Grundy SM et al. Triglyceride-to-High-Density-Lipoprotein-Cholesterol Ratio is an index of heart disease mortality and of incidence of type 2 diabetes mellitus in men. J Investig Med 2014;62:345–9.
13. Onat A, Can G, Kaya H, Hergenç G. “Atherogenic index of plasma”(log10 triglyceride/high-density lipoprotein-cholesterol) predicts high blood pressure, diabetes, and vascular events. J Clin Lipidol 2010;4:89–98.
14. Hermans MP, Ahn SA, Rousseau MF. The atherogenic dyslipidemia ratio [log(TG)/HDL-C] is associated with residual vascular risk, beta-cell function loss and microangiopathy in type 2 diabetes females. Lipids Health Dis 2012;11:132.
15. Di Bonito P, Valerio G, Grugni G et al. Comparison of non-HDL-cholesterol versus triglycerides-to-HDL-cholesterol ratio in relation to cardiometabolic risk factors and preclinical organ damage in overweight/obese children: The CARITALY study. Nutr Metab Cardiovasc Dis 2015;25:489-94.
16. Di Bonito P, Moio N, Scilla C et al. Usefulness of the high triglyceride-to-HDL cholesterol ratio to identify cardiometabolic risk factors and preclinical signs of organ damage in outpatient children. Diabetes Care 2012;35:158-62.