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5 October 2013

How to target residual cardiovascular risk?

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

An Editorial from the R3i Trustees
Prof. Jean Charles Fruchart, Prof. Jean Davignon, Prof. Michel Hermans Against the rising tide of obesity and type 2 diabetes, questions persist about the optimal targets for assessment and management of lipid-related residual cardiovascular risk. Current guidelines recommend non-high-density lipoprotein cholesterol (non-HDL-C) as a secondary lipid target for intervention. Non HDL-C provides an estimate of the total number of atherogenic particles in plasma, as by definition cholesterol in low-density lipoproteins (LDL), triglyceride-rich lipoproteins, including very-low density lipoproteins (VLDL) and their remnants, intermediate-density lipoproteins (IDL), chylomicron remnants and lipoprotein(a), is included. Thus, in atherogenic dyslipidaemia associated with type 2 diabetes, non-HDL-C is preferable to LDL cholesterol (LDL-C) for risk estimation.(1,2) Such an approach is validated by evidence for the importance of triglyceride-rich lipoproteins as a driver of residual cardiovascular risk.(3) Indeed, the Residual Risk Reduction Initiative (R3i) has consistently drawn attention to the role of atherogenic dyslipidaemia, characterised by elevated triglyceride-rich lipoproteins, often with low HDL-C and a preponderance of small dense LDL, as a key driver of accelerated atherosclerosis and residual cardiovascular risk in high-risk patients on statin therapy.(4)

Not only are triglyceride-rich lipoproteins (including remnants) clearly implicated in residual coronary risk,(3,5) but there is also support for a direct contributory role in ischaemic stroke risk.(6,7) Indeed, a study highlighted in Focus provides a pathophysiological rationale for their relevance to ischaemic stroke risk.(8) This study showed that cholesterol carried in triglyceride-rich lipoproteins, together with dense LDL, was directly predictive of carotid macrophage content, a marker of unstable plaque, thus implicating triglyceride-rich lipoproteins in progression of the cerebrovascular atherothrombotic process, from stable to unstable plaque.

In addition, this study provides support for the relevance of non-HDL-C as a target for residual risk assessment and treatment. When plaque composition was analysed by non-HDL-C tertiles, patients in the highest tertile (mean non-HDL-C 223 mg/dL or 5.8 mmol/L) had significantly increased macrophage content and fewer smooth muscle cells, indicative of an increase in carotid plaques instability. Further, non-HDL-C was the only significant predictor of plaque macrophage content (besides LDL density).

With this in mind, it is highly relevant to question whether current guideline-recommended targets for non-HDL-C are appropriate. This issue was addressed in the Very Large Database of Lipids study (VLDL-2 Study),(9) featured in News from the Literature. This study evaluated the extent of patient-level discordance between non-HDL-C and LDL-C percentiles at different levels of LDL-C and triglycerides. What they found was critical: there was greater patient level disconcordance between non-HDL-C and LDL-C when LDL-C was low and triglycerides were elevated, with obvious implications for residual risk stratification and treatment.

Guideline-recommended non-HDL-C targets are based on the assumption that VLDL cholesterol is normal (<30 mg/dL) when triglycerides are <150 mg/dL (1.7 mmol/L). However, in the light of recent studies evaluating what is a normal or optimal fasting triglyceride level, there have been calls for non-HDL-C targets to be lowered to match those of LDL-C, particularly in high to very high risk patients with hypertriglyceridemia.(10) Findings of the VLDL-2 study lend support to this proposal. This question clearly warrants evaluation by the relevant guideline bodies.

In conclusion, the R3i takes this opportunity to join with the International Atherosclerosis Society(11) in emphasising the use of non-HDL-C as a key target for residual risk assessment and management. There are also practical advantages with routine adoption of this measure, as non-HDL-C can be measured in non-fasting serum. Yet even with clear support for non-HDL-C from guidelines and international expert groups, management still lags behind that of LDL-C. Recent findings from the international L-TAP 2 study(12) show only slightly more than 50% of high-risk patients attained non-HDL-C goals. Moreover, goal attainment was even lower in high-risk patients with elevated triglycerides (≥200 mg/dL or 2.3 mmol/L).

It is clear that major gaps remain in clinicians’ awareness of what non-HDL-C measures, how it is calculated and what are guideline-recommended targets. The R3i believes that urgent action is needed to address these outstanding questions surrounding non-HDL-C which will have important implications for the assessment and management of residual cardiovascular risk.


1. Reiner Z, Catapano AL, De Backer G et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011,32:1769-818.
2. Brunzell JD, Davidson M, Furberg CD et al. Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2008;51:1512-24.
3. Chapman MJ, Ginsberg HN, Amarenco P et al; European Atherosclerosis Society Consensus Panel: Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011,32:1345-61.
4. Fruchart JC, Sacks FM, Hermans MP et al; Residual Risk Reduction Initiative (R3I). The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patients. Diab Vasc Dis Res 2008,5:319-35.
5. Varbo A, Benn M, Tybjærg-Hansen A et al. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013,61:427–36.
6. Freiberg JJ, Tybjærg-Hansen A, Jensen JS, Nordestgaard BG. Nonfasting triglycerides and risk of ischemic stroke in the general population. JAMA 2008; 300: 2142–52.
7. Kim J-Y, Park J-H, Jeong S-W et al. High levels of remnant lipoprotein cholesterol is a risk factor for large artery atherosclerotic stroke. J Clin Neurol 2011;7: 203–9.
8. Zambon A, Puato M, Faggin E, Grego F, Rattazzi M, Pauletto P. Lipoprotein remnants and dense LDL are associated with features of unstable carotid plaque: A flag for non-HDL-C. Atherosclerosis 2013;230:106-9.
9. Elshazly MB, Martin SS, Blaha MJ et al. Non-HDL cholesterol, guideline targets, and population percentiles for secondary prevention in a clinical sample of 1.3 million adults The Very Large Database of Lipids (VLDL-2 Study). J Am Coll Cardiol 2013. [Epub ahead of print 21 Aug].
10. Ballantyne CM, Pitt B, Loscalzo J et al. Alteration of relation of atherogenic lipoprotein cholesterol to apolipoprotein B by intensive statin therapy in patients with acute coronary syndrome (from the Limiting UNdertreatment of lipids in ACS With Rosuvastatin [LUNAR] Trial). Am J Cardiol 2013;111:506–9.
11. The International Atherosclerosis Society : An International Atherosclerosis Society Position Paper: Global recommendations for the management of dyslipidemia. Full report [].
12. Santos RD, Waters DD, Tarasenko L et al. A comparison of non-HDL and LDL cholesterol goal attainment in a large, multinational patient population: the Lipid Treatment Assessment Project 2. Atherosclerosis 2012;224:150-3.