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13 April 2015

The Residual Risk Debate Hots Up: Lowering LDL-C or lowering remnant cholesterol?

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 Has PCSK9 inhibition clouded other considerations?

This month’s editorial brings together both sides of the debate surrounding the optimal approach for targeting residual cardiovascular risk.

One the one hand, two recent publications 1,2 discussed in this month’s Focus, have heightened anticipation of the potential for PCSK9 inhibition for reducing residual cardiovascular risk. Both show that treatment with monoclonal antibody therapy targeting PCSK9, in addition to maximally tolerated statin therapy, results in remarkably consistent LDL-C reduction of about 60%. Moreover, after 1 year on treatment, this magnitude of LDL-C lowering translated to about 50% reduction in major cardiovascular events. We do, however, need to bear in mind that these are exploratory analyses, and therefore the limitations inherent with this approach need to be borne in mind, Additionally, it is relevant that PCSK9 inhibition also influences other atherogenic apolipoprotein B-containing lipids, including lipoprotein(a),3 which has been suggested to be a contributor to residual cardiovascular risk.4

On the other hand, there is growing support for the view that it is remnant cholesterol* that is the key important contributor to residual cardiovascular risk, beyond LDL-C. In this month’ s Landmark, Varbo and colleagues (2015) show that whereas the risk of ischaemic heart disease (and myocardial infarction) increased similarly for stepwise increasing nonfasting remnant cholesterol and LDL-C concentrations, only nonfasting remnant cholesterol was associated with increased all-cause mortality risk.5 This report has a number of methodological strengths, notably the large sample size, and the homogeneous nature of the population (all subjects were white and of Danish descent). Therefore targeting remnant cholesterol may offer the optimal approach to reducing residual cardiovascular risk.

How do we differentiate these two strategies? In the absence of results of definitive outcomes studies, this is not so far possible. However, perhaps we can gain some insights from consideration of the contribution of life-long exposure to low concentrations of remnant cholesterol or LDL-C. With the accolades about the potential of PCSK9 inhibition, it should be noted that data from the Danish group 6 showed that carriage of PCSK9 loss of function variants that reduced LDL-C levels by 12% translated to a 10% reduction in the risk for ischaemic vascular disease. In contrast, data from the same group showed that carriage of APOC3 variants was associated with a 39-44% reduction in triglycerides and a 40% reduction in risk of ischaemic heart disease. However, to test this formally, we need interventions that specifically target remnant cholesterol; ongoing research into apoCIII antisense oligonucleotides may provide the key.

Residual cardiovascular risk is even more relevant now than ever. The Residual Risk Reduction Initiative looks forward to the results of ongoing outcomes studies with the PCSK9 inhibitors, as well as clinical trials with apoCIII antisense agents to finally deliberate on this debate.

* Remnant cholesterol is the cholesterol content of the triglyceride-rich lipoproteins composed of very low-density lipoproteins and intermediate density lipoprotein in the fasting state, and both of these lipoproteins together with chylomicron remnants in the nonfasting state. It is calculated as total cholesterol – LDL-C – HDL-C.


1. Sabatine M, Giugliano R, Wiviott S, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. New Engl J Med 2015; published online 15 March, DOI:10.1056/NEJMoa1500858.
2. Robinson J, Farnier M, Krempf M et al; Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. New Engl J Med 2015; published online 15 March, DOI: 10.1056/MEJMoa1501031
3. Raal FJ, Giugliano RP, Sabatine MS et al. Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. J Am Coll Cardiol 2014;63:1278-88.
4. Khera AV, Everett BM, Caulfield MP et al. Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER Trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). Circulation 2014;129:635-42.
5. Varbo A, Freiberg J, Nordestgaard B. Extreme nonfasting remnant cholesterol vs extreme LDL cholesterol as contributors to cardiovascular disease and all-cause mortality in 90,000 individuals from the general population. Clin Chem2015;61:533-543.
6. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014;384:626-35.