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15 March 2016

Will residual cardiovascular risk meet its nemesis in 2016?

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

An Editorial from the R3i Trustees
Prof. Jean Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco Lowering low-density lipoprotein (LDL) cholesterol is indisputably the cornerstone of dyslipidaemia management for cardiovascular disease prevention. However, it is also evident that attaining LDL cholesterol goal does not eliminate the risk of a cardiovascular event and that there are other important contributors to residual cardiovascular risk. Key among these is elevated triglyceride-rich lipoproteins and their remnants, for which plasma triglycerides are a marker. The Residual Risk Reduction Initiative (R3i) has consistently made the case for elevated triglyceride-rich lipoproteins, generally associated with atherogenic dyslipidaemia,as a major contributor to lipid-related cardiovascular risk 1,2. Accumulating evidence from epidemiological and genetic evidence supporting raised triglycerides, remnant cholesterol, or triglyceride-rich lipoproteins as an additional cause of cardiovascular disease has driven renewed interest in this dyslipidaemia 3,4. Additionally, in this month’s Focus comes news from a Danish group of collaborators that remnant cholesterol (generally calculated as total cholesterol minus non-high-density lipoprotein cholesterol minus LDL cholesterol) is associated with increased risk for all-cause death, the definitive ‘hard’ clinical outcome, in subjects with ischaemic heart disease 5. In contrast, there was no association between elevated LDL cholesterol and all-cause death. Population analysis indicated that elevated remnant cholesterol explained up to 18% of the residual risk of mortality in these patients, providing a clear rationale for effective therapies directed to this dyslipidaemia.

And herein is the stumbling block for clinicians. While mechanistic, genetic and epidemiologic evidence supports the case for considering inclusion of remnant cholesterol and triglyceride-rich lipoproteins as a potential target, definitive evidence of benefit from major outcomes studies is somewhat lacking, so far generally reliant on post hoc analysis from the major fibrate trials. New approaches are clearly needed.

There is hope on the horizon. One approach is to target apolipoprotein (apo) CIII given its critical role in regulating clearance of triglyceride-rich lipoproteins 6. In phase II trials in patients with elevated triglycerides, volanesorsen, a second generation antisense oligonucleotide targeting messenger RNA potently decreased triglyceride levels by about 80%, either as monotherapy or as add-on treatment to a fibrate 7. Reduction of apoCIII was comparable in apoB-100, lipoprotein(a) and apoA-I lipoproteins 8, suggesting activity across the spectrum of apoCIII-containing lipoproteins. Selective peroxisome proliferator-activated receptor alpha modulators (SPPARM? agents) are another strategy, in more advanced development. A major outcomes study with the first of these agents, pemfibrate (K-877), in the Pemafibrate to Reduce cardiovascular OutcoMes by reducing triglycerides IN diabetic patiENTs (PROMINENT) trial in about 10,000 high cardiovascular risk type 2 diabetes patients with elevated triglycerides and low HDL cholesterol has been recently announced 9. Patients will be randomised to treatment with pemfibrate or placebo, against a background of aggressive, standard of care management of cardiovascular risk factors including treatment with high-intensity statins. However, the results are still years away.

In 2016 we will learn whether attaining very low LDL cholesterol levels, beyond current goals, with PCSK9 monoclonal antibody therapy, significantly reduces residual cardiovascular risk when results from FOURIER, the outcomes study with evolocumab, are revealed. The question, then, will be how best to address residual cardiovascular risk against a background of intensive LDL cholesterol lowering. Will targeting triglyceride-rich lipoproteins and remnant cholesterol hold the answer, or will we also need to consider other non-lipid contributors to this risk? Until we have evidence from major outcomes studies addressing this dyslipidaemia, this debate will continue incessantly.


1. Fruchart JC, Davignon J, Hermans MP et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol 2014;13:26.
2. Fruchart JC, Sacks F, Hermans MP et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Am J Cardiol 2008;102(10 Suppl):1K-34K.
3. Varbo A, Nordestgaard BG. Remnant cholesterol and ischemic heart disease. Curr Opin Lipidol 2014;25:266-73.
4. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014;384:626-35.
5. Jepsen A-MK, Langsted A, Varbo A, Bang LE, Kamstrup PR, Nordestgaard BG. Increased remnant cholesterol explains part of residual risk of all-cause mortality in 5414 patients with ischemic heart disease. Clin Chem 2016 [Epub ahead of print].
6. Norata GD, Tsimikas S, Pirillo A, Catapano AL. Apolipoprotein C-III: from pathophysiology to pharmacology. Trends Pharmacol Sci 2015;36: 675-87.
7. Gaudet D, Alexander VJ, Baker BF et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N Engl J Med 2015;373: 438-47.
8. Yang X, Lee SR2, Choi YS et al. Reduction in lipoprotein-associated apoC-III levels following volanesorsen therapy: Phase 2 randomized trial results. J Lipid Res 2016. pii: jlr.M066399. [Epub ahead of print].
9. Landmark Trial Entitled "PROMINENT" To Explore The Prevention Of Heart Disease In Diabetic Patients With High Triglycerides And Low HDL-C.