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R3i EDITORIAL

16 October 2017

Remnants and residual cardiovascular risk: triglycerides or cholesterol?

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 Non-high-density lipoprotein cholesterol (non-HDL-C) is recognized as a key therapeutic target, especially in subjects with a lipid profile characterized by elevated triglycerides and low HDL-C levels (atherogenic dyslipidaemia), which is prevalent in individuals with insulin resistant conditions such as type 2 diabetes mellitus.1 Non-HDL-C encompasses the total burden of atherogenic apolipoprotein B-containing lipoproteins, and therefore includes low-density lipoproteins (LDL). But in the setting of well controlled LDL cholesterol (LDL-C) levels with intensive statin therapy, as evident in the REVEAL study,2 or with combination LDL- lowering regimens such as in IMPROVE-IT (ezetimibe)3 or FOURIER (evolocumab),4 can we perhaps refine this measure – or define more specific therapeutic approaches? Results from an analysis based on the JUPITER study population, discussed in this month’s Focus article5, suggests promise.

The JUPITER analysis in brief
In this report, the authors used nuclear magnetic resonance (NMR) spectroscopy to measure different apoB-containing lipoprotein particle concentrations in 11,984 subjects from the JUPITER study population. The variables of interest were LDL (large, small), intermediate-density lipoproteins (IDL), and very low-density lipoproteins (VLDL, large, medium and small) particle subclasses, VLDL-cholesterol and VLDL/chylomicron triglycerides. In the statin-treated group, in which median LDL-C was 55 mg/dl (1.4 mmol/L), there was no association between LDL or IDL particle concentration and risk for major adverse cardiovascular events (MACE). There was, however, an association for VLDL particle concentration, specifically driven by small VLDL particles. Indeed, each increase by one standard deviation in small VLDL particle concentration was associated with 68% increase in the residual risk of MACE. This finding is consistent with mechanistic studies of lipoprotein/arterial wall interactions, which show that larger VLDL particles are much less likely to influx into the arterial intima than those of smaller diameter.6,7

Implications for clinical practice
Triglyceride-rich lipoproteins (TRLs) is the term used to collectively refer to apoB-containing lipoproteins beyond LDL. The largest of these lipoproteins are the chylomicrons, which mainly comprise triglycerides; the smallest are the remnant lipoproteins, i.e. IDL, VLDL and chylomicron remnants. With increasing size, the relative content of triglyceride in remnants increases, although all remnants carry a large cholesterol load. Thus, a key question is whether the atherogenicity of these small triglyceride-rich particles is due to their triglyceride or cholesterol content. This question was addressed by the authors of this JUPITER analysis. Whereas VLDL-cholesterol was associated with a significant 27% increase in residual cardiovascular risk (p=0.014), the triglyceride content was not.5

While the authors conclude that their findings should be regarded as hypothesis-generating due to the multiplicity of testing, rather than definitive, it is important to note that a growing body of evidence from observational and genetic studies supports remnant cholesterol as a causal risk factor for low-grade inflammation, atherosclerotic cardiovascular disease and even all-cause mortality.8-10
Thus, it is logical that elevated remnant cholesterol levels are likely contributors to the residual risk of atherosclerotic cardiovascular disease in patients with very well controlled LDL-C levels.

As suggested by multiple lines of evidence, targeting remnants, especially the smallest class, may drive novel therapeutic approaches to managing residual cardiovascular risk. Now, we need the agents and studies to prove this.

References

1. Catapano AL, Graham I, De Backer G et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Eur Heart J 2016;37:2999-3058.
2. HPS3/TIMI55-REVEAL Collaborative Group. Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med 2017; doi: 10.1056/NEJMoa1706444. [Epub ahead of print]
3. Cannon CP, Blazing MA, Giugliano RP et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-97.
4. Sabatine MS, Giugliano RP, Keech AC et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.
5. Lawler PR, Akinkuolie AO, Chu AY et al. Atherogenic lipoprotein determinants of cardiovascular disease and residual risk among individuals with low low-density lipoprotein cholesterol. J Am Heart Assoc;67. pii: e005549. doi: 10.1161/JAHA.117.005549.
6. Stender S, Zilversmit DB. Transfer of plasma lipoprotein components and of plasma proteins into aortas of cholesterol-fed rabbits. Molecular size as a determinant of plasma lipoprotein influx. Arteriosclerosis 1981;1:38-49.
7. Nordestgaard BG, Wootton R, Lewis B. Selective retention of VLDL, IDL, and LDL in the arterial intima of genetically hyperlipidemic rabbits in vivo: Molecular size as a determinant of fractional loss from the intima-inner media. Arterioscler Thromb Vasc Biol 1995;15:534-42.
8. Nordestgaard BG. Triglyceride-Rich Lipoproteins and Atherosclerotic Cardiovascular Disease: New Insights From Epidemiology, Genetics, and Biology. Circ Res 2016;118:547-63.
9. Varbo A, Nordestgaard BG. Remnant Cholesterol and Triglyceride-Rich Lipoproteins in Atherosclerosis Progression and Cardiovascular Disease. Arterioscler Thromb Vasc Biol 2016;36:2133-35.
10. Jepsen AM, Langsted A, Varbo A et al. Increased Remnant Cholesterol Explains Part of Residual Risk of All-Cause Mortality in 5414 Patients with Ischemic Heart Disease. Clin Chem 2016;62:593-604.