R3i Editorial

Understanding the major contributors to residual cardiovascular risk has been a tedious business. With the failure of major studies such as AIM-HIGH with niacin, and dal-OUTCOMES and ACCELERATE with the cholesteryl ester transfer protein inhibitors dalcetrapib and evacetrapib, the relevance of high-density lipoprotein cholesterol (HDL-C) has been consigned to history. Instead, researchers have refocused their attention on triglycerides (TG), given long-standing evidence for an association with increased risk for cardiovascular disease (CVD). However, as TG are metabolized by most cells in the body, it is what they represent that is most relevant.

This month’s Focus report emphasizes this issue.¹ High TG are actually a surrogate for elevated levels of TG-rich lipoproteins and their remnants. Increased production and delayed catabolism of TG-rich lipoproteins lead to increases in TG-enriched remnants, as well as in remnant cholesterol. Lipases, their activators (such as apolipoprotein [apo] CII and apoAV ) and their inhibitors (such as apoCIII and angiopoietin-like protein [ANGPTL] ⁴), and ligands for receptors involved in clearance of TG-rich lipoproteins (apoB and apoE) all play an important role in triglyceride metabolism. Indeed, insights from genetic studies have been instrumental in ‘demystifying’ the relevance of TG-rich lipoprotein metabolism to cardiovascular risk.

Much of this renewed focus has been on the atherogenic potential of remnant lipoprotein cholesterol. Accumulating evidence from observational and Mendelian randomization studies clearly supports a causal association between remnant cholesterol and risk for atherosclerotic cardiovascular disease.(2-5) However, as researchers in the ARIC (Atherosclerosis Risk In Communities) study suggest, other TG-enriched lipoproteins may be relevant. Notably, the ARIC researchers have provided results to suggest that TG-enriched low-density lipoprotein (LDL-TG), arising from cholesteryl ester transfer protein–mediated transfer of TG from chylomicrons and very low-density lipoprotein to LDLs, in exchange for cholesteryl esters, may also play a role.

Until recently, measuring LDL-TG has been complex, and thus investigation of its relevance to cardiovascular risk has had mixed results.^6,7 What is new from the ARIC study are encouraging data showing a significant association of LDL-TG with both ischaemic stroke and coronary heart disease events, even after adjustment for traditional risk factors including lipids. The ARIC investigators suggest that while both remnant cholesterol and LDL-TG are markers of remnant lipoprotein metabolism, LDL-TG may represent a preferable indicator for atherogenic altered remnant metabolism. Indeed, the shorter half-life of chylomicron and VLDL remnants compared with that of LDLs adds weight to this suggestion. Therefore, in a primary prevention setting, as in the ARIC population, inclusion of LDL-TG measurement may offer additional information for risk prediction.

Although the results from ARIC require corroboration, they are clearly thought-provoking. Is LDL-TG causal for cardiovascular disease? Should we also consider LDL-TG in risk assessment, or as a potential target for therapeutic intervention? Clearly much remains to be done to elucidate the answers to these pertinent questions. In the meantime, evidence for a role of TG-rich lipoprotein remnants and remnant cholesterol in residual cardiovascular risk continues to strengthen; we now await definitive answers as to whether targeting these parameters can reduce cardiovascular events in outcomes studies such as PROMINENT with pemafibrate, a first in class selective peroxisome proliferator-activated receptor alpha modulator (SPPARM).⁸ Indeed, topline data from the REDUCE-IT study9 showing a 25% reduction in major cardiovascular events with high-dose eicosapentaenoic acid are pivotal in supporting the case for TG-rich lipoproteins as a key contributor to residual cardiovascular risk. All ears will be tuned to the forthcoming American Heart Association Scientific Sessions this November for full details from this major study.

References

1. Saeed A, Feofanova EV, Yu B et al. Remnant-like particle cholesterol, low-density lipoprotein triglycerides, and incident cardiovascular disease. J Am Coll Cardiol 2018;72:156–69.
2. Varbo A, Benn M, Nordestgaard BG. Remnant cholesterol as a cause of ischemic heart disease: evidence, definition, measurement, atherogenicity, high risk patients, and present and future treatment. Pharmacol Ther 2014;141:358-67.
3. Varbo A, Nordestgaard BG. Remnant cholesterol and triglyceride-rich lipoproteins in atherosclerosis progression and cardiovascular disease. Arterioscler Thromb Vasc Biol 2016;36:2133–5.
4. Varbo A, Benn M, Tybjaerg-Hansen A et al. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427–36.
5. Joshi PH, Khokhar AA, Massaro JM, et al. Remnant lipoprotein cholesterol and incident coronary heart disease: the Jackson Heart and Framingham Offspring Cohort Studies. J Am Heart Assoc 2016;5:e002765.
6. Albers JJ, Slee A, Fleg JL et al. Relationship of baseline HDL subclasses, small dense LDL and LDL triglyceride to cardiovascular events in the AIM-HIGH clinical trial. Atherosclerosis 2016;251:454–9.
7. Marz W, Scharnagl H, Winkler K, et al. Low density lipoprotein triglycerides associated with low-grade systemic inflammation, adhesion molecules, and angiographic coronary artery disease: the Ludwigshafen Risk and Cardiovascular Health study. Circulation 2004;110:3068–74.
8. Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN patiENts With diabeTes (PROMINENT) (PROMINENT). https://clinicaltrials.gov/ct2/show/NCT03071692
9. REDUCE-IT™ Cardiovascular Outcomes Study of Vascepa® (icosapent ethyl) Capsules Met Primary Endpoint. Press release Sep 24th, 2018. http://investor.amarincorp.com/news-releases/news-release-details/reduce-ittm-cardiovascular-outcomes-study-vascepar-icosapent

Key words: residual cardiovascular risk; triglyceride-rich lipoproteins; remnants; low-density lipoprotein-triglycerides; ARIC study; risk prediction