R3i Editorial

Despite emphasis on low-density lipoprotein cholesterol (LDL-C) as the primary lipid target, reinforced by publication of the Sixth Joint Task Force European Guidelines for Cardiovascular Disease Prevention in Clinical Practice this month,¹ it is increasingly clear that individuals with well controlled LDL-C levels are still at high residual risk of cardiovascular events. A proportion of this risk is undoubtedly lipid-related, given that the INTERHEART study showed that dyslipidaemia was one of the top nine factors associated with risk for myocardial infarction.² The question remains: what other lipid measures should be taken into account for assessment of residual cardiovascular risk?

What is remnant cholesterol?
Remnant cholesterol is one contender. By definition, remnant cholesterol represents the cholesterol content of a subset of triglyceride-rich lipoproteins called remnants, i.e. chylomicron remnants, very low-density lipoprotein (VLDL), and intermediate-density lipoprotein (IDL) in the nonfasting state, and VLDL and IDL in the fasting state.³ There are difficulties in specific measurement, and therefore it has been suggested that a simple formula for calculation may be preferable, i.e. remnant cholesterol = total cholesterol – LDL-C – high-density lipoprotein cholesterol (HDL-C).³ Although this may not be as precise as direct measurement, such an approach had practical advantages given that these parameters are measured in the nonfasting state.

What is the evidence for remnant cholesterol as causal for heart disease?
There is accumulating evidence to support remnant cholesterol as a contributor to residual cardiovascular risk; it is beyond the scope of this editorial to review the studies individually, instead the reader is referred to a comprehensive review.³ Perhaps some of the strongest support comes from elegant Mendelian randomization studies which show that genetic variants that only influence remnant cholesterol levels were causal for ischaemic heart disease risk, increasing this risk by 2.8-fold per 1 mmol/L (39 mg/dL) higher remnant cholesterol levels. Incidentally, there were also variants that increased both remnant cholesterol and HDL-C; however, variants which solely affect HDL-C were not causally associated with ischaemic heart disease risk, thus reinforcing that it is remnant cholesterol which contributes to cardiovascular risk.⁴

Added to this, this month’s Landmark study adds to the evidence-base for a causal role for remnant cholesterol in ischaemic heart disease.⁵ In a combined cohort analysis from the Jackson Heart and Framingham Offspring Cohort Studies involving both black and white subjects without prior cardiovascular disease, Joshi and co-workers showed that each 1 standard deviation increase in remnant cholesterol levels increased the risk of coronary heart disease by 23%. While this association was slightly attenuated by adjustment for HDL-C, it remained statistically significant. Moreover, this month’s Focus report of a large genetic study from Iceland adds to this, showing that non-HDL-C, which incorporates both LDL-C and remnant cholesterol, confers risk for coronary artery disease beyond LDL-C.⁶ This therefore provides further argument for the causality of remnant cholesterol in ischaemic heart disease. Indeed, the Sixth Joint Task Force has recognized that remnant cholesterol is causally related to atherosclerosis.¹ The main hurdle before recommendations for management can be made relate to the absence of “hard” cardiovascular outcome prospective clinical trials focused on this parameter.

The most common cause of elevated remnant cholesterol (and triglycerides, a surrogate for remnant cholesterol) is obesity. Given the ongoing obesity pandemic, particularly in the Middle East where more than 50% of individuals in some countries are overweight or obese,⁷ this argues for urgent action for treatments that are effective in lowering remnant cholesterol (and its surrogate, triglycerides). A number of promising novel agents are in development and we await the results of advanced trials with interest. As with all clinical development, it is important that the agent is efficacious in reducing remnant cholesterol levels, largely free of side effects, and shows definitively that the treatment reduces the risk of cardiovascular disease in statin-treated patients. Watch this space for further news.

References
1. Piepoli MF, Hoes AW, Agewall S et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2016; DOI: http://dx.doi.org/10.1093/eurheartj/ehw106 ehw106 First published online: 23 May 2016.
2. Yusuf S, Hawken S, Ounpuu S et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet;364:937-52.
3. 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.
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, on behalf of the Lipoprotein Investigators Collaborative (LIC) Study Group. Remnant lipoprotein cholesterol and incident coronary heart disease: the Jackson Heart and Framingham Offspring Cohort Studies. Am Heart Assoc J 2016;5:e002765.
6. Helgadottir A, Gretarsdottir S, Thorleifsson G et al. Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease. Nat Genet 2016 May 2. doi: 10.1038/ng.3561. [Epub ahead of print].
7. Ng M, Fleming T, Robinson M et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014;384:766-81.