R3i Editorial

Despite best evidence-based treatment, patients with atherosclerotic cardiovascular disease are at high risk of recurrent events. While targeting inflammation (as in CANTOS), or further lowering low-density lipoprotein cholesterol (LDL-C, as in the FOURIER and ODYSSEY OUTCOMES trials) provides added clinical benefit, either strategy does not obviate this risk ^1-3. This suggests that a myriad of other factors may contribute to residual cardiovascular risk. These may be lipid-related, such as the risk conferred by elevated triglyceride-rich lipoproteins or lipoprotein(a) levels ⁴, or non-lipid related factors, including pro-thrombotic factors. Indeed, a very recent report focuses attention on the potential role of inflammasome activation, which may contribute to residual risk by modulating NOD-like receptor protein-3 expression ^5,6.

While the concept of residual cardiovascular risk is now established, how best to identify those individuals at high risk of recurrent events is less well defined. Indeed, with the integration of highly efficacious LDL-C lowering treatments within routine clinical practice, there may be uncertainty regarding the role of LDL-C as a residual risk biomarker, or whether other lipid biomarkers recommended by clinical guidelines may be preferable. Such questions are critical to personalizing risk prediction and treatment, as we attain the limits of benefit of currently available therapies. This rationale underpins the study discussed in this month’s Focus.

Briefly, the authors used data from 13,015 statin-treated patients from the Copenhagen General Practice Study, a prospective observational study, to evaluate the performance of LDL-C, non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein (apo)B as biomarkers of lipid-related residual cardiovascular risk ⁷. The study used discordance analysis to investigate the value of these related variables, according to the direction of change from median values (i.e., when LDL-C was below the median and non-HDL-C or apoB was above the median value or vice versa). The key findings of this report were that either elevated apoB or non-HDL-C, but not LDL-C, were associated with residual risk of all-cause mortality and myocardial infarction. The authors suggested that apoB may be a more accurate marker of residual risk than non-HDL-C among statin-treated patients with controlled LDL-C levels, consistent with some but not all previous reports ^8,9.

What are the implications of this study for clinical practice?
For clinicians, there are two important ‘take home messages’ from this study. First, LDL-C remains the priority lipoprotein target for therapeutic intervention, in accordance with the ‘lower is better’ paradigm emphasized by the last iteration of the European dyslipidaemia guidelines (10). However, the findings of the study also show the limitations of only considering LDL-C concentration in risk assessment. For high-risk patients with well-controlled LDL-C levels, either non-HDL-C or apoB may better reflect residual cardiovascular risk. When considering what these markers represent, this makes scientific sense. Non-HDL-C is a marker of the total burden of atherogenic lipoproteins including LDL-C, whereas apoB is a direct measure of the circulating numbers of atherogenic apoB-containing lipoproteins (each of these lipoproteins contains one apoB molecule). Thus, both are to be preferred in the setting of high-risk statin-treated patients with mild-to-moderate hypertriglyceridemia, common with diabetes, obesity or metabolic syndrome. Such an approach offers the possibility to take account of the residual risk attributed to the cholesterol contained in remnant lipoproteins, the metabolic products of triglyceride-rich lipoprotein metabolism.

In conclusion, addressing residual cardiovascular risk not only requires new therapeutic targets, but also new strategies for identifying this risk. Both will become increasing relevant with the advent of novel therapies targeting triglyceride-rich lipoproteins and lipoprotein(a), potential lipid-related contributors to this risk.

References

1. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119–31.
2. 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
3. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097–107.
4. Hoogeveen RC, Ballantyne CM. Residual cardiovascular risk at low LDL: remnants, lipoprotein(a), and inflammation. Clin Chem 2021;67:143-53.
5. Schunk SJ, Kleber ME, März W, et al. Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality. Eur Heart J 2021: doi: 10.1093/eurheartj/ehab107. Online ahead of print.
6. Papac-Milicevic N, J Binder CJ. Can a single genetic variant explain residual cardiovascular risk by modifying NLRP3 expression? Eur Heart J 2021; doi: 10.1093/eurheartj/ehab201. Online ahead of print.
7. Johannesen CDL, Mortensen MB, Langsted A, Nordestgaard BG. Apolipoprotein B and non-HDL cholesterol better reflect residual risk than LDL cholesterol in statin-treated patients. J Am Coll Cardiol 2021;77:1439-50.
8. Sniderman AD, Islam S, Yusuf S, McQueen MJ. Discordance analysis of Apolipoprotein B and non-high density lipoprotein cholesterol as markers of cardiovascular risk in the INTERHEART study. Atherosclerosis 2012;225:444-9.
9. Boekholdt SM, Arsenault BJ, Mora S, et al. Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. JAMA 2012;307:1302-9.
10. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111–88.