R3i Editorial

Treatment guidelines prioritise low-density lipoprotein cholesterol (LDL-C) as the primary lipid target for intervention to prevent atherosclerotic cardiovascular disease (ASCVD).¹ The evidence for this is indisputable.^2,3 Yet even with highly efficacious LDL-C lowering, patients at high and very high-risk experience recurrent cardiovascular events.^4,5 This persistent residual vascular risk implies the need to consider other targets. Triglycerides (TG) levels – a surrogate for TG-rich lipoproteins and their remnants – is an attractive candidate, supported by evidence from epidemiologic studies and genetic analyses showing a causal association with vascular risk.⁶ This has driven efforts to develop novel agents targeting TG, which also have a favourable benefit versus risk profile.

A key question in this context is whether the extent of reduction in vascular risk associated with lowering TG is comparable to that observed with LDL-C lowering. Fundamental to this question is how best to standardise the benefit derived from lowering each lipid parameter. In the setting of residual vascular risk, two measures are recommended as secondary targets: non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein (apo) B. Non-HDL-C represents the total amount of cholesterol contained in lipoproteins other than HDL-C, and thus includes LDL and TG-rich lipoproteins such as very low-density lipoproteins (VLDL). ApoB generally refers to apoB100, produced by the liver, although intestinally produced apoB48 is also relevant. While it is presumed that the mass of cholesterol within atherogenic lipoproteins such as VLDL and LDL primarily determines how much cholesterol is deposited within the arterial wall, it is pertinent that each of these particles contains one molecule of apoB.⁷

Returning to the question, two recent studies offer insights. This month’s Focus report discusses a meta-regression analysis which compared the clinical benefit from lowering LDL-C versus TG with that of the effect on non-HDL-C (reference).⁸ Overall, it was concluded that the benefit from TG lowering was slightly less than that determined with either LDL-C or non-HDL-C (relative risk reductions 16% per mmol/L decrease in TG versus 20% and 21% per mmol/L decrease in LDL-C or non-HDL-C).

Another report used apoB as a marker of atherogenic risk⁹. The authors used a Mendelian randomization approach to investigate the association of genetic scores based on of TG-lowering variants in the lipoprotein lipase (LPL) gene and LDL-C–lowering variants in the LDLR gene, with the risk of cardiovascular events. Data were derived from over 650,000 subjects in 63 cohort or case-control studies conducted in North America or Europe. The risk of coronary heart disease (CHD) events was standardised per 10-mg/dL lower concentration of apoB-containing lipoproteins. Overall, the study showed that TG-lowering LPL variants and LDL-C–lowering LDLR variants were associated with similar lower CHD risk per unit lower level of apoB-containing lipoproteins (odds ratio [95% confidence interval] 0.771 [0.741-0.802] for TG-lowering versus 0.773 [0.747-0.801] for LDL-C lowering). Notably, these associations were independent, additive, and proportional to the absolute change in apoB.⁹ The take-home message from this analysis is that the clinical benefit from treatments that either lower TG or LDL-C is proportional to the absolute change in apoB. It should be noted, however, that this model does not take account of potential pleiotropic effects, independent of lipid lowering, that may skew study results, such as observed in REDUCE-IT.¹⁰ Overall, this study provides robust support that the lipid-related clinical benefit from lowering TG and LDL-C is comparable, and that the absolute change in apoB explains this.

Taken together, apoB is the key discriminator of benefit when evaluating the effect of a treatment in reducing lipid-related atherogenic risk. This finding has important implications for the design of clinical trials of novel therapies targeting elevated TG, which aim to address the conundrum of residual cardiovascular risk.

References

1. 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.
2. Borén J, Chapman MJ, Krauss RM, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2020; doi: 10.1093/eurheartj/ehz962.
3. Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017;38:2459-72.
4. Murphy SA, Pedersen TR, Gaciong ZA, et al. Effect of the PCSK9 inhibitor evolocumab on total cardiovascular events in patients with cardiovascular disease: a prespecified analysis from the FOURIER Trial. JAMA Cardiol 2019;4:613-9.
5. Szarek M, White HD, Schwartz GG, et al. Alirocumab reduces total nonfatal cardiovascular and fatal events: the ODYSSEY OUTCOMES Trial. J Am Coll Cardiol 2019;73:387-96.
6. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014;384:626–35.
7. Sniderman AD, Thanassoulis G, Glavinovic T, et al. Apolipoprotein B particles and cardiovascular disease: a narrative review. JAMA Cardiol 2019; doi: 10.1001/jamacardio.2019.3780.
8. Marston NA, Giugliano RP, Im KA, et al. Association between triglyceride lowering and reduction of cardiovascular risk across multiple lipid-lowering therapeutic classes. A systematic review and meta-regression analysis of randomized controlled trials. Circulation 2019;140:1308–17.
9. Ference BA, Kastelein JJP, Ray KK, et al. Association of triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants with risk of coronary heart disease. JAMA 2019;321:364-73.
10. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11–22.