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R3i EDITORIAL

28 July 2017

Targeting residual cardiovascular risk: lipids and beyond…

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 Accumulation of cholesterol from atherogenic apolipoprotein B-containing lipoproteins in the arterial wall has long been considered the instigator of atherosclerosis 1. As a result, preventive measures have focused on reducing levels of these atherogenic lipoproteins, with low-density lipoprotein cholesterol (LDL-C) the priority lipid target. Add-on treatments, such as ezetimibe and the PCSK9 inhibitors, to standard of care therapy have been shown to reduce the residual risk of cardiovascular events in high risk patients 2,3; recent news from the REVEAL (Randomized EValuation of the Effects of Anacetrapib through Lipid modification) study provides further support for this strategy 4.

Yet lowering LDL-C levels alone is insufficient. Even with attainment of LDL-C levels below guideline-recommended goals, high-risk patients continue to experience cardiovascular events. Accumulating evidence has supported the importance of atherogenic non-LDL lipoproteins, specifically triglyceride-rich lipoproteins and their remnants, often in combination with low plasma concentration of high-density lipoprotein cholesterol (HDL-C), i.e. atherogenic dyslipidaemia. The Residual Risk Reduction Initiative (R3i) has previously highlighted the importance of this dyslipidaemia as a contributor to lipid-related residual cardiovascular risk, especially in individuals with insulin resistant conditions such as type 2 diabetes 5,6. Indeed, a post hoc analysis of fibrate trials showed that individuals with this dyslipidaemic profile had 35% relative reduction in risk for cardiovascular events versus 6% in those individuals without this dyslipidaemia 7.

Added to this, both observational and genetic studies have been concordant in showing that remnant cholesterol (which includes intermediate-density lipoproteins, very-low-density lipoproteins, and chylomicron remnants, the products of the lipolytic degradation of triglyceride-rich lipoproteins produced by the liver and intestine) is causal for ischaemic heart disease 8. Genetic studies have also shown associations between different players in triglyceride metabolism, apolipoprotein CIII and the angiopoietins-like 3 and 4 (ANGPTL3, ANGPTL4) and coronary artery disease (9-11); the latest Focus report discusses recent data for ANGPTL3 inhibition. Moreover, given the pivotal role of peroxisome proliferator-activated receptor ? (PPAR?) in controlling the expression of a number of key genes in triglyceride and HDL metabolism, efforts have been directed to modulating the unique receptor–cofactor binding profile to improve the potency and selectivity of PPAR? ligands (the SPPARM? concept). The culmination of this work is pemafibrate, which is now being evaluated in the PROMINENT cardiovascular outcomes study 12. So, with a range of novel agents in development, there is hope that targeting triglyceride-rich lipoprotein-related residual risk is within our grasp.

Recent positive topline results from the CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study), however, reinforce that atherosclerosis is a multidimensional process; we need to consider targets beyond lipid contributors to residual risk. Canakinumab is a human monoclonal antibody that selectively neutralizes IL-1?, a pro-inflammatory cytokine that plays multiple roles in the atherothrombotic process and that undergoes activation by the NLRP3 inflammasome, a process promoted by cholesterol crystals in plaques that in turn leads directly to increased production of IL-1 and IL-6 . While full results are awaited, canakinumab monoclonal antibody therapy in combination with standard of care reduced the primary composite endpoint of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke, in patients with a prior myocardial infarction and inflammatory atherosclerosis 13.

Perhaps, therefore, we need to revise how we manage residual cardiovascular risk, bearing in mind that atherosclerosis is multifactorial in aetiology. As suggested recently, not only do we need to consider cholesterol-related residual risk, typified by residual high LDL-C levels, but also residual risk associated with high levels of triglyceride-rich lipoproteins (triglyceride residual risk) or increased inflammation (inflammatory residual risk) 14. Although definitive evidence is awaited, such an approach will help to personalise the management of residual vascular risk. Given the escalating global burden of cardiometabolic disease, this would make sense clinically and fiscally.

References
1. Borén J, Williams KJ. The central role of arterial retention of cholesterol-rich apolipoprotein-B-containing lipoproteins in the pathogenesis of atherosclerosis: a triumph of simplicity. Curr Opin Lipidol 2016;27:473-83.
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. 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. Press release, Merck, 27 June 2017. http://www.mrknewsroom.com/news-release/research-and-development-news/merck-provides-update-reveal-outcomes-study-anacetrapib
5. Fruchart JC, Sacks F, Hermans MP et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Am J Cardiol 2008;102(10 Suppl):1K-34K.
6. Fruchart JC, Davignon J, Hermans MP et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol 2014 Jan 24;13:26.
7. Sacks FM, Carey VJ, Fruchart JC. Combination lipid therapy in type 2 diabetes. N Engl J Med 2010;363:692-4.
8. Varbo A, Benn M, Tybjærg-Hansen A et al. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427-36.
9. Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med 2014;371:32-41.
10. Stitziel NO, Khera AV, Wang X et al; PROMIS and Myocardial Infarction Genetics Consortium Investigators. ANGPTL3 deficiency and protection against coronary artery disease. J Am Coll Cardiol 2017;69:2054-63.
11. Hegele RA. Variants in ANGPLT4 and the risk of coronary artery disease. N Engl J Med 2016;375:2303-4.
12. Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN patiENts With diabeTes (PROMINENT) (PROMINENT). ClinicalTrials.gov Identifier: NCT03071692.
13. Press release, Novartis 22 June 2017. https://www.novartis.com/news/media-releases/novartis-phase-iii-study-shows-acz885-canakinumab-reduces-cardiovascular-risk
14. Ridker PM. Residual inflammatory risk. Addressing the obverse side of the atherosclerosis prevention coin. Eur Heart 2016;37:1720-2.