R3i Editorials

September 2021
Residual vascular risk: What matters?
Prof. Jean-Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco

The Residual Risk Reduction Initiative (R3i) has led the field in highlighting the importance of residual vascular risk 1,2. This risk encompasses both macrovascular and microvascular residual risk, the latter highly relevant to the management of diabetic microvascular complications such as retinopathy, nephropathy and amputation due to lower extremity complications which confer substantial burden of disease. With residual vascular risk now established in the lexicon of the clinical community 3, it is an opportune time to take a step back and review what we know – and need to know – about contributors to this risk.

Much of the focus is on residual cardiovascular risk, specifically identifying the contributors to this risk, beyond low-density lipoprotein cholesterol (LDL-C). Atherogenic dyslipidemia, characterised by elevated plasma triglycerides (TG), low plasma concentration of high-density lipoprotein cholesterol (HDL-C) and a preponderance of small, dense LDL particles, is present among 10-15% of high-risk individuals, especially those with type 2 diabetes mellitus 4-6 While early attention focused on HDL-C, given that low plasma HDL-C concentration is a marker of cardiovascular risk and included in SCORE risk assessment 7, the failure of outcomes studies of novel HDL-targeted therapies, and lack of association demonstrated in genetic studies 2, turned the tide in favour of TG. It is, however, important to note that TG are a surrogate for the likely culprits – TG-rich lipoproteins and their remnants, often measured using remnant cholesterol 8.

Establishing causality for TG (or TG-rich lipoproteins and their remnants) is challenging given that TG-related metabolism is more complex than that of LDL. There have also been difficulties with cardiovascular outcomes studies, specifically in recruiting patients with sufficiently elevated TG, against a background of well-controlled LDL-C levels, as exemplified by ACCORD Lipid 6. Despite these obstacles, there is accumulating evidence that TG-rich lipoproteins play a role in the causal pathway of atherosclerotic cardiovascular disease 9. Genetic studies evaluating variants affecting the expression of different proteins involved in the regulation of TG levels have provided critical support (10), as well as driving the development of novel therapeutic strategies for managing hypertriglyceridemia.

Key questions remain, notably in defining the level at which elevated TG become clinically relevant. On this point, recent insights from the PESA (Progression of Early Subclinical Atherosclerosis) Study are informative, showing increased incident subclinical atherosclerosis from a TG level of 150 mg/dL (1.7 mmol/L), as discussed in this month’s Focus 11. Guidelines have, however, not defined a goal for TG due to insufficient evidence from cardiovascular outcomes studies that lowering elevated TG, against a background of well-controlled LDL-C levels, reduces cardiovascular events 7. PROMINENT (Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN patients With diabetes) will be pivotal to resolving this uncertainty 12.

Beyond TG, there are other contributors to residual cardiovascular risk. There is clearly a role for targeting residual inflammatory risk, which affects up to 25% of high-risk individuals, as demonstrated by the proof-of-concept CANTOS (Canakinumab Antiinflammatory Thrombosis Outcome Study) 13,14. Residual thrombotic risk is another consideration, supported by the COMPASS trial (Cardiovascular Outcomes for People using Anticoagulation Strategies), in which low dose rivaroxaban plus aspirin significantly reduced cardiovascular events and major adverse limb events in patients with stable atherosclerotic cardiovascular disease 15. Other lipoproteins and lipids may be implicated; lipoprotein(a) is one potential contributor, currently being evaluated in the HORIZON trial.

Finally, further study of contributors to residual microvascular risk is urgently needed, against the escalating pandemic of obesity and type 2 diabetes mellitus. Plasma TG may be relevant to diabetic kidney disease, and possibly retinopathy 16. Understanding the underlying molecular mechanisms is essential. For example, emerging evidence implicates a role for dysregulation of long non-coding RNAs in modulating the expression of key inflammatory genes and fibrotic genes associated with diabetic vascular complications, which may offer direction for future therapeutic innovation 17.

We face ongoing challenges to reduce the high residual vascular risk that persists despite best evidence-based treatment. The burden of cardiovascular disease and microvascular diabetic complications continues to escalate globally, especially among lower- and middle-income countries. The R3i will continue its mission to educate and advocate to reduce residual vascular risk.

References

  1. 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.
    2. Fruchart JC, Davignon J, Hermans MP, et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol 2014;13:26.
    3. Patel KV, Pandey A, de Lemos JA. Conceptual framework for addressing residual atherosclerotic cardiovascular disease risk in the era of precision medicine. Circulation 2018;137:2551–3.
    4. Halcox JP, Banegas JR, Roy C, et al. Prevalence and treatment of atherogenic dyslipidemia in the primary prevention of cardiovascular disease in Europe: EURIKA, a cross-sectional observational study. BMC Cardiovasc Disord. 2017;17:160
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    6. ACCORD Study Group, Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Eng J Med. 2010;362:1563–74.
    7. 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.
    8. Nordestgaard BG, Langlois MR, Langsted A, et al. Quantifying atherogenic lipoproteins for lipid-lowering strategies: Consensus-based recommendations from EAS and EFLM. Atherosclerosis 2020;294:46-61.
    9. Sandesara PB, Virani SS, Fazio S, Shapiro MD. The forgotten lipids: triglycerides, remnant cholesterol, and atherosclerotic cardiovascular disease risk. Endocr Rev 2019;40:537-57.
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    11. Raposeiras-Roubin S, Rosselló X, Oliva B et al. Triglycerides and residual atherosclerotic risk. J Am Coll Cardiol 2021;22: 3031 – 41.
    12. Pradhan AD, Paynter NP, Everett BM, et al. Rationale and design of the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) study. Am Heart J 2018;206:80-93.
    13. Klingenberg R, Aghlmandi S, Gencer B, et al. Residual inflammatory risk at 12 months after acute coronary syndromes is frequent and associated with combined adverse events. Atherosclerosis 2021;320:31-7.
    14. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119-31.
    15. Anand SS, Bosch J, Eikelboom JW, et al. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 2018;391:219–29.
    16. Sacks FM, Hermans MP, Fioretto P, et al. Association between plasma triglycerides and high-density lipoprotein cholesterol and microvascular kidney disease and retinopathy in type 2 diabetes mellitus: a global case-control study in 13 countries. Circulation 2014;129:999-1008.
    17. Tanwar VS, Reddy MA, Natarajan R. Emerging role of long non-coding RNAs in diabetic vascular complications. Front Endocrinol (Lausanne). 2021;12:665811.