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Aug 2021
Understanding vein graft failure: a role for PPARalpha in pathobiology
May 2021
Residual cardiovascular risk: how to identify?
Apr 2021
Metabolic syndrome and COVID-19
Mar 2021
Elevated triglyceride: linking ASCVD and dementia
Feb 2021
Does SPPARMα offer new opportunities in metabolic syndrome and NAFLD?
Jan 2021
Omega-3 fatty acids for residual cardiovascular risk: more questions than answers
Oct 2020
Targeting triglycerides: Novel agents expand the field
Jul 2020
Why multidrug approaches are needed in NASH: insights with pemafibrate
Jun 2020
Triglyceride-rich remnant lipoproteins: a new therapeutic target in aortic valve stenosis?
Mar 2020
Lowering triglycerides or low-density lipoprotein cholesterol: which provides greater clinical benefit?
Feb 2020
The omega-3 fatty acid conundrum
Dec 2019
Focus on stroke: more input to address residual cardiovascular risk
Jul 2019
International Expert Consensus on Selective Peroxisome Proliferator-Activated Receptor Alpha Modulator (SPPARMα): New opportunities for targeting modifiable residual cardiovascular risk
Nov 2018
Residual cardiovascular risk: triglyceride metabolism and genetics provide a key
Jul 2018
The clinical gap for managing residual cardiovascular risk: will new approaches make the difference?
Apr 2018
Residual cardiovascular risk: refocus on a multifactorial approach
Feb 2018
Optimizing treatment benefit: the tenet of personalized medicine
Jan 2018
Addressing residual cardiovascular risk – back to basics?
Dec 2017
Residual risk of heart failure: how to address this global epidemic?
Oct 2017
Remnants and residual cardiovascular risk: triglycerides or cholesterol?
Jul 2017
Targeting residual cardiovascular risk: lipids and beyond…
Jun 2017
Why we need to re-focus on Latin America.
Apr 2017
Residual cardiovascular risk in the Middle East: a perfect storm in the making
Feb 2017
A global call to action on residual cardiovascular risk
Dec 2016
SPPARM?: more than one way to tackle residual risk
Oct 2016
Remnants linked with diabetic myocardial dysfunction
Sep 2016
New study links elevated triglycerides with plaque progression
Aug 2016
Atherogenic dyslipidaemia: a risk factor for silent coronary artery disease
Jul 2016
SPPARM?: a concept becomes clinical reality
Jun 2016
Remnant cholesterol back in the news
May 2016
Back to the future: triglycerides revisited
Apr 2016
Unravelling the heritability of triglycerides and coronary risk
Mar 2016
Will residual cardiovascular risk meet its nemesis in 2016?
Feb 2016
Tackling residual cardiovascular risk: a case for targeting postprandial triglycerides?
Jan 2016
Looking back at 2015: lipid highlights
Dec 2015
Legacy effects in cardiovascular prevention
Nov 2015
Residual cardiovascular risk: it’s not just lipids!
Oct 2015
Addressing residual vascular risk: beyond pharmacotherapy
Sep 2015
Back to basics: triglyceride-rich lipoproteins, remnants and residual vascular risk
Jul 2015
Beyond the PCSK9 decade: what's next?
Jun 2015
Targeting triglycerides: what lies on the horizon for novel therapies?
May 2015
Do we need new lipid biomarkers for residual cardiovascular risk?
Apr 2015
The Residual Risk Debate Hots Up: Lowering LDL-C or lowering remnant cholesterol?
Mar 2015
Call for action on stroke
Feb 2015
Triglycerides: the tide has turned
Jan 2015
Post IMPROVE-IT: Where to now for residual risk?
Dec 2014
R3i publishes new Call to Action paper: Residual Microvascular Risk in Type 2 Diabetes in 2014: Is it Time for a Re-Think?
Sep 2014
Targeting residual vascular risk: round-up from ESC Congress 2014 and beyond
Jul 2014
Lipid-related residual cardiovascular risk: a new therapeutic target on the horizon
Mar 2014
Non-HDL-C and residual cardiovascular risk: the Lp(a) perspective
Feb 2014
REALIST Micro, atherogenic dyslipidaemia and residual microvascular risk
Jan 2014
Looking back at 2013: what have we learned about residual vascular risk?
Dec 2013
Long-overdue US guidelines for lipid management oversimplify the evidence
Nov 2013
Triglycerides and residual cardiovascular risk: where now?
Oct 2013
How to target residual cardiovascular risk?
Sep 2013
The Residual Vascular Risk Conundrum: Why we should target atherogenic dyslipidaemia
Jul 2013
Targeting atherogenic dyslipidemia: we need to do better
Apr 2013
Is PCSK9- targeted therapy the new hope for residual risk?
Mar 2013
Scope for multifocal approaches for reducing residual cardiovascular risk?
Feb 2013
Renewing the R3i call to action: Now more than ever we need to target and treat residual cardiovascular risk
Jan 2013
Time for a re-think on guidelines to reduce residual microvascular risk in diabetes?
Jan 2013
Addressing the residual burden of CVD in renal impairment: do PPARa agonists provide an answer?
Jan 2013
Re-evaluating options for residual risk post-HPS2-THRIVE : are SPPARMs the answer?
Dec 2012
Dysfunctional HDL: an additional target for reducing residual risk
Nov 2012
Egg consumption: a hidden residual risk factor
Oct 2012
Call to action: re-emphasising the importance of targeting residual vascular risk
Jun 2012
Time to prioritise atherogenic dyslipidaemia to reduce residual microvascular risk?
Jan 2012
Residual vascular risk in chronic kidney disease: an overlooked high-risk group
Dec 2011
Introducing the HDL Resource Center: HDL science now available for clinicians
Oct 2011
Targeting reverse cholesterol transport: the future of residual vascular risk reduction?
Sep 2011
After SPARCL: Targeting cardio-cerebrovascular metabolic risk and thrombosis to reduce residual risk of stroke
Jul 2011
Challenging the conventional wisdom: Lessons from the FIELD study on diabetic nephropathy
Jul 2010
ACCORD Eye Study: a milestone in residual microvascular risk reduction for patients with type 2 diabetes
May 2010
Lipids and residual risk of coronary heart disease in statin-treated patients
Mar 2010
ACCORD Lipid Study brings new hope to people with type 2 diabetes and atherogenic dyslipidemia
Mar 2010
Reducing residual risk of diabetic nephropathy: the role of lipoproteins
Dec 2009
ARBITER 6-HALTS: Implications for residual cardiovascular risk
Nov 2009
Microvascular event risk reduction in type 2 diabetes: New evidence from the FIELD study
Aug 2009
Fasting versus nonfasting triglycerides: Importance of triglyceride-regulating genetic polymorphisms to residual cardiovascular risk
Jul 2009
Residual risk of microvascular complications of diabetes: is intensive multitherapy the solution?
Apr 2009
Reducing residual vascular risk: modifiable and non modifiable residual vascular risk factors
Jan 2009
Micro- and macrovascular residual risk: one of the most challenging health problems of the moment
Nov 2008
Treated dyslipidemic patients remain at high residual risk of vascular events

R3i Editorial

7 September 2021
Residual vascular risk: What matters?
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 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.


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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.
10. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res 2016;118:547–63.
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.