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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

21 May 2021
Residual cardiovascular risk: how to identify?
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 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.


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.