Register now to R3i !
Your login
Your password
Confirm your password
Your email
I agree to receive the R3i newsletter
Sep 2021
Residual vascular risk: What matters?
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?
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

13 April 2015
The Residual Risk Debate Hots Up: Lowering LDL-C or lowering remnant cholesterol?
Prof. Jean Charles Fruchart, Prof. Jean Davignon, Prof. Michel Hermans, Prof. Pierre Amarenco
An Editorial from the R3i Trustees
Prof. Jean Charles Fruchart, Prof. Jean Davignon, Prof. Michel Hermans, Prof. Pierre Amarenco Has PCSK9 inhibition clouded other considerations?

This month’s editorial brings together both sides of the debate surrounding the optimal approach for targeting residual cardiovascular risk.

One the one hand, two recent publications 1,2 discussed in this month’s Focus, have heightened anticipation of the potential for PCSK9 inhibition for reducing residual cardiovascular risk. Both show that treatment with monoclonal antibody therapy targeting PCSK9, in addition to maximally tolerated statin therapy, results in remarkably consistent LDL-C reduction of about 60%. Moreover, after 1 year on treatment, this magnitude of LDL-C lowering translated to about 50% reduction in major cardiovascular events. We do, however, need to bear in mind that these are exploratory analyses, and therefore the limitations inherent with this approach need to be borne in mind, Additionally, it is relevant that PCSK9 inhibition also influences other atherogenic apolipoprotein B-containing lipids, including lipoprotein(a),3 which has been suggested to be a contributor to residual cardiovascular risk.4

On the other hand, there is growing support for the view that it is remnant cholesterol* that is the key important contributor to residual cardiovascular risk, beyond LDL-C. In this month’ s Landmark, Varbo and colleagues (2015) show that whereas the risk of ischaemic heart disease (and myocardial infarction) increased similarly for stepwise increasing nonfasting remnant cholesterol and LDL-C concentrations, only nonfasting remnant cholesterol was associated with increased all-cause mortality risk.5 This report has a number of methodological strengths, notably the large sample size, and the homogeneous nature of the population (all subjects were white and of Danish descent). Therefore targeting remnant cholesterol may offer the optimal approach to reducing residual cardiovascular risk.

How do we differentiate these two strategies? In the absence of results of definitive outcomes studies, this is not so far possible. However, perhaps we can gain some insights from consideration of the contribution of life-long exposure to low concentrations of remnant cholesterol or LDL-C. With the accolades about the potential of PCSK9 inhibition, it should be noted that data from the Danish group 6 showed that carriage of PCSK9 loss of function variants that reduced LDL-C levels by 12% translated to a 10% reduction in the risk for ischaemic vascular disease. In contrast, data from the same group showed that carriage of APOC3 variants was associated with a 39-44% reduction in triglycerides and a 40% reduction in risk of ischaemic heart disease. However, to test this formally, we need interventions that specifically target remnant cholesterol; ongoing research into apoCIII antisense oligonucleotides may provide the key.

Residual cardiovascular risk is even more relevant now than ever. The Residual Risk Reduction Initiative looks forward to the results of ongoing outcomes studies with the PCSK9 inhibitors, as well as clinical trials with apoCIII antisense agents to finally deliberate on this debate.

* Remnant cholesterol is the cholesterol content of the triglyceride-rich lipoproteins composed of very low-density lipoproteins and intermediate density lipoprotein in the fasting state, and both of these lipoproteins together with chylomicron remnants in the nonfasting state. It is calculated as total cholesterol – LDL-C – HDL-C.


1. Sabatine M, Giugliano R, Wiviott S, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. New Engl J Med 2015; published online 15 March, DOI:10.1056/NEJMoa1500858.
2. Robinson J, Farnier M, Krempf M et al; Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. New Engl J Med 2015; published online 15 March, DOI: 10.1056/MEJMoa1501031
3. Raal FJ, Giugliano RP, Sabatine MS et al. Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. J Am Coll Cardiol 2014;63:1278-88.
4. Khera AV, Everett BM, Caulfield MP et al. Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER Trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). Circulation 2014;129:635-42.
5. Varbo A, Freiberg J, Nordestgaard B. Extreme nonfasting remnant cholesterol vs extreme LDL cholesterol as contributors to cardiovascular disease and all-cause mortality in 90,000 individuals from the general population. Clin Chem2015;61:533-543.
6. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014;384:626-35.