Register now to R3i !
Your login
Your password
Confirm your password
Your email
I agree to receive the R3i newsletter
Nov 2021
New ACC guidance addresses unmet clinical needs for high-risk patients with mild to moderate hypertriglyceridemia
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?
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

16 October 2017
Remnants and residual cardiovascular risk: triglycerides or cholesterol?
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 Non-high-density lipoprotein cholesterol (non-HDL-C) is recognized as a key therapeutic target, especially in subjects with a lipid profile characterized by elevated triglycerides and low HDL-C levels (atherogenic dyslipidaemia), which is prevalent in individuals with insulin resistant conditions such as type 2 diabetes mellitus.1 Non-HDL-C encompasses the total burden of atherogenic apolipoprotein B-containing lipoproteins, and therefore includes low-density lipoproteins (LDL). But in the setting of well controlled LDL cholesterol (LDL-C) levels with intensive statin therapy, as evident in the REVEAL study,2 or with combination LDL- lowering regimens such as in IMPROVE-IT (ezetimibe)3 or FOURIER (evolocumab),4 can we perhaps refine this measure – or define more specific therapeutic approaches? Results from an analysis based on the JUPITER study population, discussed in this month’s Focus article5, suggests promise.

The JUPITER analysis in brief
In this report, the authors used nuclear magnetic resonance (NMR) spectroscopy to measure different apoB-containing lipoprotein particle concentrations in 11,984 subjects from the JUPITER study population. The variables of interest were LDL (large, small), intermediate-density lipoproteins (IDL), and very low-density lipoproteins (VLDL, large, medium and small) particle subclasses, VLDL-cholesterol and VLDL/chylomicron triglycerides. In the statin-treated group, in which median LDL-C was 55 mg/dl (1.4 mmol/L), there was no association between LDL or IDL particle concentration and risk for major adverse cardiovascular events (MACE). There was, however, an association for VLDL particle concentration, specifically driven by small VLDL particles. Indeed, each increase by one standard deviation in small VLDL particle concentration was associated with 68% increase in the residual risk of MACE. This finding is consistent with mechanistic studies of lipoprotein/arterial wall interactions, which show that larger VLDL particles are much less likely to influx into the arterial intima than those of smaller diameter.6,7

Implications for clinical practice
Triglyceride-rich lipoproteins (TRLs) is the term used to collectively refer to apoB-containing lipoproteins beyond LDL. The largest of these lipoproteins are the chylomicrons, which mainly comprise triglycerides; the smallest are the remnant lipoproteins, i.e. IDL, VLDL and chylomicron remnants. With increasing size, the relative content of triglyceride in remnants increases, although all remnants carry a large cholesterol load. Thus, a key question is whether the atherogenicity of these small triglyceride-rich particles is due to their triglyceride or cholesterol content. This question was addressed by the authors of this JUPITER analysis. Whereas VLDL-cholesterol was associated with a significant 27% increase in residual cardiovascular risk (p=0.014), the triglyceride content was not.5

While the authors conclude that their findings should be regarded as hypothesis-generating due to the multiplicity of testing, rather than definitive, it is important to note that a growing body of evidence from observational and genetic studies supports remnant cholesterol as a causal risk factor for low-grade inflammation, atherosclerotic cardiovascular disease and even all-cause mortality.8-10
Thus, it is logical that elevated remnant cholesterol levels are likely contributors to the residual risk of atherosclerotic cardiovascular disease in patients with very well controlled LDL-C levels.

As suggested by multiple lines of evidence, targeting remnants, especially the smallest class, may drive novel therapeutic approaches to managing residual cardiovascular risk. Now, we need the agents and studies to prove this.


1. Catapano AL, Graham I, De Backer G et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Eur Heart J 2016;37:2999-3058.
2. HPS3/TIMI55-REVEAL Collaborative Group. Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med 2017; doi: 10.1056/NEJMoa1706444. [Epub ahead of print]
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. 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.
5. Lawler PR, Akinkuolie AO, Chu AY et al. Atherogenic lipoprotein determinants of cardiovascular disease and residual risk among individuals with low low-density lipoprotein cholesterol. J Am Heart Assoc;67. pii: e005549. doi: 10.1161/JAHA.117.005549.
6. Stender S, Zilversmit DB. Transfer of plasma lipoprotein components and of plasma proteins into aortas of cholesterol-fed rabbits. Molecular size as a determinant of plasma lipoprotein influx. Arteriosclerosis 1981;1:38-49.
7. Nordestgaard BG, Wootton R, Lewis B. Selective retention of VLDL, IDL, and LDL in the arterial intima of genetically hyperlipidemic rabbits in vivo: Molecular size as a determinant of fractional loss from the intima-inner media. Arterioscler Thromb Vasc Biol 1995;15:534-42.
8. Nordestgaard BG. Triglyceride-Rich Lipoproteins and Atherosclerotic Cardiovascular Disease: New Insights From Epidemiology, Genetics, and Biology. Circ Res 2016;118:547-63.
9. Varbo A, Nordestgaard BG. Remnant Cholesterol and Triglyceride-Rich Lipoproteins in Atherosclerosis Progression and Cardiovascular Disease. Arterioscler Thromb Vasc Biol 2016;36:2133-35.
10. Jepsen AM, Langsted A, Varbo A et al. Increased Remnant Cholesterol Explains Part of Residual Risk of All-Cause Mortality in 5414 Patients with Ischemic Heart Disease. Clin Chem 2016;62:593-604.