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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?
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

19 March 2020
Lowering triglycerides or low-density lipoprotein cholesterol: which provides greater clinical benefit?
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 Treatment guidelines prioritise low-density lipoprotein cholesterol (LDL-C) as the primary lipid target for intervention to prevent atherosclerotic cardiovascular disease (ASCVD).1 The evidence for this is indisputable.2,3 Yet even with highly efficacious LDL-C lowering, patients at high and very high-risk experience recurrent cardiovascular events.4,5 This persistent residual vascular risk implies the need to consider other targets. Triglycerides (TG) levels – a surrogate for TG-rich lipoproteins and their remnants – is an attractive candidate, supported by evidence from epidemiologic studies and genetic analyses showing a causal association with vascular risk.6 This has driven efforts to develop novel agents targeting TG, which also have a favourable benefit versus risk profile.

A key question in this context is whether the extent of reduction in vascular risk associated with lowering TG is comparable to that observed with LDL-C lowering. Fundamental to this question is how best to standardise the benefit derived from lowering each lipid parameter. In the setting of residual vascular risk, two measures are recommended as secondary targets: non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein (apo) B. Non-HDL-C represents the total amount of cholesterol contained in lipoproteins other than HDL-C, and thus includes LDL and TG-rich lipoproteins such as very low-density lipoproteins (VLDL). ApoB generally refers to apoB100, produced by the liver, although intestinally produced apoB48 is also relevant. While it is presumed that the mass of cholesterol within atherogenic lipoproteins such as VLDL and LDL primarily determines how much cholesterol is deposited within the arterial wall, it is pertinent that each of these particles contains one molecule of apoB.7

Returning to the question, two recent studies offer insights. This month’s Focus report discusses a meta-regression analysis which compared the clinical benefit from lowering LDL-C versus TG with that of the effect on non-HDL-C (reference).8 Overall, it was concluded that the benefit from TG lowering was slightly less than that determined with either LDL-C or non-HDL-C (relative risk reductions 16% per mmol/L decrease in TG versus 20% and 21% per mmol/L decrease in LDL-C or non-HDL-C).

Another report used apoB as a marker of atherogenic risk9. The authors used a Mendelian randomization approach to investigate the association of genetic scores based on of TG-lowering variants in the lipoprotein lipase (LPL) gene and LDL-C–lowering variants in the LDLR gene, with the risk of cardiovascular events. Data were derived from over 650,000 subjects in 63 cohort or case-control studies conducted in North America or Europe. The risk of coronary heart disease (CHD) events was standardised per 10-mg/dL lower concentration of apoB-containing lipoproteins. Overall, the study showed that TG-lowering LPL variants and LDL-C–lowering LDLR variants were associated with similar lower CHD risk per unit lower level of apoB-containing lipoproteins (odds ratio [95% confidence interval] 0.771 [0.741-0.802] for TG-lowering versus 0.773 [0.747-0.801] for LDL-C lowering). Notably, these associations were independent, additive, and proportional to the absolute change in apoB.9 The take-home message from this analysis is that the clinical benefit from treatments that either lower TG or LDL-C is proportional to the absolute change in apoB. It should be noted, however, that this model does not take account of potential pleiotropic effects, independent of lipid lowering, that may skew study results, such as observed in REDUCE-IT.10 Overall, this study provides robust support that the lipid-related clinical benefit from lowering TG and LDL-C is comparable, and that the absolute change in apoB explains this.

Taken together, apoB is the key discriminator of benefit when evaluating the effect of a treatment in reducing lipid-related atherogenic risk. This finding has important implications for the design of clinical trials of novel therapies targeting elevated TG, which aim to address the conundrum of residual cardiovascular risk.


1. 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.
2. Borén J, Chapman MJ, Krauss RM, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2020; doi: 10.1093/eurheartj/ehz962.
3. Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017;38:2459-72.
4. Murphy SA, Pedersen TR, Gaciong ZA, et al. Effect of the PCSK9 inhibitor evolocumab on total cardiovascular events in patients with cardiovascular disease: a prespecified analysis from the FOURIER Trial. JAMA Cardiol 2019;4:613-9.
5. Szarek M, White HD, Schwartz GG, et al. Alirocumab reduces total nonfatal cardiovascular and fatal events: the ODYSSEY OUTCOMES Trial. J Am Coll Cardiol 2019;73:387-96.
6. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014;384:626–35.
7. Sniderman AD, Thanassoulis G, Glavinovic T, et al. Apolipoprotein B particles and cardiovascular disease: a narrative review. JAMA Cardiol 2019; doi: 10.1001/jamacardio.2019.3780.
8. Marston NA, Giugliano RP, Im KA, et al. Association between triglyceride lowering and reduction of cardiovascular risk across multiple lipid-lowering therapeutic classes. A systematic review and meta-regression analysis of randomized controlled trials. Circulation 2019;140:1308–17.
9. Ference BA, Kastelein JJP, Ray KK, et al. Association of triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants with risk of coronary heart disease. JAMA 2019;321:364-73.
10. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11–22.