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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?
Mar 2020
Lowering triglycerides or low-density lipoprotein cholesterol: which provides greater clinical benefit?
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

17 February 2020
The omega-3 fatty acid conundrum
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 Omega-3 fatty acids have seen a resurgence of interest over the last couple of years. This has been largely driven by the landmark study REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial), which demonstrated a 25% reduction in major adverse cardiovascular events (MACE), in individuals with elevated triglycerides (TG), with an even higher relative risk reduction when total MACE were considered.1,2 There are, however, clouds on the horizon, with the early termination of STRENGTH (Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia) this year. The decision to stop the STRENGTH study was based on the recommendation of an independent Data Monitoring Committee as it was unlikely to demonstrate a benefit to patients. Although the only public information available to date is from the press release,3 it is useful to consider the background to the two studies which may help to inform on this conundrum.

Both REDUCE-IT and STRENGTH were conducted in patients at high to very high cardiovascular risk, either with a prior cardiovascular event or diabetes and other cardiovascular risk factors, with elevated TG levels and controlled low-density lipoprotein cholesterol (LDL-C). Lipid inclusion criteria were generally similar. In REDUCE-IT, patients were required to have fasting TG ≥150 mg/dL (subsequently amended to >200 mg/dL) and <500 mg/dL. In STRENGTH, inclusion criteria were TG ≥ 180 to <500 mg/dL and high-density lipoprotein cholesterol <42 mg/dL (men) or <47 mg/dL (women), against a background of controlled LDL-C levels (on statin ± ezetimibe).4

While the total omega-3 fatty acid dose was approximately similar, the components differed between the two trials. REDUCE-IT used a regimen of 4 g/day eicosapentaenoic acid (EPA) ethyl ester, whereas in STRENGTH, the investigational treatment was Epanova 4 g/day, a mixture of EPA and docosahexaenoic acid (DHA), as ethyl esters (each 1-g capsule containing 0.465 g EPA and 0.375 DHA). Thus, the actual EPA daily dose was lower (less than 50%) in STRENGTH than in REDUCE-IT. The choice of placebo in the two studies also differed. REDUCE-IT used mineral oil as a placebo, whereas in STRENGTH, the placebo was corn oil. This may have some relevance in explaining the different results of the studies, given debate regarding the effects of the mineral oil placebo in REDUCE-IT. Notably, the placebo group in this study showed a 32% increase from baseline in C-reactive protein and 11.5% increase in LDL-C, which would indicate that the placebo was not neutral and may have confounded the study findings. No information is currently available from STRENGTH.

Prior to REDUCE-IT, controversy had raged regarding the potential cardiovascular benefit of marine omega-3 fatty acids. In 2018, a meta-analysis of aggregated data from 10 studies concluded that ‘omega-3 fatty acids had no significant association with fatal or nonfatal coronary heart disease or any major vascular events’; however, this was based on a dose range of 0.226-1.8 g/day, substantially lower than in REDUCE-IT.1,5 Last year, another meta-analysis of 13 studies (including REDUCE-IT) revisited this question.6 This analysis concluded that marine omega-3 fatty acids significantly reduce the risk of cardiovascular events (overall relative risk reduction 12%, p<0.001); the significance of this finding persisted even after exclusion of REDUCE-IT (overall relative risk reduction 8%, p=0.02). Moreover, the risk reductions appeared to be linearly related to the omega-3 fatty acid dose.

It is, however, important to bear in mind that this cardiovascular benefit may be attributed partly to effects beyond TG lowering. Two lines of evidence from REDUCE-IT support this. First, the magnitude of TG-lowering in REDUCE-IT (median decrease from baseline to 1 year 18.3%, 39.0 mg/dL) was less than that expected based on the cardiovascular benefit.1 Second, there was no evidence of a dose-response relationship for TG lowering and cardiovascular benefit.7 Potential contenders for these non-lipid effects might include anti-inflammatory, anti-arrhythmic and anti-thrombotic effects, based on current knowledge of the pharmacology of omega-3 fatty acids.8

In the absence of the results of STRENGTH, these explanations are speculative. Clinicians will be eagerly awaiting public presentation of the STRENGTH data to draw their own conclusions.

1. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11–22.
2. Bhatt DL, Steg PG, Miller M, et al. Effects of Icosapent Ethyl on total ischemic events: from REDUCE-IT. J Am Coll Cardiol 2019;73:2791-802.
3. Update on Phase III STRENGTH trial for Epanova in mixed dyslipidaemia. Press release 13 January 2020.
4. Nicholls SJ, Lincoff AM, Bash D, et al. Assessment of omega-3 carboxylic acids in statin-treated patients with high levels of triglycerides and low levels of high-density lipoprotein cholesterol: Rationale and design of the STRENGTH trial. Clin Cardiol 2018;41:1281-8.
5. Aung T, Halsey J, Kromhout D, et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: meta-analysis of 10 trials involving 77 917 individuals. JAMA Cardiol 2018;3:225-34.
6. Hu Y, Hu FB, Manson JE. Marine omega-3 supplementation and cardiovascular disease: an updated meta-analysis of 13 randomized controlled trials involving 127 477 participants. J Am Heart Assoc 2019;819:e013543.
7. Bhatt DL, Steg PG, Miller M, et al. Reduction in first and total ischemic events with icosapent ethyl across baseline triglyceride tertiles. J Am Coll Cardiol 2019;74:1159-61.
8. Boden WE, Bhatt DL, Toth PP, et al. Profound reductions in first and total cardiovascular events with icosapent ethyl in the REDUCE-IT trial: why these results usher in a new era in dyslipidaemia therapeutics. Eur Heart J 2019 ;doi: 10.1093/eurheartj/ehz778. [Epub ahead of print]