DEFINING TOMORROW'S VASCULAR STRATEGIES
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Sep 2023
Remnant cholesterol – evolving evidence
Jul 2023
Call to action on residual stroke risk
Apr 2023
Residual risk in 2023: where to?
Dec 2022
Lipid-related residual risk: lessons from PROMINENT?
Sep 2022
Residual cardiovascular risk: is apolipoprotein B the preferred marker?
Jul 2022
Residual vascular risk in chronic kidney disease: new options on the horizon
Feb 2022
Looking back at 2021 – what made the news?
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?
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

8 January 2024
Targeting residual cardiovascular risk: what’s in the pipeline?
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 Individuals with atherosclerotic cardiovascular disease remain at high risk of recurrent events. Some of this risk may be ascribed to practical factors such as clinical inertia or cross-country disparities in access to effective lipid lowering therapies, as highlighted by the EU-wide DA VINCI study. Across 18 countries in the European Union, less than half of secondary prevention patients received high intensity statin therapy for managing low-density lipoprotein cholesterol (LDL-C), as recommended by clinical guidelines (1,2). Inadequacies in guideline implementation are also common to other global regions (3). Additionally, strict reimbursement criteria or lack of funding limit access to newer treatments in some regions. Even with best guideline-based treatment, however, lipid-related residual risk is a major contributor to the substantial risk of recurrent events, underlining the need to identify atherogenic targets beyond LDL-C.

An ongoing focus of interest is triglyceride-rich lipoproteins (TRL) and their remnants, supported by extensive evidence from epidemiologic, mechanistic and genetic studies (4). Even with intensive statin therapy, the residual risk associated with TRL still predicts cardiovascular risk (5,6). An ongoing conundrum is how best to target this TRL-associated risk, given mixed results from clinical outcomes studies evaluating different therapeutic approaches (7-9). In part, the lack of clarity relates to the complexity of TRL metabolism, suggesting that it may be necessary to target production, remodelling and clearance of TRL for significant clinical benefit (5). New data presented at this year’s European Society of Cardiology Congress highlight new therapeutic strategies for reducing TRL. First in-man data for ARO-ANG3, a novel RNA interference (RNAi) therapy targeting angiopoietin-like protein 3 (ANGPTL3) showed almost complete inhibition of ANGPTL3 and up to 70% reduction in plasma triglycerides, as well as modest lowering of LDL-C and apolipoprotein (apo) B, with a short-term multiple dose regimen (10). Additionally, there were promising preclinical data with anti-APOC3 GalNAc-siRNA agent, RBD5044, targeting apoC3, which showed more than 50% reduction in plasma triglycerides in different animal models (11).
Another important contributor to lipid-related residual risk is lipoprotein(a) [Lp(a)]. While extensive observational and genetic evidence supports elevated Lp(a) as causal for atherosclerotic cardiovascular disease (12), clinicians lack targeted treatments to manage this risk factor. PCSK9 monoclonal antibody therapy has been shown to lower Lp(a) levels by 20-30%, but most of the risk reduction associated with these treatments is attributed to the substantial lowering of LDL-C levels with PCSK9 inhibition (13).
There is hope on the horizon for specific Lp(a)-lowering treatments. The first of these novel agents, pelacarsen, an antisense oligonucleotide targeting apo(a) synthesis, has been shown to reduce Lp(a) levels by up to 80% and was well tolerated (14). In addition, there are at least two short interference RNA (siRNA) therapies under investigation (olpasiran and SLN360), both shown to being highly effective in lowering Lp(a) concentration (15,16). However, these agents are injectables, which may adversely impact patient access and acceptability. The ‘holy grail’ is an oral treatment; first in-man data with muvalaplin, an oral small molecule inhibitor of Lp(a) formation, which is discussed in this month’s Landmark report, indicates potential for addressing this unmet need (17). The key uncertainty is whether lowering Lp(a) reduces cardiovascular outcomes in patients at very high risk of recurrent events, which is being evaluated in two ongoing outcomes studies, HORIZON and OCEAN(a).
The future offers the prospect of new strategies for managing lipid-related residual cardiovascular risk. Now the focus should be on improving the identification of these risk factors by incorporating them into routine lipid testing in high-risk patients in clinical practice.

References

1. Ray KK, Molemans B, Schoonen WM, et al. EU-wide cross-sectional observational study of lipid-modifying therapy use in secondary and primary care: the DA VINCI study. Eur J Prev Cardiol 2021;28:1279–89.
2. 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.
3. Yang YS, Lee SY, Kim JS, et al. Achievement of LDL-C targets defined by ESC/EAS (2011) guidelines in risk-stratified Korean patients with dyslipidemia receiving lipid-modifying treatments. Endocrinol Metab (Seoul) 2020;35:367–76.
4. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res 2016;118:547-63.
5. Ginsberg HN, Packard CJ, Chapman MJ, et al. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society. Eur Heart J 2021; 42:4791–806.
6. Navarese EP, Vine D, Proctor S, et al. Independent causal effect of remnant cholesterol on atherosclerotic cardiovascular outcomes: a Mendelian Randomization Study. Arterioscler Thromb Vasc Biol 2023; doi: 10.1161/ATVBAHA.123.319297
7. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019; 380: 11–22.
8. Nicholls SJ, Lincoff AM, Garcia M, et al. Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH randomized clinical trial. JAMA 2020; 324: 2268–80.
9. Das Pradhan A, Glynn RJ, Fruchart JC, et al. Triglyceride lowering with pemafibrate to reduce cardiovascular risk. N Engl J Med 2022; 387: 1923–34.
10. Watts GF, Schwabe C, Scott R, et al. RNA interference targeting ANGPTL3 for triglyceride and cholesterol lowering: phase 1 basket trial cohorts. Nat Med 2023; doi: 10.1038/s41591-023-02494-2.
11. Luo H, Guo Z, Zheng S et al. RBD5044 – a novel anti-APOC3 GalNAc-siRNA drug resulted in sustained and profound reduction of triglycerides in mice and Rhesus monkeys. Presented at ESC Congress 2023, Amsterdam, The Netherlands (25-28 August). Session: Hypertriglyceridaemia treatment: icosapent ethyl and fibrates
12. Kronenberg F, Mora S, Stroes ESG, et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur Heart J 2022;43:3925-46.
13. Donoghue ML, Fazio S, Giugliano RP, et al. Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk. Circulation 2019;139:1483–92.
14. Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, et al. Lipoprotein(a) reduction in persons with cardiovascular disease. N Engl J Med 2020;382:244–55.
15. O'Donoghue ML, Rosenson RS, Gencer B, et al; OCEAN(a)-DOSE Trial Investigators. Small interfering RNA to reduce Lipoprotein(a) in cardiovascular disease. N Engl J Med 2022;387:1855-64.
16. Nissen SE, Wolski K, Balog C, et al. Single ascending dose study of a short interfering RNA targeting Lipoprotein(a) production in individuals with elevated plasma Lipoprotein(a) levels. JAMA 2022;327:1679-87.
17. Nicholls SJ, Nissen SE, Fleming C, et al. Muvalaplin, an oral small molecule inhibitor of lipoprotein(a) formation: a randomized clinical trial. JAMA 2023;e2316503. Doi: 10.1001/jama.2023.16503.
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