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Mar 2024
The microvascular-macrovascular interplay: the next target?
Jan 2024
Targeting residual cardiovascular risk: what’s in the pipeline?
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 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

15 July 2011
Challenging the conventional wisdom: Lessons from the FIELD study on diabetic nephropathy
Jean-Charles FRUCHART
President of the R3i Foundation
 
Jean-Charles FRUCHART For all those who wish to fight the residual risk of nephropathy in patients with type 2 diabetes, the most recently published analysis conducted in participants of the FIELD study are very encouraging.

Dose reductions of fenofibrate, the active treatment assessed in the FIELD study, are recommended in patients with impaired renal function and this PPARα agonist is contraindicated in patients with severe renal disease. This is based on the increase in plasma creatinine occurring early after initiation of fenofibrate therapy. However, the FIELD study not only shows the reversibility of this early increase but also indicates that fenofibrate has a renoprotective effect in patients with type 2 diabetes.

A pre-specified analysis of renal outcomes during treatment and after drug cessation compared changes in renal function, classically assessed by changes in the estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes treated for 5 years with fenofibrate or placebo. The FIELD study was also designed to compare the changes in plasma creatinine levels between the active treatment group and the placebo group. As expected, plasma creatinine levels increased early in patients treated with fenofibrate. However, 8 weeks after treatment cessation, plasma creatinine was actually significantly lower in fenofibrate-treated patients. The FIELD investigators state that this early, reversible increase does not reflect a deterioration of renal function but is probably due to an effect of fenofibrate on the synthesis of creatinine.

The other remarkable finding of this analysis is that fenofibrate exerts a renoprotective effect in patients with type 2 diabetes. Indeed, after 5 years of treatment and after the washout period, eGFR decrease was significantly lower in fenofibrate-treated patients than in those allocated to placebo. Although confirmation by further studies is needed, this remarkable effect strongly suggests that we have here a major breakthrough in terms of management of residual risk of nephropathy in diabetic patients. Suffice to say that kidney disease remains the first cause of mortality in patients with diabetes to stress the clinical importance of this finding.

What the FIELD study cannot tell is by which mechanism(s) fenofibrate exerts its renoprotective effect. There is now a growing body of evidence showing that, given on top of background statin therapy, fenofibrate may also reduce the residual risk of other microvascular complications of diabetes. We may speculate that a common mechanism explains why the FIELD and ACCORD studies demonstrated that fenofibrate reduces nephropathy, retinopathy, and amputations with a predominantly microvascular etiology in patients with type 2 diabetes. Whether the effects on lipids and/or the pleiotropic effects on blood vessels of this PPARα agonist are at the origin of its clinical effects remains to be clarified.

In this context, results of the REALIST studies, which are part of the R3i research program, are awaited with great interest. In particular, the REALIST microvascular study will show whether atherogenic dyslipidemia is associated with the microvascular complications of diabetes, in particular diabetic nephropathy. These results should be released very soon.

Supposing that REALIST shows a significant association of low HDL-C and/or elevated TG levels with microvascular complications of diabetes, two issues will remain to be addressed: are these two abnormalities risk factors of microvascular complications or just markers of the underlying pathophysiology? And, will interventions that increase HDL-C or lower TG levels result in significant reductions of microvascular risk?

Answering the first question will require an extensive amount of research. Regarding HDL-C and TG as therapeutic targets, the unexpected negative results of the AIM-HIGH trial remind us that clinical benefits are not the natural consequence of demonstrated effects on the components of atherogenic dyslipidemia. Only well-conducted clinical outcome trials can produce the evidence on which modern medicine is based. This is the general rule to which all therapeutic agents currently developed with the aim of reducing Residual Vascular Risk will be submitted.

On the same token, a study designed to assess the clinical efficacy of fenofibrate in a population of diabetic patients presenting with atherogenic dyslipidemia would be very informative. No such study has been hitherto conducted. The FIELD and ACCORD study included unselected diabetic patients and analyses performed in those with and without atherogenic dyslipidemia were only secondary objectives.

What will be the next advances in the area of residual vascular risk reduction? One should not forget that adoption of a healthy lifestyle by people at risk will remain the first step of any RVR reduction strategy. But, hopefully, new, effective pharmacological agents will emerge. PPARα/γ agonists, CETP inhibitors, fish oils and other molecules are currently in development. Whether using PCSK9 inhibitors – to overcome the self-limiting effect of statins and thus reduce more effectively LDL-C – may help reduce RVR is also a topic of interest. But whatever their mechanisms of action, all these agents will have to demonstrate clinical benefits before being recommended in clinical practice.



References

1. Davis TME, Ting R, Best JD, et al. Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. Diabetologia 2011;54:280–90.
2. National Institutes of Health. NIH stops clinical trial on combination cholesterol treatment [press release]. May 26, 2011. http://www.theheart.org/article/1231453.do
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