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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
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

20 July 2020
Why multidrug approaches are needed in NASH: insights with pemafibrate
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 Nonalcoholic fatty liver disease (NAFLD) is a major challenge for the 21st century. Already more than 25% of the global population is affected 1, with similar rates among industrialised and less developed countries 2. As the prevalences of obesity, dyslipidaemia and diabetes escalate, NAFLD is likely to become even more common. Progression to nonalcoholic steatohepatitis (NASH), the most severe form of NAFLD, is also increasing in line with the pandemics of insulin resistance and obesity. Indeed, the most significant clinical burden in individuals with diabetes and NAFLD is among those with NASH 3; in the USA, cirrhosis from NASH is the leading cause of liver transplantation in women and the second leading cause of liver transplantation in men, and is a major contributor to the increased incidence of hepatocellular carcinoma 4. To date, however, no therapeutic agents are approved for the management of NASH.

Understanding the pathogenesis of NASH is critical to developing novel treatments. During disease progression, lipotoxicity and interactions between myeloid cells and sinusoidal endothelial cells in the liver are pivotal 5. Triglycerides (TG) accumulation is also thought to play a key role, although the underlying pathogenetic mechanisms are not fully clarified. Since peroxisome proliferator-activated receptor alpha (PPARα) is integral to the transcriptional regulation of lipoprotein metabolism, fatty acid transport and beta-oxidation, and impaired PPARα function is one factor involved in NASH development, targeting this receptor may offer potential. Pemafibrate, a selective PPARα modulator (SPPARMα), with enhanced potency and PPARα subtype specificity compared with traditional PPARα agonists, has demonstrated efficacy in managing hypertriglyceridaemia, especially in insulin-resistant conditions, reducing TG by up to 50% 6, with a favourable safety profile 7. Furthermore, a recent study has also suggested potential benefit in experimental NASH 8. Together, these insights provided a rationale to investigate pemafibrate in a preclinical NASH model, highly relevant given the unmet clinical need.

This study 9 used the STAM mouse model, which is characterised by almost complete destruction of pancreatic insulin-secreting β-cells with severe hyperglycaemia, representative of diabetes-based NASH in the clinical setting. Briefly, C57BL/6J mice were injected with 200 μg of anti-β-cells toxin streptozocin 2 days after birth and fed with a high fat diet from 4 weeks. At 6 weeks of age, mice were allocated to pemafibrate 0.1 mg/kg or a vehicle control for 3 weeks. Findings were compared with normal mice fed a normal chow diet. Investigations included measurement of lipids, liver histology, NAFLD activity score and gene transcriptome analysis.

It was hypothesised that pemafibrate would reduce hepatic TG accumulation and thereby improve NASH. While pemafibrate did significantly improve liver histology and the NAFLD activity score, as well as inflammatory and fibrosis marker gene expression, there was no change in hepatic TG content. Global gene analysis showed that pemafibrate induced TG hydrolysis and fatty acid beta-oxidation, as well as TG re-esterification, and also induced the expression of genes involved in lipolysis and lipid droplet formation. Additionally, dosing with pemafibrate modulated inflammation by reducing expression of the cell adhesion molecule VCAM-1, myeloid markers, and inflammation and fibrosis-related genes in STAM mice 8. In vitro studies showed that pemafibrate reduced VCAM-1 expression induced by high glucose levels 8.

In conclusion, the results of studies with pemafibrate in experimental NASH models suggest that while pemafibrate reduces steatosis and lipotoxicity by reducing excess free fatty acids, TG reduction in the liver may be insufficient 8,9. This is because PPARα is mainly involved in regulating nutrient flux to peripheral tissues, rather than providing an energy source to the liver. Instead, pemafibrate may prevent NASH by targeting immune cell interactions in the liver. Overall, these findings underline the need for multidrug approaches to manage NASH. This could explain why the search for new treatments for NASH, which has broadly focused on modulation of metabolic pathways, inflammatory cascades, and/or mechanisms impacting fibrosis, has been tortuous. Clinicians will also face challenges in identifying patients with advanced liver fibrosis who are likely to derive most benefit from treatment.


1. Younossi ZM, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64:73–84.
2. Review Team, LaBrecque DR, Abbas Z, et al; World Gastroenterology Organisation. World Gastroenterology Organisation global guidelines: Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. J Clin Gastroenterol 2014;48:467–73.
3. Younossi ZM, et al. Economic and clinical burden of non alcoholic steatohepatitis in patients with type 2 diabetes in the U.S. Diabetes Care 2020;43:283-9.
4. White DL, et al. Incidence of hepatocellular carcinoma in all 50 United States, from 2000 through 2012. Gastroenterology 2017;152:812‐20.
5. Miyao M, et al. Pivotal role of liver sinusoidal endothelial cells in NAFLD/NASH progression. Lab. Invest 2015;95:30–44.
6. Yamashita S, Masuda D, Matsuzawa Y. Pemafibrate, a new selective PPARα Modulator: drug concept and its clinical applications for dyslipidemia and metabolic diseases. Curr Atheroscler Rep 2020;221:5.
7. Yamashita S, et al. Efficacy and safety of pemafibrate, a novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα): pooled analysis of phase 2 and 3 studies in dyslipidemic patients with or without statin combination. Int J Mol Sci 2019; doi: 10.3390/ijms20225537.
8. Honda, Y. et al. Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, improves the pathogenesis in a rodent model of nonalcoholic steatohepatitis. Sci Rep 2017;7:42477.
9. Sasaki Y, et al. Pemafibrate, a selective PPARα modulator, prevents non-alcoholic steatohepatitis development without reducing the hepatic triglyceride content. Sci Rep 2020;10:7818.
10. Alkhouri N, et al. Looking into the crystal ball: predicting the future challenges of fibrotic NASH treatment. Hepatol Commun 2019;3:605-13.
11. Colca J. NASH (nonalcoholic steatohepatitis), diabetes, and macrovascular disease: multiple chronic conditions and a potential treatment at the metabolic root. Expert Opin Investig Drugs 2020;29:191-6.