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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

6 December 2022
Lipid-related residual risk: lessons from PROMINENT?
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 Triglyceride-rich lipoproteins have attracted much attention as a likely therapeutic target to reduce residual cardiovascular risk, supported by evidence from extensive epidemiologic, genetic, and mechanistic studies 1. There are also insights from the fibrate trials suggesting clinical benefit in patients with type 2 diabetes and atherogenic dyslipidemia, i.e., the combination of mild-to-moderate hypertriglyceridemia, and low plasma concentration of high-density lipoprotein cholesterol (HDL-C) 2. Despite this, randomized controlled studies have so far failed to demonstrate conclusively that lowering triglycerides (TG), a surrogate for triglyceride-rich lipoproteins, reduces residual cardiovascular risk (3-5). Additionally, the observed relative risk reductions in cardiovascular events in REDUCE-IT did not relate to the extent of TG lowering with icosapent ethyl 6.

This background provided impetus for the development of the selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) pemafibrate, aiming to address issues with current fibrates (PPARα agonists) by improving potency, selectivity and tolerability 7. In clinical trials, pemafibrate showed robust lowering of TG, remnant cholesterol and apolipoprotein (apo)CIII, and a favourable safety profile (8-11). The next logical step was to investigate whether lowering TG with pemafibrate would reduce cardiovascular events in high-risk patients, specifically those with type 2 diabetes and atherogenic dyslipidemia on intense statin therapy.

PROMINENT (Pemafibrate to Reduce cardiovascular OutcoMes by reducing triglycerides IN patiENts with diabetes) was designed to answer this question 12. Disappointingly, however, the results from the trial were neutral. Despite lowering TG, very low-density lipoprotein cholesterol, remnant cholesterol, and apoCIII by 20 to 30%, pemafibrate did not impact cardiovascular event rates in patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, low HDL-C, and well-controlled low-density lipoprotein cholesterol (LDL-C) levels 13. These results were similar across the various subgroups, including those with and without cardiovascular disease, or with TG above or below the population median 13.

What are the messages that we can take from PROMINENT? The lack of significant effect with pemafibrate in high-risk patients with low LDL-C levels (median LDL-C at baseline 78 mg/dL or 2.0 mmol/L), reinforces LDL-C as the prime driver of lipid-related residual risk. In support, two major prospective studies with PCSK9 monoclonal antibody therapy (FOURIER and ODYSSEY OUTCOMES) showed that in patients with controlled LDL-C levels on intense statin therapy (~90 mg/dL or 2.3 mmol/L), further lowering LDL-C by 50-60% significantly reduced major adverse cardiovascular events by 15% over the relatively short duration of the trials (<3 years) 14,15. Another interpretation, however, is that the mode of action of TG lowering is relevant. Indeed, this is a valid consideration given the complexity of pathways involved in the regulation of TG levels and the metabolic processing of TRL and their remnants. It may be necessary to target both remnant formation and clearance pathways to deliver clinically meaningful cardiovascular benefit 16. Other novel TG-lowering therapeutics in development may provide answers to this question.

Insights from the PROMINENT safety data also merit discussion. Compared with placebo, the pemafibrate group showed increases in venous thromboembolism events and renal adverse events. These findings are perhaps not unexpected given similar prior observations with fenofibrate 17. A novel finding, however, was reduction in hepatic adverse events (219 versus 265, hazard ratio 0.83, 95% CI 0.69–0.99) and investigator-reported non-alcoholic fatty liver (155 versus 200, hazard ratio 0.78, 95% CI 0.63–0.96) 13. Although requiring validation, these results suggest that pemafibrate may have therapeutic potential in the setting of non-alcoholic fatty liver disease (NAFLD), or metabolic (dysfunction) associated fatty liver disease (MAFLD), in accordance with changed nomenclature 18. In support, mechanistic studies showed that pemafibrate improved non-alcoholic steatohepatitis (NASH) and prevented disease progression in rodent NASH models (19,20), and a phase 2 trial showed that treatment with pemafibrate for up to 72 weeks improved magnetic resonance elastography -based liver stiffness 21. Given the scale of the MAFLD pandemic, already affecting up to 30% of the worldwide population 22, further study is clearly merited. An ongoing trial is investigating the potential of pemafibrate in patients with NASH with liver fibrosis 23.

In conclusion, although PROMINENT was a neutral trial, exploratory data have opened the door to the possibility of alternative indications for pemafibrate. Given that management of MAFLD represents a major unmet clinic need, an ongoing trial with pemafibrate in this setting offers new opportunities. The SPPARMα story in cardiometabolic risk continues.


1. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014;384:626-35.
2. Sacks FM, Carey VJ, Fruchart J-C. Combination lipid therapy in type 2 diabetes. N Engl J Med 2010;363:692-4.
3. 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.
4. The AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255-67.
5. The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-74.
6. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.
7. Fruchart J-C. Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor alpha modulator for management of atherogenic dyslipidaemia. Cardiovasc Diabetol 2017;16:124.
8. Ishibashi S, Yamashita S, Arai H, et al. Effects of K-877, a novel selective PPARα modulator (SPPARMα), in dyslipidaemic patients: a randomized, double blind, active- and placebo-controlled, phase 2 trial. Atherosclerosis 2016;249:36-43.
9. Arai H, Yamashita S, Yokote K, et al. Efficacy and safety of K-877, a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα), in combination with statin treatment: two randomised, double-blind, placebo-controlled clinical trials in patients with dyslipidaemia. Atherosclerosis 2017;261:144-52.
10. Araki E, Yamashita S, Arai H, et al. Effects of pemafibrate, a novel selective PPARα modulator, on lipid and glucose metabolism in patients with type 2 diabetes and hypertriglyceridemia: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care 2018;41:538-46.
11. Ginsberg HN, Hounslow NJ, Senko Y, et al. Efficacy and safety of K-877 (pemafibrate), a selective PPARα modulator, in European patients on statin therapy. Diabetes Care 2022;45:898-908.
12. Pradhan AD, Paynter NP, Everett BM, et al. Rationale and design of the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) study. Am Heart J 2018;206:80-93.
13. Pradhan AD, Glynn RJ, Fruchart JC, et al. Triglyceride lowering with pemafibrate to reduce cardiovascular risk. New Engl J Med 2022; DOI: 10.1056/NEJMoa2210645.
14. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-1722.
15. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379:2097-107
16. 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.
17. Keech A, Simes RJ, Barter P, et al. Ef fects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366:1849-61.
18. Eslam M, Sanyal AJ, George J, International Consensus Panel. MAFLD: A consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterol 2020;158:1999-2014.
19. Honda Y, Kessoku T, Ogawa 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.
20. Sasaki Y, Asahiyama M, Tanaka T, et al. Pemafibrate, a selective PPARα modulator, prevents non-alcoholic steatohepatitis development without reducing the hepatic triglyceride content. Sci Rep 2020;10:7818.
21. Nakajima A, Eguchi Y, Yoneda M, et al. Randomised clinical trial: Pemafibrate, a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα), versus placebo in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2021;54:1263-77.
22. Younossi Z, Anstee QM, Marietti M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15:11-20.
23. Study to Evaluate the Efficacy and Safety of K-877-ER and CSG452 in Participants With NASH With Liver Fibrosis. Identifier: NCT05327127.