R3i Publications

All reviews in this section are authored by members of R3i. This collaborative effort is significant because it brings together a diverse pool of expertise and insights. By having R3i members contribute, the publications reflect a collective commitment to addressing residual cardiovascular risk, promoting advancements in treatment, and enhancing patient care. This not only fosters a sense of community among professionals in the field but also drives forward the initiative’s mission to reduce residual risk effectively.

Latest Publication

Lessons from PROMINENT and prospects for permafibrate

Jean-Charles Fruchart, Jamila Fruchart-Najib, Shizuya Yamashita, Peter Libby, Koutaro Yokote, Tatsuhiko Kodama, Yohei Tomita, Paul M. Ridker, Michel P. Hermans and Alberto Zambon

The neutral result of the PROMINENT trial has led to questions about the future for pemafibrate. This commentary discusses possible reasons for the lack of benefit observed in the trial. There were, however, indicators suggesting therapeutic potential in microvascular ischaemic complications associated with peripheral artery disease, with subsequent analysis showing reduction in the incidence of lower extremity ischaemic ulceration or gangrene. Reassurance about the safety of pemafibrate, together with emerging data from PROMINENT and experimental studies, also suggest benefit with pemafibrate in non-alcoholic fatty liver disease (alternatively referred to as metabolic dysfunction-associated steatotic liver disease) and microangiopathy associated with diabetes, which merit further study.

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Other Publications

2020

Selective Peroxisome Proliferator–Activated Receptor Alpha Modulators (SPPARMα): New Opportunities to Reduce Residual Cardiovascular Risk in Chronic Kidney Disease?

Jean-Charles Fruchart, Michel P. Hermans, Jamila Fruchart-Najib

Purpose of Review
Chronic kidney disease (CKD) poses a major global challenge, which is exacerbated by aging populations and the pandemic of type 2 diabetes mellitus. Much of the escalating burden of CKD is due to cardiovascular complications. Current treatment guidelines for dyslipidemia in CKD prioritize low-density lipoprotein cholesterol management, but still leave a high residual cardiovascular risk. Targeting elevated triglycerides and low plasma high-density lipoprotein cholesterol, a com- mon feature of CKD, could offer additional benefit. There are, however, safety issues with current fibrates (peroxisome proliferator–activated receptor alpha [PPARα] agonists), notably the propensity for elevation in serum creatinine, indicating the need for new approaches.

Recent Findings
Interactions between the ligand and PPARα receptor influence the specificity and potency of receptor binding, and downstream gene and physiological effects. The peroxisome proliferator–activated receptor alpha modulator (SPPARMα) concept aims to modulate the ligand structure so as to enhance binding at the PPARα receptor, thereby improving the ligand’s selectivity, potency, and safety profile. This concept has led to the development of pemafibrate, a novel SPPARMα agent. This review discusses evidence that differentiates pemafibrate from current fibrates, especially the lack of evidence for elevation in serum creatinine or worsening of renal function in high-risk patients, including those with CKD.

Summary
Differentiation of pemafibrate from current fibrates aims to address unmet clinical needs in CKD. The ongoing PROMINENT study will provide critical information regarding the long-term efficacy and safety of pemafibrate in patients with type 2 diabetes mellitus, including those with CKD, and whether the favorable lipid-modifying profile translates to reduction in residual cardiovascular risk.

Residual vascular risk in diabetes : Will the SPPARMα concept hold the key?

Jean-Charles Fruchart , Raul D. Santos, Shizuya Yamashita, Peter Libby, on behalf of the International Atherosclerosis Society/R3i Foundation Consensus Panel

Clinicians need to consider other targets to reduce residual cardiovascular risk in diabetes. The SPPARMα concept is a leading contender, offering the opportunity to act at multiple targets relevant to vascular risk.

Even with best guideline-recommended treatment, patients with diabetes continue to experience cardiovascular events. This high residual cardiovascular risk is an urgent unmet clinical need. We need to intervene against other targets, especially high triglycerides that are common in these patients.

A key contender to overcoming this enigma is PPARα, which controls key metabolic and inflammatory pathways. But current fibrates are not the answer; these did not definitively reduce cardiovascular events against a background of statin treatment, and may have safety issues.

One approach to tackling this high residual cardiovascular risk in diabetes patients is the SPPARMα concept. This concept has been a catalyst for the development of a novel SPPARMα agent, pemafibrate, which acts at multiple targets relevant to vascular risk. Will pemafibrate be the key to reducing residual cardiovascular risk? The answer lies in PROMINENT.

Jean‐Charles Fruchart, Raul D. Santos, Carlos Aguilar‐Salinas, Masanori Aikawa, Khalid Al Rasadi, Pierre Amarenco, Philip J. Barter, Richard Ceska, Alberto Corsini, Jean‐Pierre Després, Patrick Duriez, Robert H. Eckel, Marat V. Ezhov, Michel Farnier, Henry N. Ginsberg, Michel P. Hermans, Shun Ishibashi, Fredrik Karpe, Tatsuhiko Kodama, Wolfgang Koenig, Michel Krempf, Soo Lim, Alberto J. Lorenzatti, Ruth McPherson, Jesus Millan Nunez‐Cortes, Børge G. Nordestgaard, Hisao Ogawa, Chris J. Packard, Jorge Plutzky, Carlos I. Ponte‐Negretti, Aruna Pradhan, Kausik K. Ray, Zeljko Reiner, Paul M. Ridker, Massimiliano Ruscica, Shaukat Sadikot, Hitoshi Shimano, Piyamitr Sritara, Jane K. Stock, Ta‐Chen Su, Andrey V. Susekov, André Tartar, Marja‐Riitta Taskinen, Alexander Tenenbaum, Lale S. Tokgözoğlu, Brian Tomlinson, Anne Tybjærg‐Hansen, Paul Valensi, Michal Vrablík, Walter Wahli,, Gerald F. Watts, Shizuya Yamashita, Koutaro Yokote, Alberto Zambon and Peter Libby

Over 50 internationally renowned clinical and scientific experts came together to discuss the SPPARMα concept and its therapeutic potential for addressing residual vascular risk. This landmark paper provides the essentials for clinicians.

Atherogenic dyslipidemia remains the enigma for clinicians in this era of precision medicine. It is clear that we need new treatments to target this dyslipidemia, characterised by elevated plasma triglycerides with or without low levels of high-density lipoprotein cholesterol, that is common in high risk patients, especially those with type 2 diabetes mellitus. The development of selective peroxisome proliferator- activated receptor α modulators (SPPARMα) offers an approach to address this treatment gap.

This Joint Consensus of the R3i and the International Atherosclerosis Society, comprising over 50 world- leading experts, reviewed the evidence for the first SPPARMα agonist, pemafibrate. This expert consensus concluded that pemafibrate represents a novel therapeutic class, distinct from fibrates, based on pharmacological activity, and, importantly, a safe hepatic and renal profile. The ultimate answer lies with the PROMINENT cardiovascular outcomes trial with pemafibrate in 10,000 very high-risk patients with type 2 diabetes mellitus and atherogenic dyslipidemia.

Jean-Charles Fruchart , Raul D. Santos

SPPARMaα – a revival of the fibrates or a new drug class?

Atherogenic dyslipidemia, elevated triglycerides with or without low HDL cholesterol, has been previously overlooked as a contributor to residual cardiovascular risk. In part, this was because clinical studies with the fibrates, PPARα agonists, did not conclusively show that targeting this dyslipidemia, against a background of statin treatment, reduces cardiovascular events. Some also had safety issues.

This review discusses the evidence for the SPPARMα concept and its therapeutic application, with pemafibrate. Clinical trials to date have indicated a favourable benefit vs. risk profile, especially with the lack of elevation in serum creatinine, evident with fenofibrate, and improved renal and hepatic safety. The cardiovascular outcomes study PROMINENT will be critical to validating the SPPARMαconcept as an approach to reducing residual cardiovascular risk.

Residual Microvascular Risk in Type 2 Diabetes in 2014: Is it Time for a Re-Think? A Perspective from the Residual Risk Reduction Initiative (R3i)

Michel P Hermans, Jean-Charles Fruchart, Jean Davignon, Khalid Al-Rubeaan, Pierre Amarenco, Gerd Assmann, Philip Barter, John Betteridge, Eric Bruckert, M John Chapman, Ada Cuevas, Michel Farnier, Ele Ferrannini, Paola Fioretto, Jacques Genest Henry N Ginsberg, Antonio M Gotto Jr, Dayi Hu, Takashi Kadowaki, Tatsuhiko Kodama, Michel Krempf, Yuji Matsuzawa, Jesús Millán Núñez-Cortés, Carlos Calvo Monfil Hisao Ogawa, Jorge Plutzky, Daniel J Rader, Željko Reiner, Shaukat Sadikot, Raul D Santos, Evgeny Shlyakhto, Piyamitr Sritara, Rody Sy, Alan Tall, Chee-Eng Tan, Lale Tokgözo?lu, Peter P Toth, Paul Valensi, Christoph Wanner, Alberto Zambon, JunRen Zhu and Paul Zimmet J Diabetes Metab 5:413. doi: 10.4172/2155-6156.1000413

Microvascular complications associated with type 2 diabetes, including diabetic retinopathy, nephropathy and neuropathy, account for much of the societal burden of diabetes. Even with effective multifactorial intervention, targeting glycemia, blood pressure and lowdensity lipoprotein cholesterol, in addition to lifestyle intervention, a high residual microvascular risk persists. The Residual Risk Reduction Initiative (R3i) highlights two key priorities for reducing this residual risk. First, there should be optimal management of cardiometabolic risk factors, including atherogenic dyslipidemia, elevated triglycerides and low plasma high-density lipoprotein cholesterol, to improve lipid goal attainment. Second, consistent evidence from two major trials may merit consideration of adjunctive fenofibrate therapy to slow progression of diabetic retinopathy in type 2 diabetes patients with pre-existing disease. These data provide a strong rationale for testing in a prospective study. The R3i strongly believes that addressing both priorities is critical to reducing the substantial residual risk of microvascular complications in type 2 diabetes.

Jean-Charles Fruchart, Jean Davignon, Michel P. Hermans, Khalid Al-Rubeaan, Pierre Amarenco, Gerd Assmann, Philip Barter, John Betteridge, Eric Bruckert, Ada Cuevas, Tan Chee Eng, Michel Farnier, Ele Ferrannini, Paola Fioretto, Jacques Genest, Henry N. Ginsberg, Dayi Hu, Takashi Kadowaki, Michel Krempf, Yuji Matsuzawa, Jesús Millán Núñez-Cortés, Carlos Calvo Monfil, Hisao Ogawa, Jorge Plutzky, Daniel J. Rader, Shaukat Sadikot, Raul D. Santos, Evgeny Shlyakhto, Piyamitr Sritara, Rody Sy, Alan Tall, Lale Tokgözo?lu, Peter P. Toth, Paul Valensi, Christoph Wanner, Alberto Zambon, Junren Zhu and Paul Zimmet for the Residual Risk Reduction Initiative (R3i). Cardiovacular Diabetology, 13:26 January 2014

The International Steering Committee of the Residual Risk Reduction Initiative (R3i), comprising 40 leading specialists from North and South America, Europe, the Middle East, Asia and Japan, has today highlighted priorities for action against atherogenic dyslipidaemia, an important contributor to lipid-related residual cardiovascular risk. The R3i defines atherogenic dyslipidaemia as the imbalance between triglyceride-rich apolipoprotein B-containing-lipoproteins, for which triglycerides are a marker, and apolipoprotein A-I-lipoproteins (as in high-density lipoprotein, HDL). The R3i has identified three key priorities: • To improve recognition of atherogenic dyslipidaemia in high risk patients, including those with diabetes • To target atherogenic dyslipidaemia, using non-HDL cholesterol (total cholesterol – HDL cholesterol) for treatment decisions • To improve management of atherogenic dyslipidaemia, and adherence to guideline-recommended therapies. The addition of a fibrate, niacin (North and South America), omega-3 fatty acids or ezetimibe to statin therapy are all approaches to reduce non-HDL cholesterol. The R3i recognises that there is a need for new treatment options that can more effectively target atherogenic dyslipidaemia, and reviews future possibilities in this paper. This paper will have important implications for the routine management of patients who remain at high residual cardiovascular risk despite well controlled low-density lipoprotein (LDL) cholesterol levels

Association Between Plasma Triglycerides and HDL-cholesterol and Microvascular Nephropathy and Retinopathy in Type 2 Diabetes: A global case:control study in 13 countries

Frank M. Sacks, Michel P. Hermans, Paola Fioretto, Paul Valensi, Timothy Davis, Edward Horton, Christoph Wanner, Khalid Al-Rubeaan, Ronnie Aronson, Isabella Barzon, Louise Bishop, Enzo Bonora, Pongamorn Bunnag, Lee-Ming Chuang, Chaicharn Deerochanawong, Ronald Goldenberg, Benjamin Harshfield, Cristina Hernández, Susan Herzlinger-Botein, Hiroshi Itoh, Weiping Jia, Yi-Der Jiang, Takashi Kadowaki, Nancy Laranjo, Lawrence Leiter, Takashi Miwa, Masato Odawara, Ken Ohashi, Atsushi Ohno, Changyu Pan, Jiemin Pan, Juan Pedro-Botet, Zeljko Reiner, Carlo Maria, Rotella, Rafael Simo, Masami Tanaka, Eugenia Tedeschi-Reiner, David Twum-Barima, Giacomo, Zoppini and Vincent J. Carey. Circulation. published online December 18, 2013

Background

Microvascular renal and retinal diseases are common major complications of type 2 diabetes mellitus. The relation between plasma lipids and microvascular disease is not well established.

Methods and Results

The case subjects were 2535 patients with type 2 diabetes mellitus with an average duration of 14 years, 1891 of whom had kidney disease and 1218 with retinopathy. The case subjects were matched for diabetes mellitus duration, age, sex, and low-density lipoprotein cholesterol to 3683 control subjects with type 2 diabetes mellitus who did not have kidney disease or retinopathy. The study was conducted in 24 sites in 13 countries. The primary analysis included kidney disease and retinopathy cases. Matched analysis was performed by use of site-specific conditional logistic regression in multivariable models that adjusted for hemoglobin A_1c, hypertension, and statin treatment. Mean low-density lipoprotein cholesterol concentration was 2.3 mmol/L. The microvascular disease odds ratio increased by a factor of 1.16 (95% confidence interval, 1.11–1.22) for every 0.5 mmol/L (≈1 quintile) increase in triglycerides or decreased by a factor of 0.92 (0.88–0.96) for every 0.2 mmol/L (≈1 quintile) increase in high-density lipoprotein cholesterol. For kidney disease, the odds ratio increased by 1.23 (1.16–1.31) with triglycerides and decreased by 0.86 (0.82–0.91) with high-density lipoprotein cholesterol. Retinopathy was associated with triglycerides and high-density lipoprotein cholesterol in matched analysis but not significantly after additional adjustment.

Conclusions

Diabetic kidney disease is associated worldwide with higher levels of plasma triglycerides and lower levels of high-density lipoprotein cholesterol among patients with good control of low-density lipoprotein cholesterol. Retinopathy was less robustly associated with these lipids. These results strengthen the rationale for studying dyslipidemia treatment to prevent diabetic microvascular disease.

Effect of Combination Therapy With Fenofibrate and Simvastatin on Postprandial Lipemia in the ACCORD Lipid Trial

G. Reyes-Soffer, C Ngai, L Lovato, W Karmally, R Ramakrishan, S Holleran, H Ginsberg Diabetes Care

This ancillary study evaluated postprandial lipaemia after an oral fat test in a subgroup of patients in the ACCORD Lipid study. Fenofibrate treatment reduced postprandial exposure to atherogenic apolipoprotein B48 only in patients with elevated fasting triglycerides at baseline. This suggests that fenofibrate improves clearance of atherogenic triglyceride-rich remnant lipoproteins and reduces residual macrovascular risk in type 2 diabetes patients, only if fasting levels are sufficiently increased at baseline.

PCSK9: the functional relevance of fenofibrate-statin combination therapy to reduce residual cardiovascular risk

JC Fruchart International Journal of Diabetes Mellitus

The author reminds the physiology and roles of PCSK9, notably in the regulation of LDL-C levels through its ability to target the LDL-C receptor. Then, he describes the way statins and fibrates, notably fenofibrate, act on PCSK9. Finally, he concludes that the existing data (1) provide a functional rationale for the combination of fenofibrate with a statin for optimizing LDL-C lowering efficacy, (2) suggest that PSCK9 may be a potential target in patients with type 2 diabetes or metabolic syndrome, opening new approaches that could impact the substantial residual cardiovascular risk that exists in statin-treated patients.

RS Rosenson, P Fioretto, PM Dodson Atherosclerosis

This review, based on 25 studies including 54,117 patients highlights the association between micro- and macrovascular disease in type 2 diabetes, underlining the importance of early detection of microangiopathy for vascular risk assessment in type 2 diabetes.

Implications of the ACCORD lipid study: perspective from the Residual Risk Reduction initiative (R3i) Current Medical Research and Opinion

Fruchart JC, Sacks FM, Hermans MP

Discussing the ACCORD Lipid study results, this commentary concludes that they suggest that dyslipidemia management in type 2 diabetes requires a targeted approach based on the lipid profile of individual patients. In particular, in statin-treated patients with atherogenic dyslipidemia, adding fenofibrate can provide additional reduction in cardiovascular risk.

Assmann G, Cullen P, Schulte H. Diabetes and Vascular Disease Research

To assess the non-LDL-C-related dyslipidaemia risk of MI, 823 men aged 23 to 65 with a first MI were compared with 823 MI-free PROCAM controls matched for sex, age, smoking, DM, BP and LDL-C. This case-control study has two main findings: first, dyslipidemia is associated with the greatest increase in relative risk of MI in persons with low levels of LDL-C; second, low HDL-C makes a greater contribution to MI risk than do high TG once other conventional MI risk factors are accounted for.

Sacks FM, Carey VJ, Fruchart JC New England Journal of Medicine

Based on a meta-analysis of 5 trials (FIELD, BIP, HHS, VA-HIT and ACCORD), the authors conclude that fibrate treatment reduces coronary heart disease events among patients with dyslipidemia.

Residual microvascular risk in diabetes: unmet needs and future directions

Fioretto P, Dodson PM, Ziegler D, Rosenson RS Nature Reviews / Endocrinology

In this review, the authors highlight an urgent need to address the residual microvascular risk that remains high in patients with type 2 diabetes mellitus even if they receive optimal management according to current standards of care. They also conclude that correction of atherogenic dyslipidemia might provide additional benefit.

R3i Position Paper

Jean-Charles Fruchart PhD, Frank Sacks MD, Michel P. Hermans MD PhD, Gerd Assmann MD, W. Virgil Brown MD FACC, Richard Ceska MD PhD, M. John Chapman PhD DSc, Paul M. Dodson MD, Paola Fioretto MD, Henry N. Ginsberg MD, Takashi Kadowaki MD, Jean-Marc Lablanche MD, Nikolaus Marx MD, Jorge Plutzky MD FACC, Željko Reiner MD PhD, Robert S. Rosenson MD FACC, Bart Staels PhD, Jane K. Stock PhD, Rody Sy MD, Christoph Wanner MD, Alberto Zambon MD PhD, Paul Zimmet MD PhD The R3i Position Paper is authored by all the Officers and Members of the International Steering Committee.

The Residual Risk Reduction Initiative: A call to action to reduce residual vascular risk in dyslipidemic patients