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PCS9 as a therapeutic target: Insights from clinical trials
TP downloadable slidekit
This booklet/slidedeck, the second in the series, focuses on evidence from clinical trials with PCSK9-targeted therapeutics.
Elevated LDL cholesterol is established as causal for atherosclerotic cardiovascular disease. Statin treatment, although effective in lowering LDL cholesterol, still leaves an unacceptably high residual cardiovascular risk, underlining the need for additional therapies.
PCSK9-targeted treatments, which include monoclonal antibody therapies and siRNA therapeutics, are highly efficacious in lowering LDL cholesterol on top of statin therapy. This booklet and accompanying slidedeck overview the clinical trials with these novel therapies in different high-risk patient groups. These include the landmark outcomes studies - FOURIER and ODYSSEY OUTCOMES - which definitively demonstrated reduction in residual cardiovascular risk among patients with stable cardiovascular disease or acute coronary syndrome.
Finally, the booklet/slide deck discuss potential with gene-editing technology, which may offer the possibility a ‘one-time’ approach to LDL cholesterol management in the future.
Trigkyceride-rich lipoproteins and atherosclerotic cardiovascular disease
TP downloadable slidekit
This booklet provides a critical background to triglyceride-rich lipoproteins and their role in ASCVD, concluding with discussion of the trials – past and present – that have targeted elevated triglycerides to lower residual cardiovascular risk.

Lowering low-density lipoprotein cholesterol (LDL-C) is the primary lipid target to prevent atherosclerotic cardiovascular disease (ASCVD) . Yet even at very low LDL-C levels, high-risk patients continue to experience cardiovascular events .

In the search for possible lipid contributors to this high residual cardiovascular risk, attention focuses on atherogenic dyslipidemia, the combination of low plasma concentration of high-density lipoprotein cholesterol (HDL-C) and elevated triglycerides.

The ‘HDL hypothesis’, which proposed that HDL-C could be protective against ASCVD has been largely abandoned after trials testing numerous HDL-C raising strategies, against a background of best evidence-based medicine including statins, failed to show cardiovascular benefit.

The stage is now set for reconsideration of triglyceride-rich lipoproteins as a causal cardiovascular risk factor . Since 2007, there has been renewed interest in elevated plasma triglycerides, a surrogate for triglyceride-rich lipoproteins and their remnants . This sea-change in thinking has been driven by new genetic insights showing that triglyceride-rich lipoproteins are implicated in the causal pathway for ASCVD . Accumulating epidemiologic evidence also supports an association between triglyceride-rich lipoproteins and ASCVD risk.

The critical test is whether lowering elevated levels of triglycerides reduces residual cardiovascular risk . The PROMINENT trial (Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN patiENts With diabetes) is a critical test of the hypothesis that lowering elevated triglycerides with the novel selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) pemafibrate, will reduce the high residual cardiovascular risk in type 2 diabetes patients (with and without ASCVD) on intensive statin therapy.

This booklet created by professors Børge G. Nordestgaard, Michel P. Hermans, and Jean-Charles Fruchart provides a critical background to triglyceride-rich lipoproteins and their role in ASCVD, concluding with discussion of the trials – past and present – that have targeted elevated triglycerides to lower residual cardiovascular risk.
Differentiating SPPARMα and fibrates (PPARα agonists)
SSPARM downloadable slidekit
Professor Jean-Charles Fruchart PharmD, PhD President of the R3i Foundation.

Atherosclerotic cardiovascular disease (ASCVD) is a growing global health challenge, exacerbated by a changing risk factor landscape associated with chronic lifestyle-related diseases such as visceral obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic fatty liver disease. Atherogenic dyslipidemia, elevated triglycerides with or without low levels of high-density lipoprotein cholesterol, is common to high-risk individuals, especially those with T2DM, and contributes to residual cardiovascular risk despite optimal low-density lipoprotein cholesterol control.

Current options for managing atherogenic dyslipidemia issues, especially for renal and hepatic safety. New approaches are clearly needed.

The SPPARMα concept provides a precision medicine approach to this problem This booklet discusses the evidence for the novel SPPARMα agonist, pemafibrate, that differentiates it as a distinct therapeutic class from traditional fibrates.

The ultimate test for SPPARMα is the PROMINENT cardiovascular outcomes trial, which is evaluating whether treatment with pemafibrate safely reduces residual cardiovascular risk in high-risk T2DM patients with atherogenic dyslipidemia.
SSPARMα at the Crossroads of Obesity, Diabetes and Cardiovascular Diseases - SECOND EDITION
SSPARM downloadable slidekit
Originally created by Professor Jean-Charles Fruchart, President of the R3i Foundation and an internationally recognised leader in the field of PPARα research, this free-to-down slide library has been updated. The slides now include the latest information on the role of triglyceride-rich lipoproteins and their remnants in residual vascular risk, as well as the REDUCE-IT and STRENGTH cardiovascular outcomes studies.

The slide library comprises 276 slides covering:
• Atherosclerosis, metabolic syndrome, Type 2 diabetes (T2D) and associated macro- and microvascular diseases, specifically focussing on the effects of dyslipidaemia and inflammation.
• Background to triglyceride-rich lipoproteins and their remnants in residual vascular risk
• What’s new in clinical outcomes studies of triglyceride-lowering therapies.

A key focus of the slide library is the concept of selective PPARα modulation (SPPARMα), which aims to improve efficacy and minimise safety issues such as elevation in serum creatinine evident with current PPARα agonists (fibrates). The novel SPPARMα agonist pemafibrate is currently being evaluated in the PROMINENT cardiovascular outcomes study. This landmark trial will test whether treatment with this SPPARMα agonist, against a background of best evidence-based therapy including statins, reduces cardiovascular events in high risk patients with atherogenic dyslipidemia, the combination of elevated triglycerides and low HDL-C. This is the final critical test of the SPPARMα concept.

Pemafibrate is discussed in a separate slide library
PCSK9 and Atherosclerosis
PCSK9 downloadable slidekit
Created by Professors Jean Davignon (Vice-President of the R3i foundation), Jean-Charles Fruchart (President of R3i) and Michel Hermans (R3i General Secretary), the latest downloadable deck of 242 slides discusses the potential role for anti-PCSK9 mAbs in the future management of cardiovascular disease.
Authors review unmet needs in the treatment of dyslipidemia, the discovery and structure of PCSK9,PCSK9 levels in health and disease, PCSK9-drug interactions focusing on statin trials, current approaches to PCSK9 inhibition, and recent results from anti-PCSK9 mAb pre-clinical and clinical trials.
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