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5 January 2015

Post IMPROVE-IT: Where to now for residual risk?

Prof. Jean Charles Fruchart, Prof. Jean Davignon, Prof. Michel Hermans, Prof. Pierre Amarenco

An Editorial from the R3i Trustees
Prof. Jean Charles Fruchart, Prof. Jean Davignon, Prof. Michel Hermans, Prof. Pierre Amarenco Well, the relief from IMPROVE-IT, reported at the recent American heart Association Scientific Sessions, was palpable (see Landmark trial). We now have evidence that lowering low-density lipoprotein cholesterol (LDL-C) beyond current targets with non-statin therapy in patients with a recent acute coronary syndrome (ACS) provides modest benefit for cardiovascular outcomes. Notably, there was also benefit in patients with diabetes. However, it is also a salient point that in these very high risk patients, about one-third experienced further events over the 7-year study period, highlighting their persistent very high residual cardiovascular risk. Thus, while lowering LDL-C is the priority, additional therapeutic interventions are needed.

Residual cardiovascular risk: targeting all lipoproteins is key

While we await the publication of IMPROVE-IT, targeting atherogenic dyslipidaemia is one approach that is advocated. Indeed, there are data from post-hoc analyses of prospective trials in ACS and stable secondary prevention patients which reveal that elevated plasma levels of triglycerides and low plasma concentrations of high-density lipoprotein cholesterol (HDL-C) contribute to this high residual risk, even in patients below LDL-C goals.(1-4) While we so far lack definitive trial data, especially in nondiabetic patients, there is evidence that targeting this dyslipidaemia, particularly among patients with cardiometabolic disease, provides incremental benefit.(5) There is additional support from a recent Danish study, discussed in News from the Literature, that elevated non-fasting remnant cholesterol, closely associated with elevated triglycerides, partly contributes to the risk of ischaemic heart disease associated with obesity.(6) Thus, recommendations from the R3i on the management of residual cardiovascular risk, which underline the importance of managing all lipid abnormalities, including atherogenic dyslipidaemia, are clearly pertinent.

Residual microvascular risk: Given a pivotal role for PPAR? agonism, will SPPARMS offer new hope?
This month the R3i also focuses on residual microvascular risk, following recent publication of R3i recommendations for management (see box).(7)

R3i recommendations for managing residual microvascular risk

1. Control of cardiovascular risk factors, including attainment of all lipid targets, should be optimised.

2. Adjunctive fenofibrate therapy to slow progression of diabetic retinopathy in type 2 diabetes patients with pre-existing disease may be considered based on consistent evidence from two major trials.

Diabetic retinopathy is the most common cause of visual loss in adults of working age, thus conferring substantial individual and societal burden. The peroxisome proliferator-activated receptor alpha (PPAR?) agonist fenofibrate has been shown to be effective in preventing the progression of early stage diabetic retinopathy in patients with type 2 diabetes, with consistent evidence of benefit from two major prospective studies.8,9 However, given the lack of association between changes in diabetic retinopathy and lipid levels, the mechanism(s) of fenofibrate’s activity has yet to be fully elucidated. This month’s Focus article highlights the key role of PPAR? in maintaining the retinal microvasculature and preventing inflammation, based on findings from both in vitro and in vivo experimental models.10 Given these and other potentially beneficial actions,11 would a PPAR? agonist with improved potency and selectivity offer greater benefit? With the availability of novel selective PPAR? modulators (SPPARMs), this tantalising question merits further study.

2014 has seen the re-emergence of the R3i in its mission to educate clinicians about residual vascular risk, with the publication of REALIST-Micro, two new call to action papers, as well as reports from R3i activities in Brazil and Japan. The R3i aims to build on its strengths to become an even stronger force in 2015.


1. Miller M, Cannon CP, Murphy SA, Qin J, Ray KK, Braunwald E; PROVE IT-TIMI 22 Investigators. Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol 2008;51:724-730.
2. Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM, Kastelein JJ, Bittner V, Fruchart JC; Treating to New Targets Investigators. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007;357:1301-1310.
3. Olsson AG, Schwartz GG, Szarek M, Sasiela WJ, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A. High-density lipoprotein, but not low-density lipoprotein cholesterol levels influence short-term prognosis after acute coronary syndrome: results from the MIRACL trial. Eur Heart J 2005;26: 890-896.
4. Wolfram RM, Brewer HB, Xue Z, Satler LF, Pichard AD, Kent KM, Waksman R. Impact of low high-density lipoproteins on in-hospital events and one-year clinical outcomes in patients with non-ST-elevation myocardial infarction acute coronary syndrome treated with drug-eluting stent implantation. Am J Cardiol 2006;98:711-717.
5. Sacks FM, Carey VJ, Fruchart JC. Combination lipid therapy in type 2 diabetes. N Engl J Med 2010;363:692-4.
6. Varbo A, Benn M, Davey Smith G et al. Remnant cholesterol, low-density lipoprotein cholesterol, and blood pressure as mediators from obesity to ischemic heart disease. Circ Res 2014 [Epub ahead of print].
8. Keech AC, Mitchell P, Summanen PA et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 2007 ;370: 1687-97.
9. ACCORD Study Group; ACCORD Eye Study Group, Chew EY, Ambrosius WT, Davis MD et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010 ;363: 233-44.
10. Hu Y, Chen Y, Ding L, He X, Takahashi Y, Gao Y, Shen W, Cheng R, Chen Q, Qi X, Boulton ME, Ma JX. Pathogenic role of diabetes-induced PPAR-? down-regulation in microvascular dysfunction. Proc Natl Acad Sci U S A 2013;110:15401-6.
11. Simó R, Roy S, Behar-Cohen F, Keech A, Mitchell P, Wong TY. Fenofibrate: a new treatment for diabetic retinopathy. Molecular mechanisms and future perspectives. Curr Med Chem 2013;20:3258-66.