R3i Editorial

2013 has been an interesting year for macrovascular residual risk.

First, there has been renewed focus on the relevance of triglyceride-rich lipoproteins (TRLs) and their remnants, a key component of atherogenic dyslipidaemia, to residual macrovascular risk. An important genetic study provided definitive evidence linking common variants that influence plasma triglycerides levels, a marker of TRLs and their remnants, with a causal role in coronary artery disease.(1) Further, novel data from the Copenhagen group showed that remnant cholesterol was causal for ischaemic heart disease, independent of high-density lipoprotein (HDL) cholesterol. (2) In the most recent study from this group(3) (discussed in this month’s Landmark Trial), remnant cholesterol was also shown to be causally associated with low-grade inflammation, whereas low-density lipoprotein (LDL) cholesterol was not. Taken together these data reinforce the importance of TRLs, and in particular remnant cholesterol contained in TRLs, as a contributor to residual cardiovascular risk, potentially via the inflammatory component of atherosclerosis.

However, the news for HDL cholesterol has been less impressive. The failure of HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events)(4) with niacin/laropiprant is a major disappointment for the HDL field, following on from the early closure due to futility of AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) with extended-release (ER) niacin,(5) and the termination of the cholesteryl ester transfer protein inhibitor dalcetrapib. Indeed, niacin is no longer a therapeutic option in Europe, although ER niacin is still available to clinicians in North and South America. More recently, the ASSURE (ApoA-I Synthesis Stimulation and Intravascular Ultrasound for Coronary Atheroma Regression Evaluation) trial with RVX-208 (6) reported at the European Society of Cardiology Congress 2013. This first-in-class inducer of apolipoprotein A-I synthesis did not meet its primary endpoint in high-risk patients with low plasma levels of HDL cholesterol, showing only a trend to regression in percent atheroma volume at 26 weeks. We await full publication of the study to evaluate whether this may be at least partly explained by the short duration of this imaging trial.

However, the HDL story is more complicated than that told solely on the basis of plasma levels of HDL cholesterol. It is increasingly acknowledged that the HDL particle population is highly heterogeneous in terms of origin, size, composition, structure and biological function. Yet our understanding of HDL biology is still far from complete. There is growing enthusiasm for the concept that the quality or functionality of HDL is a better measure of the potential atheroprotection offered by HDL. The evidence in support of this is so far limited to the research laboratory, with much work required before it can be translated to the clinical setting. It should, however, be remembered that there are robust data showing that a low HDL cholesterol concentration is a risk factor for coronary heart disease, supporting its integration into risk estimation tools such as SCORE in Europe.

What does the future hold for managing this risk?

Currently, evidence in support of pharmacotherapeutic options for reducing residual CV risk is strongest for fibrates - peroxisome proliferator-activated receptorα (PPARα) agonists - although there is still a lack of definitive data from major outcomes studies. Given that PPARα plays a key role in the regulation of lipid homeostasis, this nuclear receptor is a highly logical target in individuals with cardiometabolic disease.(7) Therefore, would improving the selectivity and hence potency of PPARα agonists improve the benefit versus risk profile compared with current agents? Phase II studies with the selective PPARα modulator (SPPARMα) K-877 showed superior benefit to fenofibrate in patients with atherogenic dyslipidaemia, with no evidence of deleterious effects on markers of renal or hepatic function.(8) The results of ongoing Phase II/III trials with this agent in patients with atherogenic dyslipidaemia are awaited.

There is also much interest in the potential of monoclonal antibody therapy targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) for managing lipid-related residual CV risk. Not only have phase II studies showed substantial reductions in LDL cholesterol, on top of statin therapy, but there is also evidence of reduction in non-HDL-cholesterol (>60%), triglycerides (by ∼20-30%, depending on the agent), as well as lipoprotein(a).(9,10) So far there is no evidence of any adverse signal with these treatments, even over 52 weeks as reported for evolocumab in the Open-Label Study of Long-term Evaluation Against LDL-C (OSLER) study,(11) although clearly long-term data are needed. The key question is whether this lipid-modifying profile translates to CV outcome benefits. Prospective outcomes studies (ODYSSEY OUTCOMES with alirocumab and FOURIER with evolocumab) are currently ongoing, but results will not be available for at least 5 years.

What have we learned about managing residual microvascular risk?

Here there is so far a paucity of evidence, predominantly focused on fenofibrate. Indeed, supported by robust data from both the FIELD (Fenofibrate and Event Lowering in Diabetes) and ACCORD-Eye (Action to Control Cardiovascular Risk in Diabetes-Eye) studies, fenofibrate was recently approved in Australia as an adjunctive therapy to prevent progression in early-stage diabetic retinopathy. On the strength of these data, a reappraisal of clinical management algorithms for diabetes is clearly warranted.

The continuing crucial role of the Residual Risk Reduction Initiative

Clearly residual vascular risk continues to be a hot topic for clinicians and researchers alike. Yet recognition of the importance of lipid contributors to this risk lags behind, as shown by recent data from the US National Health and Nutrition Examination Survey (NHANES). Despite the availability of effective lipid lowering treatments, there has been little discernible improvement in non-HDL cholesterol goal attainment among people with atherogenic dyslipidaemia.(12) Indeed, the recent American College of Cardiology (ACC) and American Heart Association (AHA) guidelines for management of cholesterol do little to improve this, given their failure to acknowledge the relevance of non-LDL lipoproteins, notably TRLs, to lipid-related CV risk.(13)

The mission of the R3i is to improve recognition and management of residual vascular risk. Clearly there is still much to do to reduce the substantial burden of residual macrovascular and microvascular risk.

In conclusion, the Editors would like to take this opportunity to wish all readers the very best for the Season and the New Year. We look forward to new insights into residual vascular risk in 2014.

References

1. Do R, Willer CJ, Schmidt EM et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet 2013 Oct 6. doi: 10.1038/ng.2795
2. Varbo A, Benn M, Tybjærg-Hansen A et al. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427–36.
3. Varbo A, Benn M, Tybjærg-Hansen A, Nordestgaard BG. Elevated remnant cholesterol causes both low-grade inflammation and ischemic heart disease, whereas elevated low-density lipoprotein cholesterol causes ischemic heart disease without inflammation. Circulation 2013;128:1298-1309.
4. HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J 2013;
5. AIM HIGH Investigators. Boden WE, Probstfield JL, Anderson T et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255-67
6. Nicholls SJ, Ballantyne CM, Barter PJ et al. ASSURE: Effect of an oral agent inducing apo A-I synthesis on progression of coronary atherosclerosis: Results of the ASSURE Study [abstract 708] [http://www.escardio.org/congresses/esc-2013/congress-reports/Pages/708-ASSURE.aspx#.UkBP3IYqiSo].
7. Fruchart JC. Selective peroxisome proliferator-activated receptor α modulators (SPPARMα): the next generation of peroxisome proliferator-activated receptor α-agonists. Cardiovasc Diabetol 2013;12:82.
8. Ishibashi S, Arai H, Yamashita S, Araki E, Yamada N. Benefical effects of K-877, a potent and highly selective PPARα agonist, on plasma lipoprotein profile in patients with atherogenic dyslipidemia. Atheroscler Suppl 2012; 12:Abstr 525
9. Giugliano RP, Desai NR, Kohli P, et al on behalf of the LAPLACE-TIMI 57 Investigators. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet 2012;380:2007-17.
10. McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand AC, Stein EA. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol 2012;59:2344-53.
11. Koren MJ, Giugliano RP, Raal FJ et al. Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial. Circulation 2013 Nov 19. [Epub ahead of print].
12. Toth PP, Doyle C, Henriksson K: Prevalence of suboptimal non-high-density lipoprotein cholesterol levels in US adults with hypertriglyceridemia: The National Health and Nutrition Examination Survey 2003-2010. American Heart Association Scientific Sessions 2013: Dallas, Texas, in press.
13. Stone NJ, Robinson J, Lichtenstein AH et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. J Am Coll Cardiol 2013; doi:10.1016/j.jacc.2013.11.002 [Epub ahead of print].