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R3i EDITORIAL

1 July 2013

Targeting atherogenic dyslipidemia: we need to do better

Prof. JC Fruchart, Prof. J. Davignon, Prof. M Hermans

An Editorial from the R3i Trustees
Prof. JC Fruchart, Prof. J. Davignon, Prof. M Hermans Atherosclerosis is not a new phenomenon. Indeed, as highlighted in News from the literature, atherosclerosis appears to be inherent to human ageing, even in ancient civilisations.1 Since this time, it is clear that we have made great advances in the diagnosis, prevention and management of atherosclerosis and cardiovascular disease. The statins story reflects this; lowering low-density lipoprotein cholesterol (LDL-C) with a statin is now regarded as the cornerstone of pharmacological lipid management among preventive strategies.2

However, management of other lipids and non-LDL lipoproteins, specifically atherogenic dyslipidemia, is also relevant. Atherogenic dyslipidemia is a key modifiable driver of cardiovascular risk, especially in the context of cardiometabolic disease,2,3 and an important contributor to the high level of residual cardiovascular risk that remains in statin-treated patients.4-6. For example, data from the REALIST Macrovascular study, showed that the combination of elevated triglycerides (≥190 mg/dL) and low high-density lipoprotein cholesterol (HDL-C, <30 mg/dL) contributed synergistically to increased cardiovascular risk even at LDL-C levels <130 mg/dL.7 Furthermore, in the ACCORD Lipid study, patients with type 2 diabetes and optimally treated LDL-C levels had a 70% higher risk of developing an incident cardiovascular event when atherogenic dyslipidemia was present at baseline compared with those without this dyslipidemia.8

Thus, there is a clear rationale for targeting atherogenic dyslipidemia, as previously presented by the Residual Risk Reduction Initiative (R3i) in their Call to Action.9 Despite this, recent data from the US National Health and Nutrition Examination Survey discussed in this month’s Focus highlights substantial undertreatment. This poses a key question: Why are we failing to adequately manage atherogenic dyslipidemia?

Certainly, recent guidelines have focused on the importance of managing atherogenic dyslipidemia. However, are such guidelines being appropriately implemented? Findings from the EUROASPIRE survey in Europe show that this is not the case, with risk factor management in patients with or at high risk of cardiovascular disease far from optimal. About 40% of patients on lipid-lowering therapy failed to attain total cholesterol goals.10 Risk factor management was also poor in the primary care setting, with about two-thirds of patients exceeding total cholesterol goals.11 Data from the OPTIMISE (OPtimal Type 2 dIabetes Management Including benchmarking and Standard treatment) study also indicate equally poor rates of risk factor management in type 2 diabetes patients in primary care.12 that management of atherogenic dyslipidemia.

Have disappointing results from recent lipid-lowering trials being a contributing factor? The use of combination therapy with niacin plus a statin has come under the spotlight, especially after HPS2-THRIVE,13 which it must be recognised, did not specifically recruit a patient population with low HDL-C, or atherogenic dyslipidemia. Safety issues highlighted in this study may also have contributed to clinical concern about the usefulness of this combination therapy. Indeed, controversy regarding the role of HDL as a modifiable CVD risk factor is unlikely to be resolved until we have the results of ongoing trials with novel agents, not expected before 2017.

Against this, there is growing support for elevated triglyceride-rich lipoproteins as a key contributor to residual cardiovascular risk. Indeed, a recent Mendelian randomisation study14 showed that genetically elevated levels of remnant cholesterol were associated with causal risk for ischemic heart disease, independent of reduced HDL-C concentration. These results also add to the considerable mechanistic evidence that remnant lipoproteins are atherogenic.

The R3i recognises that action on several fronts is needed to target atherogenic dyslipidemia to reduce residual vascular risk. Education to improve guideline implementation is one priority. The R3i has a key role in educating clinicians about residual vascular risk; the website is now a leading educational resource in this area. Building on this, the R3i will feature a number of Expert Opinion videos each month about residual vascular risk, starting with:

• Professor Anthony Keech, Sydney, Australia: Is residual risk clinically relevant?
• Professor Henry Ginsberg, New York, USA: How can I best evaluate the risk related to lipids? What is the relative importance of the different lipids?
• Professor Alberto Zambon, Padova, Italy: How can you explain the residual risk observed in TNT and PROVE IT?
• Professor Lale Tokgozöglu, Ankara Turkey: How often do we see patients with high TG and low HDL-C and who are these patients?

Furthermore, it is recognised that clinicians need to be more aggressive in diagnosing and managing atherogenic dyslipidemia. There are therapeutic options available, of which combination therapy with fenofibrate and a statin is supported by clinical outcomes evidence, in particular in type 2 diabetes patients.8 Additionally, there are a number of novel agents in development that offer opportunities for improved attainment of multiple lipid goals, and potentially, greater reduction in the residual burden of cardiovascular disease.

The combination of education, improved guideline implementation and novel therapies targeting atherogenic dyslipidemia are all key to addressing the substantial clinical and socioeconomic burden of residual vascular risk.

References

1. Thompson RC, Allam AH, Lombardi GP et al. Atherosclerosis across 4000 years of human history: the Horus study of four ancient populations. Published Online March 10, 2013. http://dx.doi.org/10.1016/S0140-6736(13)60598-X.
2. Reiner Z, Catapano AL, De Backer G et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32:1769-818.
3. Chapman MJ, Ginsberg HN, Amarenco P et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345-61.
4. 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;51:724-30.
5. Barter P, Gotto AM, LaRosa JC et al; Treating to New Targets Investigators. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007;357:1301-10.
6. Assmann G, Cullen P, Schulte H. Non-LDL-related dyslipidemia and coronary risk: a case-control study. Diab Vasc Dis Res 2010;7:204-212.
7. Carey VJ, Bishop L, Laranjo N, Harshfield BJ, Kwiat C, Sacks FM. Contribution of high plasma triglycerides and low high-density lipoprotein cholesterol to residual risk of coronary heart disease after establishment of low-density lipoprotein cholesterol control. Am J Cardiol 2010;106:757-63.
8. ACCORD Study Group, Ginsberg HN, Elam MB, Lovato LC et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-74.
9. Fruchart JC, Sacks FM, Hermans MP et al; Residual Risk Reduction Initiative (R3I). The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patient. Diab Vasc Dis Res 2008;5:319-35.
10. Kotseva K on behalf of the EUROASPIRE Study Group. Lessons from EUROASPIRE I, II, and III surveys. Heart Metab 2011;50:32–35.
11. Kotseva K, Wood D, De Backer G, De Bacquer D, Pyorala K, Keil U, on behalf of EUROASPIRE study Group. EUROASPIRE III. Management of cardiovascular risk factors in asymptomatic high risk subjects in general practice: cross- sectional survey in 12 European countries. Europ J Cardiovasc Prev Rehabilitation 2010;17:530–40.
12. Hermans MP, Brotons C, Elisaf M, Michel G, Muls E, Nobels F. Optimal type 2 diabetes mellitus management: the randomised controlled OPTIMISE benchmarking study: baseline results from six European countries. Eur J Prev Cardiol. 2012 May 17 [Epub ahead of print].
13. 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; online ahead of print 27 February 2013.
14. 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.