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R3i EDITORIAL

13 February 2014

REALIST Micro, atherogenic dyslipidaemia and residual microvascular risk

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

An Editorial from the R3i Trustees
Prof. Jean Charles Fruchart, Prof. Jean Davignon, Prof. Michel Hermans Atherogenic dyslipidaemia, the combination of elevated triglycerides and low plasma concentration of high-density lipoprotein cholesterol (HDL-C), is well recognised as a modifiable risk factor for cardiovascular disease.(1) Now, new data from the REALIST Microvascular Study (discussed in this month’s Focus On article(2)) implicate triglycerides and HDL-C with risk for diabetic kidney disease. These important findings provide a clear rationale for targeting atherogenic dyslipidaemia to reduce the high residual risk of both macrovascular and microvascular complications in patients with type 2 diabetes receiving current standards of care.

Diabetes is the major non-communicable healthcare challenge facing clinicians in the 21st century.(3) World-wide, it is estimated that 382 million people have diabetes, and this is projected to increase by 55% by 2035. Almost 80% of people with diabetes live in low and middle- income countries, and thus the impact of managing diabetes and its vascular complications is greater here than in high-income countries. This scenario is relevant in the context of microvascular complications, specifically diabetic kidney disease and diabetic retinopathy. According to the Global Burden of Disease 2010 these complications account for more than 50% of the burden of disability associated with diabetes.(4) Furthermore, management costs rapidly rise as the complication progresses to more serious sequelae, specifically end-stage renal disease and visual loss..

However, until recently clinicians have been hampered by the lack of additional therapeutic strategies beyond optimising control of glycaemia, blood pressure and low-density lipoprotein cholesterol (LDL-C). The case for intensifying these interventions to reduce the residual risk of microvascular complications, taking into account both efficacy and safety considerations, is also contentious.

In a previous position paper, the Residual Risk Reduction Initiative (R3i) highlighted a role for atherogenic dyslipidaemia, elevated triglycerides and low-HDL-C, as a contributor to residual vascular risk, including risk for microvascular complications, in patients with type 2 diabetes.(5) However, it was recognised that the level of evidence was variable, especially with respect to diabetic retinopathy. In two major prospective randomised controlled studies, fenofibrate was shown to prevent progression of early-stage diabetic retinopathy, although it was far from clear whether effects on lipids and lipoproteins were critical.(6-8) Clearly, there was a real need to systematically investigate the potential association between triglycerides and HDL-C and microvascular complications in type 2 diabetes.

What does REALIST Micro bring new to the debate?

REALIST-Micro, a case-control study in patients with type 2 diabetes and broadly at LDL-C goal (average LDL-C 2.3 mmol/L or 89 mg/dL), has provided important insights.2 The study highlighted a significant and independent association between atherogenic dyslipidaemia components and microvascular complications, specifically diabetic kidney disease. Among patients with high triglycerides (≥2.83 mmol/L or ≥250 mg/dL) the risk of diabetic kidney disease was more than 2-fold higher than in individuals in the lowest quintile for triglycerides (≤0.74 mmol/L or ≤∼50 mg/dL). Furthermore, while current European guidelines recommend that triglycerides <1.7 mmol/L (or <150 mg/dL) are desirable,9 REALIST-Micro showed that even among patients with triglycerides between 1.36 and <1.77 mmol/L (∼120 and 160 mg/dL), there is ∼1.5-fold increase in risk for diabetic kidney disease. For HDL-C, each 0.2 mmol/L (∼8 mg/dL) increase in HDL-C was associated with an 8% decrease in risk. The association between triglycerides, HDL-C and diabetic retinopathy was less robust, which is perhaps not surprising given that multiple pathways appear to underlie the pathophysiology of this complication.(8)

The clinical implications of REALIST-Micro are strengthened by the fact that this is a global case-control study involving 13 countries across Europe, North America, the Middle East, Asia (including Japan and China), and Australasia. Given that sensitivity analyses showed no effect on geographic region or ethnicity, the study provides a strong rationale for targeting elevated triglycerides and low HDL-C to reduce the high residual risk of renal complications in patients with type 2 diabetes across the globe. Furthermore, given variability in the categorisation of hypertriglyceridaemia, the recent European Atherosclerosis Society Consensus Panel calls to simplify this definition(10) – as discussed in News – clearly offer practical advantages for the many clinicians routinely involved in managing diabetic patients.

Diabetic kidney disease is an important contributor to the morbidity and mortality of diabetes. The R3i believes that REALIST Micro provides important evidence that supports targeting atherogenic dyslipidaemia to reduce the high level of residual vascular risk, including microvascular complications, that remains in diabetes patients despite current standards of care for blood glucose, blood pressure and LDL-C.

References

1. 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.
2. Sacks FM, Hermans MP, Fioretto P et al. Association between plasma triglycerides and HDL-cholesterol and microvascular kidney disease and retinopathy in type 2 diabetes: A global case-control study in 13 countries. Circulation 2013 Dec 18. [Epub ahead of print].
3. International Diabetes Federation. Facts and figures, available at http://www.idf.org/worlddiabetesday/toolkit/gp/facts-figures. 21 January 2014.
4. Lim SS, Vos T, Flaxman AD et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2224 –60.
5. Fruchart JC, Sacks FM, Hermans MP et al. 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.
6. Keech AC, Mitchell P, Summanen Paet al, FIELD study investigators. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 2007;370:1687-97.
7. 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. New Engl J Med 2010;363:233-44.
8. Simó R, Roy S, Béhar-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.
9. 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.
10. Hegele RA, Ginsberg HN, Chapman MJ et al. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol 2013. Published Online December 23, 2013. http://dx.doi.org/10.1016/S2213-8587(13)70191-8.