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1 December 2014

R3i publishes new Call to Action paper: Residual Microvascular Risk in Type 2 Diabetes in 2014: Is it Time for a Re-Think?

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 The Residual Risk Reduction Initiative (R3i) is pleased to announce the publication of this new Call to Action statement, authored by 41 international experts in the fields of diabetes, atherosclerosis and cardiovascular disease prevention. The paper is free to download here...

The R3i makes two clear recommendations for reducing the burden of residual microvascular risk in patients with type 2 diabetes:

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.

Why a new Call to Action on Residual Microvascular Risk?

The pandemic of diabetes is one of the major challenges facing societies in the 21st century. The escalation in prevalence, with latest estimates suggesting that 382 million people have diabetes, predominantly type 2 diabetes, brings with it an overwhelming burden of cardiovascular disease and microvascular complications.(1) While the future offers the possibility of novel agents aimed at managing hyperglycaemia and macroangiopathies associated with type 2 diabetes, there are only limited options for diabetologists managing the associated microangiopathies, beyond multifactorial best-evidence-based treatments to control glycaemia, hypertension and low-density lipoprotein cholesterol. This is despite the fact that the two major diabetic microangiopathies, diabetic retinopathy and diabetic nephropathy, account for more than 50% of the burden of disability associated with type 2 diabetes.(2)

Indeed, diabetic retinopathy clearly illustrates the burden of diabetes-related microvascular complications. It is estimated that about one in three adults aged at least 40 years with diabetes has some degree of chronic hyperglycaemia-induced retinal damage.(3) However, in many patients, early-stage diabetic retinopathy is often insidious and overlooked until the extent of damage becomes clinically significant. This has important societal implications for the management of this complication. If treated at an early stage, the management costs are relatively minor; however, at later stages of the disease, the cost is much larger.(4) We also need to be bear in mind that type 2 diabetes increasingly affects younger individuals, especially in regions in economic transition such as Latin America, Asia and the Middle East and therefore the societal impact of vision loss associated with diabetic retinopathy is substantial. The situation in China clearly illustrates this; diabetes is now at crisis point in China; over 100 million people now have diabetes, and a recent report suggests that nearly 50% of these have some degree of diabetic retinopathy.(5,6)

What is new to this challenge?

Clearly, consistent evidence of benefit with Peroxisome Proliferator Activated-Receptor (PPAR) agonists in attenuating progression of early stage diabetic retinopathy and microalbuminuria, a marker of diabetic nephropathy, from two major prospective studies (ACCORD-Eye and FIELD) is the most recent development.(7-9) These findings have supported the licensing of fenofibrate for this indication in Australia. It is likely that this is a class effect of PPAR agonism, although evidence is needed in support.(10 )
Beyond this, there is little on the horizon, emphasising the urgent need for the development of novel agents that may be able to address the escalating burden of diabetes-related microvascular complications. Research should be directed to further elucidating the underlying mechanism(s) of diabetic retinopathy, which may offer future therapeutic potential.
R3i recommendations for managing residual microvascular risk in type 2 diabetes
Consideration of the metabolic profile of patients, in particular targeting atherogenic dyslipidaemia – the combination of elevated triglycerides and low high-density lipoprotein cholesterol (HDL-C) - is relevant, especially for managing diabetic nephropathy. Indeed, REALIST (REsiduAl risk Lipids and Standard Therapies)-Micro showed that both elevated triglycerides and low HDL cholesterol were significantly and independently associated worldwide with diabetic microvascular complications, specifically diabetic kidney disease, supporting the rationale for targeting atherogenic dyslipidaemia to reduce the residual diabetic renal disease risk.(11)
The R3i believes that implementation of the strategies recommended in this Call to Action paper will help to address the escalating personal and societal burden of residual microvascular risk in individuals with type 2 diabetes. Collaborative strategies across primary and secondary care will help to drive these improvements in patient care.


1. International Diabetes Federation (2013) IDF Atlas Sixth Edition.
2. 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.
3. Zhang X, Saaddine JB, Chou CF et al. Prevalence of diabetic retinopathy in the United States, 2005-2008. JAMA 2010;304:649-56.
4. Pelletier EM, Shim B, Ben-Joseph R, Caro JJ. Economic outcomes associated with microvascular complications of type 2 diabetes mellitus: results from a US claims data analysis. Pharmacoeconomics 2009 ;27: 479-90.
5. Chan JC, Zhang Y, Ning G. Diabetes in China: a societal solution for a personal challenge. Lancet Diabetes Endocrinol 2014 Sep 10 [E pub ahead of print].
6. Wang FH, Liang YB, Zhang Fet al. Prevalence of diabetic retinopathy in rural China: The Handan Eye Study. Ophthalmology 2009;116:461-7.
7. Davis TM, Ting R, Best JD et al. Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. Diabetologia 2011 ;54:280-90.
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. Morgan CL, Owens DR, Aubonnet P et al. Primary prevention of diabetic retinopathy with fibrates: a retrospective, matched cohort study. BMJ Open 2013 ;3:e004025.
11. Sacks FM, Hermans MP, Fioretto P, Valensi P, Davis T, 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 2014 ;129: 999-1008.