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7 January 2013

Time for a re-think on guidelines to reduce residual microvascular risk in diabetes?

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

Board of the R3i Trustees
Prof. JC Fruchart, Prof. J. Davignon, Prof. M Hermans The escalating diabetes epidemic is a major global challenge. Undoubtedly, reducing cardiovascular complications is the number one priority. However, with the consequences of increasing longevity comes an increasing burden of diabetic microvascular complications, such as diabetic retinopathy, neuropathy and nephropathy. Aside from the healthcare costs of managing microvascular complications, the societal burden is substantial because working-age people are most likely to be affected. Preventing these debilitating complications would be expected to have the widest impact on this burden of disease.

Current guidelines recommend intensive control of glycaemia and blood pressure in addition to lifestyle modification for reducing the risk of diabetes-related microvascular complications.(1) Yet despite best practice, the residual risk of incident microvessel damage remains unacceptably high.(2,3)

Atherogenic dyslipidemia: a prognostic factor for microvascular risk

Emerging evidence implicates atherogenic dyslipidemia, the combination of elevated triglycerides and low high-density (HDL) cholesterol concentration, as a contributor to this risk.(4) Earlier this year the R3i highlighted a study showing that the ratio of triglycerides to HDL cholesterol was independently predictive of new-onset microvascular complications. Indeed, in individuals with well-controlled plasma levels of low-density lipoprotein (LDL) cholesterol, an elevated triglycerides-HDL cholesterol ratio had greater prognostic significance.5 These data suggest that targeting atherogenic dyslipidemia may offer added clinical benefits. This approach is supported by findings from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies, which showed that targeting atherogenic dyslipidemia with fenofibrate had protective effects on three major target end-organs for microvessel damage (e.g., retina, kidney and lower-limb).(6-8)

Comprehensive lipid management impacts microvascular risk

Indeed, a new study reported by Toth et al (2012),(9) reviewed in the current R3i Focus, shows that effective management, in terms of goal-attainment, of atherogenic dyslipidemia components beneficially impacts the risk for microvascular events among patients with type 2 diabetes. In this cohort analysis, based on claims data from over 70,000 individuals, attainment of desirable levels for triglycerides (<150 mg/dL or 1.7 mmol/L) or HDL cholesterol (>40 mg/dL or 1.0 mmol/L in men and >50 mg/dL or 1.3 mmol/L in women), was associated with significant 11% -15% reduction in the risk of microvascular complications. Moreover, among individuals at LDL cholesterol goal who achieved desirable levels for both triglycerides and HDL cholesterol, there was 24% reduction in the risk of microvascular events. The strengths of this study include the large sample size and the real-world managed care setting.

Translating to practice

Taking this evidence into consideration, the R3i suggests that the time has come to re-think our approach to preventing micro- and macrovascular disease in diabetes patients. As well as current recommendations for control of LDL cholesterol, blood pressure and glycaemia, atherogenic dyslipidemia should also be included as therapeutic target. A renewed focus on more comprehensive lipid management beyond LDL may give new hope for reducing the substantial debilitating burden of diabetic microvascular disease.

On this positive note, the R3i extends Season Greetings to all.

In 2013, we look forward to results from key outcomes studies – including HPS2-THRIVE – for new insights into managing atherogenic dyslipidemia to reduce residual vascular risk.


1. Standards of Medical Care in Diabetes—2012. Diabetes Care 2012;35(Suppl 1): S11-S63.

2. UK Prospective Diabetes Study Group: Tight blood pressure control and risk of macrovascular and microvascular complications in Type 2 diabetes. UKPDS 38. BMJ 317, 703–713 (1998).

3. The UKPDS Group: Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with Type 2 diabetes. UKPDS 33. Lancet 1998;352(9131):837-53.

4. Fruchart J-C, Sacks F, Hermans MP et al.; for the Residual Risk Reduction Initiative: The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Am J Cardiol 2008;102(Suppl): 1–34.

5. Zoppini G, Negri C, Stoico V, Casati S, Pichiri I, Bonora E. Triglyceride-high-density lipoprotein cholesterol is associated with microvascular complications in type 2 diabetes mellitus. Metabolism 2012;61:22-9

6. 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.

7. 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.

8. Rajamani K, Colman PG, Li LP et al. Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial. Lancet 2009;373:1780-8.

9. Toth PP, Simko RJ, Palli SR et al. The impact of serum lipids on risk for microangiopathy in patients with type 2 diabetes mellitus. Cardiovasc Diabetol 2012;11:109.