Triglyceride-HDL cholesterol ratio: a prognostic role in microvascular complications of type 2 diabetes?

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12 June 2012

A higher triglyceride-high-density lipoprotein cholesterol (TG-HDL-C) ratio doubles the risk of developing retinopathy and/or chronic kidney disease in type 2 diabetes patients, independent of glycaemic, blood pressure and low-density lipoprotein cholesterol (LDL-C) control, according to a report from the Verona Diabetes Study. This increased risk was even more pronounced in patients with LDL-C levels at or below goal (<100 mg/dL or 2.6 mmol/L).

Zoppini G, Negri C, Stoico V, Casati S, Pichiri I, Bonora E

STUDY SUMMARY

Objectives

To evaluate whether an elevated TG-HDL-C ratio is associated with increased risk for retinopathy or chronic kidney disease (CKD) in type 2 diabetes patients

Study polupation

Cohort of 979 type 2 diabetes outpatients included in the Verona Diabetes Study, a longitudinal, observational study. Patients with a history of cardiovascular disease or malignancy, evidence of retinopathy and/or CKD at baseline, or with missing data for baseline retinopathy or CKD assessments were excluded.

Key endpoints

Occurrence of

Retinopathy, assessed by two-field stereoscopic retinal photography by a single trained ophthalmologist and/or
CKD, defined as estimated glomerular filtration rate (eGFR) £60 mL/min/1.73 m2 . This was calculated according to the Modification of Diet in Renal Disease formula i.e. eGFR = 186.3 x (serum creatinine -1.154) x (age -0.203) x 1.212 (if black) x 0.742 (if female)

Main results

During a mean 4.9 year follow-up period:

22% (n=217) of patients developed retinopathy and/or CKD
111 patients (about one-half) had retinopathy alone, 85 CKD alone, and 21 developed both complications

The TG-HDL-C ratio was higher in patients with these complications (mean ± SD 1.4 ± 1.0 vs. 1.2 ± 1.0, p=0.002)
Each 1 standard deviation increase in the log TG-HDL-C ratio increased the risk of retinopathy and/or CKD more than 2-fold, (odds ratio 2.15, 95% CI 1.09-4.25, p=0.02), and CKD alone more than 4-fold (odds ratio 4.65, 95% CI 1.50-14.90, p=0.02).
This association was independent of confounding factors including haemoglobin A1c, blood pressure, LDL-C, albuminuria, diabetes duration, BMI and smoking.
The association was more pronounced in patients at LDL-C goal (<100 mg/dL or <2.6 mmol/L) (data not shown).

COMMENT

This report from the Verona Diabetes Study adds to emerging evidence (1) linking atherogenic dyslipidaemia, the combination of elevated TG and low HDL-C, with the development of microvascular complications of type 2 diabetes. In particular, the TG-HDL-C ratio, which grades atherogenic dyslipidaemia as a continuous variable, was especially useful in detecting risk for CKD beyond conventional risk factors for microvascular disease, such as glycaemic and blood pressure control. The prognostic significance of an elevated TG-HDL-C ratio was also more pronounced in patients with well controlled LDL-C levels. The study findings are strengthened by the prospective nature of the study, the large cohort size, large number of events (>200) and adjustment for multiple confounding factors. Thus, these important data highlight the potential of targeting atherogenic dyslipidaemia to impact the substantial burden of diabetic microvascular disease that persists despite improvements in standards of diabetes care.

The R3i supported REALIST (REsiduAl risk Lipids and Standard Therapies) microvascular study previously showed that both nephropathy and retinopathy were associated with elevated TG and/or low HDL-C in patients with type 2 diabetes at goal for LDL-C (2). Consistent with this, the Verona Diabetes Study also showed that the TG-HDL-C ratio was higher in patients with retinopathy and/or CKD.

The study does not provide any insights into the mechanisms underlying this increased risk. However, potentially, endothelial dysfunction, increased oxidative stress, vascular inflammation and abnormalities in thrombotic function may be implicated (3-5).

From a practical perspective, determination of the TG-HDL-C ratio is readily performed in daily practice, from routine fasting lipid levels. Previous evidence has shown that a higher TG-HDL-C ratio is predictive of macrovascular disease. This report adds new information by showing that a higher TG-HDL-C ratio is also predictive of increased risk for microvascular complications of type 2 diabetes, in patients without prior cardiovascular disease. Thus, an elevated TG-HDL-C ratio may alert the clinician to the need for additional lipid-modifying therapy to prevent or delay the onset of microvascular complications and improve outcomes in patients with type 2 diabetes.

References

1. Fioretto P, Dodson PM, Ziegler D, Rosenson RS. Residual microvascular risk in diabetes: unmet needs and future directions. Nat Rev Endocrinol 2010;6:19-25.
2. Press release. New Insights Link Low HDL-Cholesterol and Elevated Triglycerides with Coronary Heart Disease and Microvascular Complications in Patients at Goal for LDL-Cholesterol. Available from http://www.r3i.org/press/pressreleases.asp.
3. Lim LS, Wong TY. Lipids and diabetic retinopathy. Expert Opin Biol Ther 2012;12:93-105.
4. Giacco F, Brownlee M. Oxidative stress and diabetic complications Circ Res 2010;107:1058-70.
5. Dalrymple LS, Kaysen GA. The effect of lipoproteins on the development and progression of renal disease. Am J Nephrol 2008;28:723-31.