Association Between Plasma Triglycerides and High-Density Lipoprotein Cholesterol and Microvascular Kidney Disease and Retinopathy in Type 2 Diabetes Mellitus

Abstract

Background-Microvascular renal and retinal diseases are common major complications of type 2 diabetes mellitus. The relation between plasma lipids and microvascular disease is not well established. Methods and Results-The case subjects were 2535 patients with type 2 diabetes mellitus with an average duration of 14 years, 1891 of whom had kidney disease and 1218 with retinopathy. The case subjects were matched for diabetes mellitus duration, age, sex, and low-density lipoprotein cholesterol to 3683 control subjects with type 2 diabetes mellitus who did not have kidney disease or retinopathy. The study was conducted in 24 sites in 13 countries. The primary analysis included kidney disease and retinopathy cases. Matched analysis was performed by use of site-specific conditional logistic regression in multivariable models that adjusted for hemoglobin A 1c , hypertension, and statin treatment. Mean low-density lipoprotein cholesterol concentration was 2.3 mmol/L. The microvascular disease odds ratio increased by a factor of 1.16 (95% confidence interval, 1.11-1.22) for every 0.5 mmol/L (≈1 quintile) increase in triglycerides or decreased by a factor of 0. 1-4 Hyperglycemia and hypertension are major risk factors for the development of microvascular disease.2,4 Intensive control of blood glucose and blood pressure to, or even beyond, currently recommended targets may provide some additional benefits in the prevention of diabetic microvascular disease but is often impossible to achieve because of the associated risks of hypoglycemia or hypotension. 5,6 Therefore, it is necessary to identify other targets and treatments to make progress in slowing the development of diabetic kidney disease and retinopathy. Clinical Perspective on p 1008Most epidemiological studies have found an association between serum triglycerides and diabetic kidney disease, although less consistently for serum high-density lipoprotein cholesterol (HDL-C). [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] Results diverged among studies on diabetic retinopathy, especially in multivariable analysis. 4,[22][23][24][25][26][27][28][29][30][31][32][33] In randomized, controlled trials, treatment of patients with type 2 diabetes mellitus with fenofibrate, a peroxisome proliferatoractivated receptor-α agonist, reduced the rate of decline in renal function, 25,34 reduced albuminuria, and reduced the requirement for laser treatment of retinopathy. 5,25,34,35 However, it is not clear whether these beneficial effects were caused by improvements in triglycerides or HDL-C or by other biological effects of peroxisome proliferator-activated receptor-α activation.The objective of the present international study was to determine whether low HDL-C or elevated triglycerides levels are associated with diabetic kidney disease and retinopathy independent of established determinants of microvascular disease in patients with type 2 diabetes mellitus with low-density lipoprotein cholesterol (LDL-C) ≤3.4 mmol/L (130 mg/dL). MethodsThe study used a case-control desi...

Associations between diabetic retinopathy and systemic risk factors

“…Likewise, in a large-scale study of 2535 patients with type 2 DM, retinopathy was not significantly associated with triglyceride or high-density lipoprotein (HDL) cholesterol levels after adjustment of confounding factors. 45 In contrast, Cheng at al 4 found that in overweight type 2 DM patients, elevated triacylglycerol levels were significantly associated with diabetic retinopathy (OR=1.29; 95% CI, 1.05-1.58; P<0.05).…”

Biomarkers in Diabetic Retinopathy

“…In the recent, very large META-EYE study, high total cholesterol level was a risk factor for diabetic retinopathy, specifically for diabetic macular edema [15]. In contrast, a 13-country study of long type 2 diabetes duration showed that plasma lipid levels (high triglycerides and low HDL-C levels) were associated with retinopathy on univariate analysis, but not at full adjustment for potential confounders [24]. In recent studies, we found that circulating levels of apolipoprotein A1 (associated with HDL) and apolipoprotein B (found in LDL, lipoprotein(a), VLDL, and chylomicrons) were stronger predictors of diabetic retinopathy than traditional lipid levels [182].…”

“…A similar process can be observed for lipid levels. Whilst high total and LDL-cholesterol (LDL-C), triglycerides, and low HDL-C levels are traditional risk factors for cardiovascular disease, and possibly also for diabetic retinopathy [15,24], lipoprotein subclass profiles based on lipoprotein particle size [25], determined by nuclear magnetic resonance (NMR) and measures of circulating oxidized LDL [26], are more recently developed, and may thus be regarded as novel biomarkers.…”

Residual Microvascular Risk in Type 2 Diabetes in 2014: Is it Time for a Re-Think? A Perspective from the Residual Risk Reduction Initiative (R3i)

“…Most recently, the evidence-base for a role for atherogenic dyslipidemia has been strengthened by the REALIST (REsiduAl risk Lipids and Standard Therapies) microvascular study [35]. This crosssectional case-control study included 2,535 type 2 diabetes patients with either diabetic kidney disease (n=1891), diabetic retinopathy (n=1,218) or both complications (n=574), and 3,683 matched controls, enrolled by 24 sites in 13 countries in Europe, North America, the Middle East, Asia (including Japan and China), and Australasia.…”

“…In this context, management of atherogenic dyslipidemia, a key driver of cardiovascular risk in this patient group, in addition to best standards of care, is relevant as supported by evidence from the REALIST-Micro study [35]. In support, a large-scale study in a real-life setting suggested that improved lipid management, targeting HDL cholesterol and triglycerides in addition to non-HDL cholesterol, can reduce the risk of diabetic retinopathy, peripheral neuropathy, and/or nephropathy in type 2 diabetes patients [39].…”