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1 March 2010

Reducing residual risk of diabetic nephropathy: the role of lipoproteins

Prof. J. Millán Núñez-Cortés

Madrid, Spain
Prof. J. Millán Núñez-Cortés Approximately 60% to 75% of patients with type 2 diabetes will suffer morbidity and/or mortality from macrovascular disease. Atherogenic dyslipidemia – characterized by elevated triglyceride levels, low high-density lipoprotein cholesterol (HD-C) levels, and a preponderance of small, dense, low-density lipoprotein (LDL) particles – is the major lipid-related causative factor of atherosclerosis in individuals with type 2 diabetes. Moreover, hyperglycemia, high blood pressure and dyslipidemia are major metabolic risk factors for microvascular complications of type 2 diabetes. Therefore, treatment of type 2 diabetes must address atherogenic dyslipidemia to prevent both microvascular disease (retinopathy, neuropathy, and nephropathy) and macrovascular complications.

Between 30% and 40% of patients with diabetes ultimately develop diabetic nephropathy, which is the commonest cause of end-stage renal disease requiring dialysis. Clinical and experimental evidence has shown that hyperlipidemia is a pathogenic factor for diabetic nephropathy. Among the different factors that may mediate the development and progression of diabetic nephropathy, hyperlipidemia is now considered an independent and major determinant. Elevated triglyceride-rich lipoproteins, a key factor of altered lipid profile in diabetic nephropathy, is present even in the earlier stages of renal disease. Previous observations revealed that diabetic patients with microalbuminuria have smaller LDL particles than those with normoalbuminuria, a relevant finding as small, dense LDL particles may be nephrotoxic. Most interventional studies assessing lipid-lowering therapy in patients with diabetic nephropathy have used HMG-CoA reductase inhibitors and have been inconclusive. So, an alternative approach to reduce residual risk related to atherogenic dyslipidemia is necessary.

Risk factors for microvascular complications of type 2 diabetes mellitus (nephropathy and retinopathy) and for concurrent accelerated atherosclerosis include alterations in lipid metabolism at different levels of lipid metabolism: lipoprotein subclass distribution and composition, lipoprotein-related enzymes, and lipoproteins-receptors interactions. Qualitative and quantitative alterations in most lipoprotein classes have been reported. There is increasing evidence implicating lipoprotein-related genotypes characteristic of atherogenic dyslipidemia in the development of diabetic nephropathy. So, lipoprotein-related mechanisms associated with damage to the macrocardiovascular system may also be relevant to damage to microvasculature (renal and ocular).

Treatment of lipoprotein-related residual risk factors with different therapeutic agents may improve early management of high-risk diabetic patients. Strict dietary control and treatment of dyslipidemia with fibrates and/or statins is a rational approach to management of lipid-related residual risk in diabetic patients as it addresses all three major components of atherogenic dyslipidemia, including triglycerides, HDL-C level and LDL particle size.
Optimal and complete lipoprotein management, as part of a multi-faceted approach to diabetes care, may reduce the excessive economic burden of microvascular complications and the associated accelerated macro- and micro-angiopathy.