Effects of Linagliptin on Renal Endothelium Function in Patients With Type 2 Diabetes.

Type 2-diabetes

Diabetes mellitus is a metabolic disease with a growing prevalence worldwide, affecting 171 million people in 2000 and an expected 366 million people in 2030 (1) and therefore diabetic nephropathy is rapidly increasing in the Western hemisphere and represents in up to 50 % the cause of end stage renal disease. Hence, early intervention is desirable to prevent any damage to the kidneys. In the early stage of diabetic nephropathy, endothelium dysfunction is a key pathogenetic process as indicated by increased leakage of albumin through the glomerular barrier (2). Hence, improvement of endothelium function is an attractive therapeutic goal of antidiabetic medication. Endothelial dysfunction, in particular basal nitric oxide activity, has been also identified as pivotal determinant of glomerular filtration rate (3). A new and promising class of antidiabetic drugs are the gliptins. Gliptins act by inhibiting the enzyme dipeptidyl peptidase-4 (DPP-4), which is responsible for the rapid inactivation of glucagon-like peptide-1 (GLP-1) - an incretin hormone of the gut (6 - 8), thereby enhancing and prolonging the effects of GLP-1. GLP-1 - member of the incretin hormones - is released into the blood after meal ingestion and stimulates the insulin secretion in a glucose dependent manner. This accounts for the marked prandial insulin response, which prevents prandial hyperglycemia. Apart from surrogate parameters like reduction of fasting and postprandial blood glucose levels or improvement of HbA1c, the effect of gliptins on micro- and macrovascular function and cardiovascular outcome has not been the primary focus of current studies. However, infusion of GLP-1, the incretin hormone affected by gliptins has been reported to ameliorate endothelial dysfunction in patients suffering from coronary artery disease (9) and it was recently shown that infusion of GLP-1 into healthy human subjects increases both normal and ACh-induced vasodilatation (10). In studies on rats with diabetes, GLP-1 infusion nearly re-established their normal vascular tone (11) and there are further data from experimental animals that indicate a beneficial effect of GLP-1 on endothelial function (12). It is of major interest whether therapy with gliptins improves endothelial function of the micro- and macrovasculature. In face of the burden that diabetic nephropathy causes, the effect of linagliptin on the renal vasculature and endothelium integrity of the renal circulation (as measured by the availability of nitric oxide), is a key stone in order to claim that linagliptin is an effective antidiabetic agents. There is a need to demonstrate that linagliptin is effective beyond its blood glucose lowering actions and improves vascular endothelium function in the kidney.

Diabetes mellitus is a metabolic disease with a growing prevalence worldwide, affecting 171 million people in 2000 and an expected 366 million people in 2030 (1) and therefore diabetic nephropathy is rapidly increasing in the Western hemisphere and represents in up to 50 % the cause of end stage renal disease. Hence, early intervention is desirable to prevent any damage to the kidneys. In the early stage of diabetic nephropathy, endothelium dysfunction is a key pathogenetic process as indicated by increased leakage of albumin through the glomerular barrier (2). Hence, improvement of endothelium function is an attractive therapeutic goal of antidiabetic medication. Endothelial dysfunction, in particular basal nitric oxide activity, has been also identified as pivotal determinant of glomerular filtration rate (3). Previously, blockade of the renin angiotensin system have been found to be effective in improving endothelium function (4). Furthermore, we observed that renal endothelium function is improved by cardiovascular risk factor control (e.g. blood pressure) and may be predictive for the development of diabetic nephropathy (5). A new and promising class of antidiabetic drugs are the gliptins. Gliptins act by inhibiting the enzyme dipeptidyl peptidase-4 (DPP-4), which is responsible for the rapid inactivation of glucagon-like peptide-1 (GLP-1) - an incretin hormone of the gut (6 - 8), thereby enhancing and prolonging the effects of GLP-1. GLP-1 - member of the incretin hormones - is released into the blood after meal ingestion and stimulates the insulin secretion in a glucose dependent manner. This accounts for the marked prandial insulin response, which prevents prandial hyperglycemia. Several efficacy studies demonstrated a significant improvement of HbA1c with gliptins. In addition, gliptins improved fasting as well as prandial glucose levels and did not induce weight gain. Due to these positive metabolic effects in combination with a very small spectrum of side effects gliptins might very well be part of the standard therapy for type 2 diabetes in the future. Apart from surrogate parameters like reduction of fasting and postprandial blood glucose levels or improvement of HbA1c, the effect of gliptins on micro- and macrovascular function and cardiovascular outcome has not been the primary focus of current studies. However, infusion of GLP-1, the incretin hormone affected by gliptins has been reported to ameliorate endothelial dysfunction in patients suffering from coronary artery disease (9) and it was recently shown that infusion of GLP-1 into healthy human subjects increases both normal and ACh-induced vasodilatation (10). In studies on rats with diabetes, GLP-1 infusion nearly re-established their normal vascular tone (11) and there are further data from experimental animals that indicate a beneficial effect of GLP-1 on endothelial function (12). Diabetes mellitus is strongly associated with microangiopathy and macroangiopathy and is a strong independent risk factor for cardiovascular disease and cardiovascular mortality (13). Endothelial dysfunction which plays a crucial role in the atherosclerotic process is commonly observed in patients with diabetes mellitus and already prediabetes and has - amongst other factors - been linked to fasting and postprandial hyperglycemia. Gliptins reduce hyperglycemia and hyperglycemic peaks by preventing inactivation of GLP-1, which exerted beneficial effects on the endothelium in previous studies. It is of major interest whether therapy with gliptins improves endothelial function of the micro- and macrovasculature. In face of the burden that diabetic nephropathy causes, the effect of linagliptin on the renal vasculature and endothelium integrity of the renal circulation (as measured by the availability of nitric oxide), is a key stone in order to claim that linagliptin is an effective antidiabetic agents. There is a need to demonstrate that linagliptin is effective beyond its blood glucose lowering actions and improves vascular endothelium function in the kidney.

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