Type 2-diabetes Clinical Trial
Official title:
Effects of Linagliptin on Renal Endothelium Function in Patients With 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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