Effects of Linagliptin on Renal Endothelium Function in Patients With Type 2 Diabetes.
Condition: Type 2-diabetes
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 3

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Linagliptin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): orally 5 mg/d for 4 weeks; orally once a day for 4 weeks
Intervention MeSH terms: Linagliptin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment