Effects of Linagliptin on Endothelial Function
Condition: Type 2 Diabetes; Coronary Artery Disease
MeSH terms: Coronary Artery Disease; Myocardial Ischemia; Coronary Disease
Study type: Interventional
Phase: Phase 4

Summary: 
      This study is planned to evaluate if linagliptin can improve endothelial function in patients
      with type 2 diabetes mellitus. In addition, the effect of linagliptin on arginine
      bioavailability ratios and postchallenge glycaemic control will be studied.
    

Detailed description: 
      Patients with type 2 diabetes (T2DM) are at increased risk of macrovascular events as well as
      microvascular complications. It is well known, that the pathophysiologic process of type 2
      diabetes starts many years before the diagnosis can be made on the basis of elevated fasting
      blood glucose. In particular the data of the United Kingdom Prospective Diabetes Study
      (UKPDS) study and the UKPDS post trial monitoring highlighted the importance of an early
      glucose lowering intervention in patients with T2DM with respect to micro- and macrovascular
      complications. The investigators and in particular the Euro Heart survey on Diabetes and the
      Heart demonstrated, that in a cardiovascular high risk population, namely patients with
      coronary artery disease (CAD), about 35% suffer from manifest type 2 diabetes. In addition,
      another 9 to 15% of CAD patients have postchallenge diabetes, diagnosed on the basis of an
      oral glucose tolerance test, which means that approximately a half of all patients with CAD
      have diabetes.

      Recently the investigators could demonstrate that not only established type 2 diabetes
      diagnosed on the basis of fasting hyperglycaemia is associated with an increased
      cardiovascular risk, but also postchallenge hyperglycemia (i.e. impaired glucose tolerance or
      postchallenge diabetes).

      Dipeptidylpeptidase-4 (DPP-4) inhibitors increase endogenous glucagon like-peptide-1 (GLP-1)
      levels and GLP-1 in turn increases the insulin release from pancreatic beta-cells in a
      glucose dependent manner as well as suppresses glucagon secretion from pancreatic alpha
      cells. Investigations in type 2 diabetic patients showed that this drug class lowers both,
      fasting and postchallenge or postmeal glucose levels and hence, HbA1c and is well tolerated.

      However, the lowering of the surrogate measurement HbA1c has not necessarily turned out to
      translate into a reduced number of cardiovascular events in patients with T2DM. In contrary
      in particular for the thiazolidinedione Rosiglitazone concerns about an increased risk of
      cardiovascular events have been raised despite a robust HbA1c lowering effect.Therefore the
      Food and Drug Administration (FDA) and the European Medicines Agency (EMA) issued in 2008 and
      2010, respectively, guidance for new glucose lowering drugs, requiring proof of at least
      cardiovascular safety. Cardiovascular outcome trials with Linagliptin are currently being
      performed (CAROLINA, CARMELINA), however, it will take a couple of years until the results
      are available.A well known and validated cardiovascular surrogate parameter is endothelial
      dysfunction. The investigators and others have shown previously, that endothelial dysfunction
      is present in patients with coronary artery disease and early diabetes and can be improved by
      pharmacological intervention. This surrogate measurement could be helpful in better
      understanding the cardiovascular effects of Linagliptin while awaiting the results of the
      definitive outcome trials.

      The aim of this study is to investigate the effects of Linagliptin in coronary patients with
      early T2DM on various cardiovascular surrogate measurements including mechanical and
      biochemical endothelial function assessments. The overarching aim of our study is to
      investigate the effects of Linagliptin on endothelial function, arginine bioavailability
      ratios and postchallenge glycaemic control in patients with early diabetes and coronary
      atherosclerosis.
    

Intervention name(s): Linagliptin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): The subject will receive Linagliptin 5mg orally once daily for 12 weeks.; The subject will receive placebo orally once daily for 12 weeks.
Other intervention name(s): Trajenta; sugar pill
Intervention MeSH terms: Linagliptin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment