Clinical trial NCT02350478: Effects of Linagliptin on Endothelial Function
Official title: Effects of Linagliptin on Endothelial Function and Global Arginine Bioavailability Ratio in Coronary Artery Disease Patients With Early Diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Type 2 Diabetes
Coronary Artery Disease
Lead sponsor: Medical University of Graz
Sponsor class: OTHER
First posted: 2015-01-29
Enrollment: 49
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: Inclusion Criteria:

* Age: 40 to 80 years
* Early diabetes (postchallenge diabetes (2h glucose \>200 mg/dl or type 2 diabetes treated with diet only or on a stable dose of metformin monotherapy)
* Coronary atherosclerosis (diagnosed via coronary angiography or coronary computer tomography)

Exclusion Criteria:

* Acute coronary syndrome or cerebrovascular event within the previous 4 weeks
* Body Mass Index (BMI) \> 35 kg/m2
* HbA1c \<6.0% (42 mmol/mol)
* Serum creatinine \> 2.5 mg/dl
* Aspartate Transaminase (AST)/Alanine Transaminase (ALT)\>3x upper limit of normal
* HbA1c \>9.0% (\>75 mmol/mol)
* Heart failure \> New York Heart Association (NYHA) class II
* Uncontrolled hypertension (blood pressure \> 165 / 100 mmHg)
* Treatment with orally administered steroids
* New onset statin or Angiotensin Converting Enzym- (ACE-) inhibitor within the previous 6 weeks
* Known Malignancy
* Pregnancy or breast feeding women.

Primary outcomes:
measure: Changes in Endothelial Function (FMD - Flow Mediated Dilatation) From Baseline to 12 Weeks
timeFrame: 12 weeks
Secondary outcomes:
measure: Changes in Global Arginine Bioavailability Ratio (Ratio of Arginine to [Ornithine + Citrulline]) and Arginine to Ornithine Ratio From Baseline to 12 Weeks
timeFrame: 12 weeks
measure: Changes in Biochemical Markers (sICAM-1)
timeFrame: 12 weeks
measure: Changes in the Area Under Curve (AUC) of Glucose, Insulin and C-peptide During the Meal Tolerance Test From Baseline to 12 Weeks
timeFrame: 12 weeks
measure: Changes in the Area Under Curve (AUC) of Free Fatty Acids During the Meal Tolerance Test From Baseline to 12 Weeks
timeFrame: 12 weeks
measure: Changes in Biochemical Markers (svCAM-1)
timeFrame: 12 weeks
Other outcomes:
Locations:
city: Graz
country: Austria
facility: Medical University of Graz, Department for Internal Medicine
Study officials:
affiliation: Medical University of Graz
name: Harald Sourij, Assoc.-Prof.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Tripolt NJ, Aberer F, Riedl R, Url J, Dimsity G, Meinitzer A, Stojakovic T, Aziz F, Hodl R, Brachtl G, Strunk D, Brodmann M, Hafner F, Sourij H. Effects of linagliptin on endothelial function and postprandial lipids in coronary artery disease patients with early diabetes: a randomized, placebo-controlled, double-blind trial. Cardiovasc Diabetol. 2018 May 17;17(1):71. doi: 10.1186/s12933-018-0716-x.
citation: Tripolt NJ, Aberer F, Riedl R, Hutz B, Url J, Dimsity G, Meinitzer A, Stojakovic T, Hodl R, Brodmann M, Hafner F, Sourij H. The effects of linagliptin on endothelial function and global arginine bioavailability ratio in coronary artery disease patients with early diabetes: study protocol for a randomized controlled trial. Trials. 2016 Oct 13;17(1):495. doi: 10.1186/s13063-016-1627-3.