Coronary Artery Disease, Type 2 Diabetes
Conditions
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.
Interventions
DRUGLinagliptin
The subject will receive Linagliptin 5mg orally once daily for 12 weeks.
DRUGPlacebo
The subject will receive placebo orally once daily for 12 weeks.
Sponsors
Medical University of Graz
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Endothelial Function (FMD - Flow Mediated Dilatation) From Baseline to 12 Weeks | 12 weeks | Endothelium-dependent FMD following reactive hyperaemia was examined in the brachial artery according to the guidelines described by Coretti et al (J Am Coll Cardiol. 2002;39(2):257-65). FMD-diameter is calculated as the average of the three diameter measurements following reactive hyperaemia. FMD was calculated as the percent change in diameter compared to baseline. Flow-mediated dilation is reported such as percentage of change in diameter (%). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Global Arginine Bioavailability Ratio (Ratio of Arginine to [Ornithine + Citrulline]) and Arginine to Ornithine Ratio From Baseline to 12 Weeks | 12 weeks | Arginine, ornithine and citrulline will be measured in serum samples with a conventional usual amino acid analysis technique, involving separation of amino acids by ion exchange chromatography followed by postcolumn continuous reaction with ninhydrin. Global arginine bioavailability ratio (GABR) will be calculated by L-arginine divided by the sum of (L-ornithine plus L-citrulline). The arginine to ornithine ratio will be calculated by dividing L-arginine by L-ornithine levels. |
| Changes in Biochemical Markers (sICAM-1) | 12 weeks | Soluble cell adhesion molecules-1 (sICAM-1) of endothelial function from baseline to 12 weeks |
| Changes in the Area Under Curve (AUC) of Glucose, Insulin and C-peptide During the Meal Tolerance Test From Baseline to 12 Weeks | 12 weeks | The Area under the curve was calculated for glucose, insulin and for the free fatty acids based on the trapezoidal rule with baseline value as the mean of the values at time points -5 and 0 minutes. The Meal Tolerance Test (MTT) was performed after an overnight fast (apart from water). A pre-meal blood sample will be taken (-5mins) and then all subjects will be asked to drink Fortimel compact (10 kcal/kg) over a period of 2-4 mins (time 0 mins). During the mixed meal test further blood samples will be taken at 15, 30, 60, and 120 minutes. All samples will be used for the determination of glucose, insulin and free fatty acids. The blood at each time point will be placed into a fluoride oxalate tube (1ml) for plasma glucose and into a serum tube for insulin and free fatty acids. |
| Changes in the Area Under Curve (AUC) of Free Fatty Acids During the Meal Tolerance Test From Baseline to 12 Weeks | 12 weeks | The Area under the curve was calculated for glucose, insulin and for the free fatty acids based on the trapezoidal rule with baseline value as the mean of the values at time points -5 and 0 minutes. The MTT was performed after an overnight fast (apart from water). A pre-meal blood sample will be taken (-5mins) and then all subjects will be asked to drink Fortimel compact (10 kcal/kg) over a period of 2-4 mins (time 0 mins). During the mixed meal test further blood samples will be taken at 15, 30, 60, and 120 minutes. All samples will be used for the determination of glucose, insulin and free fatty acids. The blood at each time point will be placed into a fluoride oxalate tube (1ml) for plasma glucose and into a serum tube for insulin and free fatty acids. |
| Changes in Biochemical Markers (svCAM-1) | 12 weeks | Soluble cell adhesion molecules-1 (svCAM-1) of endothelial function from baseline to 12 weeks |
Countries
Austria
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Linagliptin The subjects will receive Linagliptin 5mg (licensed dose for treatment of type 2 diabetes) .
Linagliptin: The subject will receive Linagliptin 5mg orally once daily for 12 weeks. | 20 |
| Placebo The subjects will receive placebo.
Placebo: The subject will receive placebo orally once daily for 12 weeks. | 23 |
| Total | 43 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 5 | 1 |
Baseline characteristics
| Characteristic | Linagliptin | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 63.3 years STANDARD_DEVIATION 7.8 | 63.3 years STANDARD_DEVIATION 8.2 | 63.3 years STANDARD_DEVIATION 8.7 |
| Alanine-Aminotransferase (U/L) | 40.4 U/l STANDARD_DEVIATION 25 | 34.4 U/l STANDARD_DEVIATION 20.1 | 29 U/l STANDARD_DEVIATION 12.7 |
| Aspartate-Aminotransferase (U/L) | 33.5 U/l STANDARD_DEVIATION 14 | 30.4 U/l STANDARD_DEVIATION 11.6 | 27.6 U/l STANDARD_DEVIATION 8.3 |
| Blood pressure diastolic (mmHg) | 79 mmHg STANDARD_DEVIATION 14 | 79 mmHg STANDARD_DEVIATION 12 | 78 mmHg STANDARD_DEVIATION 10 |
| Blood pressure systolic (mmHg) | 134 mmHg STANDARD_DEVIATION 17 | 131 mmHg STANDARD_DEVIATION 18 | 128 mmHg STANDARD_DEVIATION 18 |
| c-reactive protein (mg/L) | 3.8 mg/dl STANDARD_DEVIATION 4.2 | 5.8 mg/dl STANDARD_DEVIATION 15.2 | 7.6 mg/dl STANDARD_DEVIATION 20.4 |
| Creatinine (mg/dL) | 1.0 mg/dl STANDARD_DEVIATION 0.3 | 1.0 mg/dl STANDARD_DEVIATION 0.3 | 1.0 mg/dl STANDARD_DEVIATION 0.2 |
| estimated glomerular filtration rate (ml/min) | 76.7 ml/min STANDARD_DEVIATION 16.1 | 78.9 ml/min STANDARD_DEVIATION 17 | 80.8 ml/min STANDARD_DEVIATION 18 |
| Fasting blood glucose | 136 mg/dl STANDARD_DEVIATION 41 | 135 mg/dl STANDARD_DEVIATION 35 | 123 mg/dl STANDARD_DEVIATION 26 |
| HbA1c (mmol/mol) | 50.5 mmol/mol | 51 mmol/mol | 51 mmol/mol |
| Low density lipoprotein (mg/dl) | 66 mg/dl STANDARD_DEVIATION 31 | 71 mg/dl STANDARD_DEVIATION 37 | 76 mg/dl STANDARD_DEVIATION 43 |
| n-terminal-proBNP (pg/ml) | 419 pg/ml STANDARD_DEVIATION 528 | 317 pg/ml STANDARD_DEVIATION 492 | 228 pg/ml STANDARD_DEVIATION 452 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 20 Participants | 43 Participants | 23 Participants |
| Region of Enrollment Austria | 20 participants | 43 participants | 23 participants |
| Sex: Female, Male Female | 5 Participants | 9 Participants | 4 Participants |
| Sex: Female, Male Male | 15 Participants | 34 Participants | 19 Participants |
| Triglycerides (mg/dl) | 145 mg/dl | 128 mg/dl | 122 mg/dl |
| Urine albumine´(mg/L) | 51.8 mg/l STANDARD_DEVIATION 68.1 | 40.8 mg/l STANDARD_DEVIATION 57.1 | 30.3 mg/l STANDARD_DEVIATION 43.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 23 |
| other Total, other adverse events | 2 / 20 | 3 / 23 |
| serious Total, serious adverse events | 3 / 20 | 1 / 23 |
Outcome results
Primary
Changes in Endothelial Function (FMD - Flow Mediated Dilatation) From Baseline to 12 Weeks
Endothelium-dependent FMD following reactive hyperaemia was examined in the brachial artery according to the guidelines described by Coretti et al (J Am Coll Cardiol. 2002;39(2):257-65). FMD-diameter is calculated as the average of the three diameter measurements following reactive hyperaemia. FMD was calculated as the percent change in diameter compared to baseline. Flow-mediated dilation is reported such as percentage of change in diameter (%).
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Linagliptin | Changes in Endothelial Function (FMD - Flow Mediated Dilatation) From Baseline to 12 Weeks | 0.4 percentage of change in diameter (%) | Standard Deviation 4.8 |
| Placebo | Changes in Endothelial Function (FMD - Flow Mediated Dilatation) From Baseline to 12 Weeks | -0.5 percentage of change in diameter (%) | Standard Deviation 3 |
Secondary
Changes in Biochemical Markers (sICAM-1)
Soluble cell adhesion molecules-1 (sICAM-1) of endothelial function from baseline to 12 weeks
Time frame: 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Linagliptin | Changes in Biochemical Markers (sICAM-1) | -15 ng/ml |
| Placebo | Changes in Biochemical Markers (sICAM-1) | -21 ng/ml |
Secondary
Changes in Biochemical Markers (svCAM-1)
Soluble cell adhesion molecules-1 (svCAM-1) of endothelial function from baseline to 12 weeks
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Linagliptin | Changes in Biochemical Markers (svCAM-1) | -34 ng/ml | Standard Deviation 84 |
| Placebo | Changes in Biochemical Markers (svCAM-1) | 5 ng/ml | Standard Deviation 130 |
Secondary
Changes in Global Arginine Bioavailability Ratio (Ratio of Arginine to [Ornithine + Citrulline]) and Arginine to Ornithine Ratio From Baseline to 12 Weeks
Arginine, ornithine and citrulline will be measured in serum samples with a conventional usual amino acid analysis technique, involving separation of amino acids by ion exchange chromatography followed by postcolumn continuous reaction with ninhydrin. Global arginine bioavailability ratio (GABR) will be calculated by L-arginine divided by the sum of (L-ornithine plus L-citrulline). The arginine to ornithine ratio will be calculated by dividing L-arginine by L-ornithine levels.
Time frame: 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Linagliptin | Changes in Global Arginine Bioavailability Ratio (Ratio of Arginine to [Ornithine + Citrulline]) and Arginine to Ornithine Ratio From Baseline to 12 Weeks | Global Arginine Bioavailabilty Ratio (%) | -0.11 Ratio | Standard Deviation 0.35 |
| Linagliptin | Changes in Global Arginine Bioavailability Ratio (Ratio of Arginine to [Ornithine + Citrulline]) and Arginine to Ornithine Ratio From Baseline to 12 Weeks | Arginine to ornithine ratio (%) | -0.13 Ratio | Standard Deviation 0.45 |
| Placebo | Changes in Global Arginine Bioavailability Ratio (Ratio of Arginine to [Ornithine + Citrulline]) and Arginine to Ornithine Ratio From Baseline to 12 Weeks | Global Arginine Bioavailabilty Ratio (%) | -0.06 Ratio | Standard Deviation 0.39 |
| Placebo | Changes in Global Arginine Bioavailability Ratio (Ratio of Arginine to [Ornithine + Citrulline]) and Arginine to Ornithine Ratio From Baseline to 12 Weeks | Arginine to ornithine ratio (%) | -0.05 Ratio | Standard Deviation 0.53 |
Secondary
Changes in the Area Under Curve (AUC) of Free Fatty Acids During the Meal Tolerance Test From Baseline to 12 Weeks
The Area under the curve was calculated for glucose, insulin and for the free fatty acids based on the trapezoidal rule with baseline value as the mean of the values at time points -5 and 0 minutes. The MTT was performed after an overnight fast (apart from water). A pre-meal blood sample will be taken (-5mins) and then all subjects will be asked to drink Fortimel compact (10 kcal/kg) over a period of 2-4 mins (time 0 mins). During the mixed meal test further blood samples will be taken at 15, 30, 60, and 120 minutes. All samples will be used for the determination of glucose, insulin and free fatty acids. The blood at each time point will be placed into a fluoride oxalate tube (1ml) for plasma glucose and into a serum tube for insulin and free fatty acids.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Linagliptin | Changes in the Area Under Curve (AUC) of Free Fatty Acids During the Meal Tolerance Test From Baseline to 12 Weeks | 2.0 µmol*min/l | Standard Deviation 28.4 |
| Placebo | Changes in the Area Under Curve (AUC) of Free Fatty Acids During the Meal Tolerance Test From Baseline to 12 Weeks | -3.1 µmol*min/l | Standard Deviation 18.3 |
Secondary
Changes in the Area Under Curve (AUC) of Glucose, Insulin and C-peptide During the Meal Tolerance Test From Baseline to 12 Weeks
The Area under the curve was calculated for glucose, insulin and for the free fatty acids based on the trapezoidal rule with baseline value as the mean of the values at time points -5 and 0 minutes. The Meal Tolerance Test (MTT) was performed after an overnight fast (apart from water). A pre-meal blood sample will be taken (-5mins) and then all subjects will be asked to drink Fortimel compact (10 kcal/kg) over a period of 2-4 mins (time 0 mins). During the mixed meal test further blood samples will be taken at 15, 30, 60, and 120 minutes. All samples will be used for the determination of glucose, insulin and free fatty acids. The blood at each time point will be placed into a fluoride oxalate tube (1ml) for plasma glucose and into a serum tube for insulin and free fatty acids.
Time frame: 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Linagliptin | Changes in the Area Under Curve (AUC) of Glucose, Insulin and C-peptide During the Meal Tolerance Test From Baseline to 12 Weeks | Glucose AUC | -1135 mg*min/dl | Standard Deviation 2619 |
| Linagliptin | Changes in the Area Under Curve (AUC) of Glucose, Insulin and C-peptide During the Meal Tolerance Test From Baseline to 12 Weeks | C-peptide AUC | -3 mg*min/dl | Standard Deviation 161 |
| Linagliptin | Changes in the Area Under Curve (AUC) of Glucose, Insulin and C-peptide During the Meal Tolerance Test From Baseline to 12 Weeks | Insulin AUC | 249 mg*min/dl | Standard Deviation 4766 |
| Placebo | Changes in the Area Under Curve (AUC) of Glucose, Insulin and C-peptide During the Meal Tolerance Test From Baseline to 12 Weeks | Glucose AUC | 481 mg*min/dl | Standard Deviation 3185 |
| Placebo | Changes in the Area Under Curve (AUC) of Glucose, Insulin and C-peptide During the Meal Tolerance Test From Baseline to 12 Weeks | C-peptide AUC | -34 mg*min/dl | Standard Deviation 211 |
| Placebo | Changes in the Area Under Curve (AUC) of Glucose, Insulin and C-peptide During the Meal Tolerance Test From Baseline to 12 Weeks | Insulin AUC | 40 mg*min/dl | Standard Deviation 6357 |