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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Linagliptin | Active Comparator | The subjects will receive Linagliptin 5mg (licensed dose for treatment of type 2 diabetes) . |
|
| Placebo | Placebo Comparator | The subjects will receive placebo. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Linagliptin | Drug | The subject will receive Linagliptin 5mg orally once daily for 12 weeks. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 (%)". | 12 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Harald Sourij, Assoc.-Prof. | Medical University of Graz | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Medical University of Graz, Department for Internal Medicine | Graz | 8036 | Austria |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 29773079 | Derived | 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. | |
| 27733180 |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | Placebo | The subjects will receive placebo. Placebo: The subject will receive placebo orally once daily for 12 weeks. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 (%)". | Posted | Mean | Standard Deviation | percentage of change in diameter (%) | 12 weeks |
|
Adverse events were collected for 16 weeks (12 weeks of intervention and 4 weeks of follow-up).
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| discus prolaps | Musculoskeletal and connective tissue disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dorsal pain | Nervous system disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Assoz.-Prof. Dr. Harald Sourij | Medical University of Graz | +43316385 | 81310 | ha.sourij@medunigraz.at |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Oct 24, 2014 | May 14, 2020 | Prot_000.pdf |
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| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| D003324 | Coronary Artery Disease |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D000069476 | Linagliptin |
| D000073893 | Sugars |
| ID | Term |
|---|---|
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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| Placebo | Drug | The subject will receive placebo orally once daily for 12 weeks. |
|
|
| 12 weeks |
| Changes in Biochemical Markers (sICAM-1) | Soluble cell adhesion molecules-1 (sICAM-1) of endothelial function from baseline to 12 weeks | 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 | 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. | 12 weeks |
| 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. | 12 weeks |
| Changes in Biochemical Markers (svCAM-1) | Soluble cell adhesion molecules-1 (svCAM-1) of endothelial function from baseline to 12 weeks | 12 weeks |
| Derived |
| 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. |
The subjects will receive placebo.
Placebo: The subject will receive placebo orally once daily for 12 weeks.
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Blood pressure systolic (mmHg) | Mean | Standard Deviation | mmHg |
|
| Blood pressure diastolic (mmHg) | Mean | Standard Deviation | mmHg |
|
| Low density lipoprotein (mg/dl) | Mean | Standard Deviation | mg/dl |
|
| Triglycerides (mg/dl) | Median | Inter-Quartile Range | mg/dl |
|
| HbA1c (mmol/mol) | Median | Inter-Quartile Range | mmol/mol |
|
| Fasting blood glucose | Mean | Standard Deviation | mg/dl |
|
| Aspartate-Aminotransferase (U/L) | Mean | Standard Deviation | U/l |
|
| Alanine-Aminotransferase (U/L) | Mean | Standard Deviation | U/l |
|
| Creatinine (mg/dL) | Mean | Standard Deviation | mg/dl |
|
| estimated glomerular filtration rate (ml/min) | Mean | Standard Deviation | ml/min |
|
| c-reactive protein (mg/L) | Mean | Standard Deviation | mg/dl |
|
| Urine albumine´(mg/L) | Mean | Standard Deviation | mg/l |
|
| n-terminal-proBNP (pg/ml) | Mean | Standard Deviation | pg/ml |
|
| Placebo |
The subjects will receive placebo. Placebo: The subject will receive placebo orally once daily for 12 weeks. |
|
|
| 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. | Posted | Mean | Standard Deviation | Ratio | 12 weeks |
|
|
|
| Secondary | Changes in Biochemical Markers (sICAM-1) | Soluble cell adhesion molecules-1 (sICAM-1) of endothelial function from baseline to 12 weeks | Posted | Median | Inter-Quartile Range | ng/ml | 12 weeks |
|
|
|
| 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. | Posted | Mean | Standard Deviation | mg*min/dl | 12 weeks |
|
|
|
| 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. | Posted | Mean | Standard Deviation | µmol*min/l | 12 weeks |
|
|
|
| Secondary | Changes in Biochemical Markers (svCAM-1) | Soluble cell adhesion molecules-1 (svCAM-1) of endothelial function from baseline to 12 weeks | Posted | Mean | Standard Deviation | ng/ml | 12 weeks |
|
|
|
| 0 |
| 20 |
| 3 |
| 20 |
| 2 |
| 20 |
| EG001 | Placebo | The subjects will receive placebo. Placebo: The subject will receive placebo orally once daily for 12 weeks. | 0 | 23 | 1 | 23 | 3 | 23 |
| Borreliosis | Infections and infestations | Systematic Assessment |
|
| Coordinating disorders | Nervous system disorders | Systematic Assessment | Hospitalization due to coordinating disorders |
|
| Abdominal pain | Gastrointestinal disorders | Systematic Assessment | Hospitalisation due to abdominal pain |
|
| Toothache | Gastrointestinal disorders | Systematic Assessment |
|
| Claudicatio intermittens | Vascular disorders | Systematic Assessment |
|
| Hypotension | Cardiac disorders | Systematic Assessment |
|
| Nausea | General disorders | Systematic Assessment |
|
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| D004700 | Endocrine System Diseases |
| D003327 | Coronary Disease |
| D017202 | Myocardial Ischemia |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
| D001161 | Arteriosclerosis |
| D001157 | Arterial Occlusive Diseases |
| D014652 | Vascular Diseases |
| D011799 | Quinazolines |
| D002241 | Carbohydrates |
| Insulin AUC |
|