Effects of Linagliptin on Endothelial Function

• Sponsor: Medical University of Graz (Other)
• Overall Status: Completed
• CT.gov ID: NCT02350478
• Collaborator: (none)
• Enrollment: 49
• Location: 1
• Arms: 2
• Duration (Months): 44
• Patients Per Site Per Month: 1.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes; Coronary Artery Disease	Drug: Linagliptin; Drug: Placebo	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 49 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effects of Linagliptin on Endothelial Function and Global Arginine Bioavailability Ratio in Coronary Artery Disease Patients With Early Diabetes
• Study Start Date: Jul 1, 2013
• Actual Primary Completion Date: Jan 1, 2017
• Actual Study Completion Date: Mar 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Linagliptin The subjects will receive Linagliptin 5mg (licensed dose for treatment of type 2 diabetes) .	Drug: Linagliptin; The subject will receive Linagliptin 5mg orally once daily for 12 weeks.; Other Names: Trajenta
Placebo Comparator: Placebo The subjects will receive placebo.	Drug: Placebo; The subject will receive placebo orally once daily for 12 weeks.; Other Names: sugar pill

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. Changes in Biochemical Markers (sICAM-1) [12 weeks]

   Soluble cell adhesion molecules-1 (sICAM-1) of endothelial function from baseline to 12 weeks

3. 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.

4. 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.

5. Changes in Biochemical Markers (svCAM-1) [12 weeks]

   Soluble cell adhesion molecules-1 (svCAM-1) of endothelial function from baseline to 12 weeks

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Medical University of Graz, Department for Internal Medicine	Graz		Austria	8036

Sponsors and Collaborators

• Medical University of Graz

Investigators

• Principal Investigator: Harald Sourij, Assoc.-Prof., Medical University of Graz

Study Documents (Full-Text)

• Study Protocol - Oct 24, 2014

More Information

Publications

None provided.

• Responsible Party: Medical University of Graz
• ClinicalTrials.gov Identifier: NCT02350478
• Other Study ID Numbers: HS-2012-01
• First Posted: Jan 29, 2015
• Last Update Posted: May 15, 2020
• Last Verified: May 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Linagliptin

Study Results

Participant Flow

Arm/Group Title	Linagliptin	Placebo
Arm/Group Description	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.	The subjects will receive placebo. Placebo: The subject will receive placebo orally once daily for 12 weeks.
Period Title: Overall Study
STARTED	25	24
COMPLETED	20	23
NOT COMPLETED	5	1

Baseline Characteristics

Arm/Group Title	Linagliptin	Placebo	Total
Arm/Group Description	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.	The subjects will receive placebo. Placebo: The subject will receive placebo orally once daily for 12 weeks.	Total of all reporting groups
Overall Participants	20	23	43
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.3 (7.8)	63.3 (8.7)	63.3 (8.2)
Sex: Female, Male (Count of Participants)
Female	5 25%	4 17.4%	9 20.9%
Male	15 75%	19 82.6%	34 79.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	20 100%	23 100%	43 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Austria	20 100%	23 100%	43 100%
Blood pressure systolic (mmHg) (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	134 (17)	128 (18)	131 (18)
Blood pressure diastolic (mmHg) (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	79 (14)	78 (10)	79 (12)
Low density lipoprotein (mg/dl) (mg/dl) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dl]	66 (31)	76 (43)	71 (37)
Triglycerides (mg/dl) (mg/dl) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mg/dl]	145	122	128
HbA1c (mmol/mol) (mmol/mol) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mmol/mol]	50.5	51	51
Fasting blood glucose (mg/dl) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dl]	136 (41)	123 (26)	135 (35)
Aspartate-Aminotransferase (U/L) (U/l) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [U/l]	33.5 (14)	27.6 (8.3)	30.4 (11.6)
Alanine-Aminotransferase (U/L) (U/l) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [U/l]	40.4 (25)	29 (12.7)	34.4 (20.1)
Creatinine (mg/dL) (mg/dl) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dl]	1.0 (0.3)	1.0 (0.2)	1.0 (0.3)
estimated glomerular filtration rate (ml/min) (ml/min) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ml/min]	76.7 (16.1)	80.8 (18.0)	78.9 (17.0)
c-reactive protein (mg/L) (mg/dl) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dl]	3.8 (4.2)	7.6 (20.4)	5.8 (15.2)
Urine albumine´(mg/L) (mg/l) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/l]	51.8 (68.1)	30.3 (43.4)	40.8 (57.1)
n-terminal-proBNP (pg/ml) (pg/ml) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [pg/ml]	419 (528)	228 (452)	317 (492)

Outcome Measures

1. Primary Outcome

Title	Changes in Endothelial Function (FMD - Flow Mediated Dilatation) From Baseline to 12 Weeks
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Linagliptin	Placebo
Arm/Group Description	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.	The subjects will receive placebo. Placebo: The subject will receive placebo orally once daily for 12 weeks.
Measure Participants	20	23
Mean (Standard Deviation) [percentage of change in diameter (%)]	0.4 (4.8)	-0.5 (3.0)

2. Secondary Outcome

Title	Changes in Global Arginine Bioavailability Ratio (Ratio of Arginine to [Ornithine + Citrulline]) and Arginine to Ornithine Ratio From Baseline to 12 Weeks
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Linagliptin	Placebo
Arm/Group Description	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.	The subjects will receive placebo. Placebo: The subject will receive placebo orally once daily for 12 weeks.
Measure Participants	20	23
Global Arginine Bioavailabilty Ratio (%)	-0.11 (0.35)	-0.06 (0.39)
Arginine to ornithine ratio (%)	-0.13 (0.45)	-0.05 (0.53)

3. Secondary Outcome

Title	Changes in Biochemical Markers (sICAM-1)
Description	Soluble cell adhesion molecules-1 (sICAM-1) of endothelial function from baseline to 12 weeks
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Linagliptin	Placebo
Arm/Group Description	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.	The subjects will receive placebo. Placebo: The subject will receive placebo orally once daily for 12 weeks.
Measure Participants	20	23
Median (Inter-Quartile Range) [ng/ml]	-15	-21

4. Secondary Outcome

Title	Changes in the Area Under Curve (AUC) of Glucose, Insulin and C-peptide During the Meal Tolerance Test From Baseline to 12 Weeks
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Linagliptin	Placebo
Arm/Group Description	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.	The subjects will receive placebo. Placebo: The subject will receive placebo orally once daily for 12 weeks.
Measure Participants	20	23
Glucose AUC	-1135 (2619)	481 (3185)
C-peptide AUC	-3 (161)	-34 (211)
Insulin AUC	249 (4766)	40 (6357)

5. Secondary Outcome

Title	Changes in the Area Under Curve (AUC) of Free Fatty Acids During the Meal Tolerance Test From Baseline to 12 Weeks
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Linagliptin	Placebo
Arm/Group Description	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.	The subjects will receive placebo. Placebo: The subject will receive placebo orally once daily for 12 weeks.
Measure Participants	20	23
Mean (Standard Deviation) [µmol*min/l]	2.0 (28.4)	-3.1 (18.3)

6. Secondary Outcome

Title	Changes in Biochemical Markers (svCAM-1)
Description	Soluble cell adhesion molecules-1 (svCAM-1) of endothelial function from baseline to 12 weeks
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Linagliptin	Placebo
Arm/Group Description	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.	The subjects will receive placebo. Placebo: The subject will receive placebo orally once daily for 12 weeks.
Measure Participants	20	23
Mean (Standard Deviation) [ng/ml]	-34 (84)	5 (130)

Adverse Events

Time Frame	Adverse events were collected for 16 weeks (12 weeks of intervention and 4 weeks of follow-up).
Arm/Group Title	Linagliptin		Placebo
Arm/Group Description	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.		The subjects will receive placebo. Placebo: The subject will receive placebo orally once daily for 12 weeks.
All Cause Mortality
	Linagliptin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/23 (0%)
Serious Adverse Events
	Linagliptin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/20 (15%)		1/23 (4.3%)
Gastrointestinal disorders
Abdominal pain	1/20 (5%)	1	0/23 (0%)	0
Infections and infestations
Borreliosis	0/20 (0%)	0	1/23 (4.3%)	1
Musculoskeletal and connective tissue disorders
discus prolaps	1/20 (5%)	1	0/23 (0%)	0
Nervous system disorders
Coordinating disorders	1/20 (5%)	1	0/23 (0%)	0
Other (Not Including Serious) Adverse Events
	Linagliptin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/20 (10%)		3/23 (13%)
Cardiac disorders
Hypotension	0/20 (0%)	0	1/23 (4.3%)	1
Gastrointestinal disorders
Toothache	1/20 (5%)	1	0/23 (0%)	0
General disorders
Nausea	1/20 (5%)	1	1/23 (4.3%)	1
Nervous system disorders
Dorsal pain	1/20 (5%)	1	0/23 (0%)	0
Vascular disorders
Claudicatio intermittens	0/20 (0%)	0	1/23 (4.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.