Linagliptin's Effect on CD34+ Stem Cells

Role of Linagliptin in Improving Renal Failure by Improving CD34+ Stem Cell Number, Function and Gene Expression in Renal Function Impaired Type 2 Diabetes Patients.

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02467478

Enrollment

Registered

2015-06-10

Start date

2015-04-30

Completion date

2019-12-31

Last updated

2023-01-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Impaired Renal Function, Type 2 Diabetes

Keywords

Diabetes Mellitus, Type 2, Endothelial cells, Cellular biomarker, endothelial dysfunction, CD34+, Impaired renal function

Brief summary

Type 2 diabetes is a national epidemic. Diabetes has undesirable effects on blood vessels which may contribute to heart disease. Endothelial Progenitor Cells (EPCs) are found in the blood. Research has shown that improving the survival of these special blood cells may decrease the harmful effects of diabetes on blood vessels and reduce or reverse heart disease. Linagliptin is an Food and Drug Administration (FDA) approved prescription medicine used along with insulin or with oral medications to lower blood sugar in people with Type 2 diabetes. It is in a class of diabetes medication called Dipeptidyl peptidase-4 (DPP-4) inhibitors. DPP-4 inhibitors have been shown to increase EPCs in patients with Type 2 diabetes. Hypothesis: Both type 2 diabetes and Chronic Kidney Disease (CKD) are associated with poor stem cell number and function. Poor viability and function of EPCs in CKD and diabetes The investigators hypothesize that use of Linagliptin (along with Insulin) may help reduce cardiovascular risk by improving EPC survival and function above and beyond adequate glucose metabolism control

Detailed description

Type 2 diabetes is a national epidemic with significant macro and microvascular complications. Insulin resistance in pre-diabetes and overt diabetes are associated with endothelial dysfunction. A few studies indicate that stem cells particularly EPCs can act as a suitable bio-marker for monitoring cardiovascular morbidity. In this proposal the investigators suggest that EPCs or CD34 positive cells (defined as CD34/vascular endothelial growth factor receptor 2 (VEGFR2+) cells) can act as a suitable cellular biomarker for estimating and following endothelial dysfunction in early type 2 diabetes patients with CKD. EPCs have been shown to be dysfunctional in both CKD patients and type 2 Diabetes Mellitus (DM) patients. Linagliptin (TRADJENTA) tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. No dose adjustment is recommended for patients with renal impairment. EPCs have been used as a regenerative tool in ischemic myocardium and diabetic wound healing. Endothelial dysfunction with associated inflammation may be a consequence of excess intra-cellular super-oxide presence in a setting of diabetes which is a pro-oxidative stress condition ultimately leading to poor EPC function and senescence. Though lifestyle modification has been proposed as a main stay for prevention and treatment of early type 2 diabetes, several new therapies for diabetes have been developed in recent years. Incretins and incretin mimetics appear to hold promise. Mechanism of positive effect of exercise and oral hypoglycemic agents can be very different. DPP-4 inhibitors have been shown to increase EPCs in patients with type 2 diabetes reportedly via stromal cell-derived factor 1 (SDF-1) alpha up-regulation. Interestingly, up-regulation of SDF-1 alpha and vascular endothelial growth factor (VEGF), both chemotactic factors increase mobilization and recruitment of EPCs in the face of acute ischemic injury for repair and regeneration. Several studies have shown positive effect of incretins (Glucagon like peptide, GLP-1) and incretin receptor agonists (GLP-1 receptor agonists) on cardiovascular risk factors in type 2 diabetes patients and even in patients with chronic heart failure and left ventricular dysfunction who do not have diabetes. DPP-4 Inhibitors may have cardio-protective effects of their own, as they increase bio-availability of endogenous GLP-1. They improve blood flow and nitric oxide production in endothelium. These are unique properties not demonstrated by other oral diabetes medications. The mechanism underlying these effects may be mediated by increased nitric oxide bioavailability but is not completely known. However these beneficial effects appear to be independent of glycemia reduction. It is however unknown whether Linagliptin will have any positive effect on human EPC function where two prominent cardiovascular risk factors co-exist such as CKD and type 2 diabetes. Therefore the investigators plan to investigate if Linagliptin can alter function and gene expression of CD34+ cells in a setting of CKD and type 2 diabetes. The investigators choose to look at non geriatric adult population with early type 2 diabetes (less than 10 years of duration) at an early phase of renal impairment (stages 1-3).

Interventions

DRUGLinagliptin

5 mg tablet once daily for 12 weeks

DRUGPlacebo

1 tablet daily for 12 weeks

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

30 Years to 70 Years

Healthy volunteers

Inclusion criteria

* Adults aged 30-70 years * Diagnosis of type 2 diabetes within the previous 15 years using criteria of the American Diabetes Association * Currently being treated with 1-2 grams/day of metformin, or insulin or both stably * Hemoglobin A1c (HbA1C) between 6.5% to 10.0% (both inclusive) * Body Mass Index (BMI) between 25 and 39.9 kg/m2 (both inclusive) * Chronic Kidney disease (CKD) Stages 1-3, Creatinine clearance (CrCl) less than 90 and more than 29

Exclusion criteria

* Type 1 diabetes * History of Diabetic Ketoacidosis (DKA) or hyperosmolar nonketotic coma * Hemoglobinopathies with low hematocrit (Below 28 Units) * History of pancreatitis * History of cancer within the past 5 years (except basal cell carcinoma) * Previous cardiovascular or cerebrovascular event within 6 months of screening or active or clinically significant coronary and/or Peripheral Vascular Disease (PVD) * Statin use started in the last 3 month * Current use of oral or injectable anti-diabetic medication other than Metformin and insulin * Consistent use of steroids within the last 3 months * Any active wounds, or surgery within the past 3 months * Inflammatory disease, or the chronic use of anti-inflammatory drugs within the past 3 months * Untreated hyper/hypothyroidism * Contraindications to moderate exercise * Implanted devices that might interact with the tanita scale * Pre-existing liver disease and/or Alanine aminotransferase (ALT) and Aspartate Aminotransferase (AST) \> 2.5 times Under the Normal Limits (UNL) * Untreated Systolic blood pressure \> 140 mmHg or diastolic blood pressure\> 90 mmHg * Serum creatinine levels ≥ 2.0 * CKD Stages 4 and 5 (estimated CrCl \<30 mL/min) * Triglycerides \> 450 mg/dL * Known allergies or hypersensitivities to Linagliptin or Dipeptidyl peptidase-4 (DDP-4) inhibitors * Treatment with cytochrome p450 (CYP 3A4) inhibitors * Women of child bearing age who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study * Prisoners or subjects that are involuntarily incarcerated * Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g. infectious disease) illness * Additionally, patients who are active smokers, patients who are pregnant, nursing women, and post-menopausal women who are on hormone replacement therapy will be excluded.

Design outcomes

Primary

Measure	Time frame	Description
Cellular Markers	Week 12 expression as a fold difference to Week 0	The investigators will use participants' peripheral blood derived CD34+ cells looking at number, function, and gene expression. Post Linagliptin will be compared to pre Linagliptin measurements. Here we report fold changes in protein populations as determined by ELISA.
Urinary Function Marker in CKD	12 weeks post beginning Linagliptin or placebo treatment	We measure using microalbumin/creatinine ratio provided from a random spot urine sample.

Secondary

Measure	Time frame	Description
Glycemic Control	12 weeks post beginning Linagliptin or placebo treatment	Glycemic control is evaluated by measuring HbA1c levels to gauge changes in blood sugar control over last \ 90 days
Glycemic Control: Fasting Glucose	12 weeks post beginning Linagliptin or placebo treatment	Glycemic control is evaluated by measuring fasting blood glucose at time of measurement
Glycemic Control: Insulin	12 weeks post beginning Linagliptin or placebo treatment	Glycemic control is evaluated by measuring insulin levels at the time of the visit
Adiposity	12 weeks post beginning Linagliptin or placebo treatment	Measured using the Tanita Body Composition Analyzer scale, measured as percentage body fat.
Serum Endothelial Inflammatory Markers	12 weeks post Linagliptin or Placebo treatment	Serum endothelial inflammatory markers included here: high sensitivity C-reactive protein (hs-CRP)
Pulse Wave Analysis	12 weeks post beginning Linagliptin or placebo treatment	Vessel health is assessed by looking at Arterial stiffness. Augmentation index (AI) is defined as the ratio of the augmentation pressure to the pulse pressure, times 100, to give a percentage. Augmentation index 75 normalizes this value to an estimate of the AI at a heart rate of 75bpm. We used Vascular Flow and wave measurement equipment, SphygmoCor Central Pressure system from AtCor.
Pulse Wave Velocity	12 weeks post beginning Linagliptin or placebo treatment	Vessel health is assessed by looking at Arterial stiffness. Pulse wave velocity (PWV) measures the delay between the pulse registered at the femoral artery from the pulse at the carotid. The difference in distance between these two measurement points from the aortic notch is divided by this delay to give a speed. In stiffer, less healthy vessels, the PWV is increased. We used Vascular Flow and wave measurement equipment, SphygmoCor Central Pressure system from AtCor to perform this calculation.
Resting Metabolic Rate (RMR)	12 weeks post beginning Linagliptin or placebo treatment	(RMR, similar to Resting Energy expenditure measurement): Evaluation of changes in Basal Metabolic Rate
Estimation of Creatinine Clearance	12 weeks post beginning Linagliptin or placebo treatment	Measured via blood biochemistry eGFR, an alternative measurement to spot urine urine microalbumin/creatinine ratio presented above
Fasting Lipid Profile	12 weeks post beginning Linagliptin or placebo treatment	Measured through serum biochemistry Lipid Panel

Countries

United States

Participant flow

Participants by arm

Arm	Count
Placebo Matching placebo 1 pill daily for 12 weeks Placebo: 1 tablet daily for 12 weeks	17
Linagliptin Linagliptin 5mg once daily for 12 weeks Linagliptin: 5 mg tablet once daily for 12 weeks	14
Total	31

Baseline characteristics

Characteristic	Linagliptin	Placebo	Total
Age, Customized	61 years STANDARD_DEVIATION 5	63 years STANDARD_DEVIATION 6	62.09 years STANDARD_DEVIATION 1.4
Basal Metabolic Rate	1868 Calories/day STANDARD_DEVIATION 293	1476 Calories/day STANDARD_DEVIATION 448	1653 Calories/day STANDARD_DEVIATION 134
BMI	31.2 kg/m^2 STANDARD_DEVIATION 4.4	30.6 kg/m^2 STANDARD_DEVIATION 2.9	30.8 kg/m^2 STANDARD_DEVIATION 0.42
BP Diastolic	81 mmHg STANDARD_DEVIATION 7	77 mmHg STANDARD_DEVIATION 7	79 mmHg STANDARD_DEVIATION 7
BP Systolic	128 mmHg STANDARD_DEVIATION 10	133 mmHg STANDARD_DEVIATION 18	131 mmHg STANDARD_DEVIATION 14
Cholesterol	166 mg STANDARD_DEVIATION 52	168 mg STANDARD_DEVIATION 53	167 mg STANDARD_DEVIATION 0.7
eGFR	83 mL/min/1.73m^2 STANDARD_DEVIATION 21	84 mL/min/1.73m^2 STANDARD_DEVIATION 19	83.5 mL/min/1.73m^2 STANDARD_DEVIATION 1.41
Fasting Glucose	125 mg/dl STANDARD_DEVIATION 26	130 mg/dl STANDARD_DEVIATION 44	127.5 mg/dl STANDARD_DEVIATION 12.72
HbA1c	7.1 percentage of hemoglobin STANDARD_DEVIATION 0.7	7.4 percentage of hemoglobin STANDARD_DEVIATION 1	7.26 percentage of hemoglobin STANDARD_DEVIATION 0.21
Percent Fat	30 percentage STANDARD_DEVIATION 10	38 percentage STANDARD_DEVIATION 10	34 percentage STANDARD_DEVIATION 10
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	8 Participants	12 Participants	20 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	3 Participants	1 Participants	4 Participants
Race (NIH/OMB) White	3 Participants	4 Participants	7 Participants
Required to be on stable dose of Metformin and/or Insulin Insulin	4 participants	6 participants	10 participants
Required to be on stable dose of Metformin and/or Insulin Metformin	12 participants	14 participants	26 participants
Serum Creatinine	1.1 mg/dL STANDARD_DEVIATION 0.4	0.9 mg/dL STANDARD_DEVIATION 0.3	1 mg/dL STANDARD_DEVIATION 0.07
Sex: Female, Male Female	3 Participants	10 Participants	13 Participants
Sex: Female, Male Male	11 Participants	7 Participants	18 Participants
Waist cm	107 centimeters STANDARD_DEVIATION 17	105 centimeters STANDARD_DEVIATION 8	106 centimeters STANDARD_DEVIATION 12

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 17	0 / 14
other Total, other adverse events	0 / 17	0 / 14
serious Total, serious adverse events	1 / 17	1 / 14

Outcome results

Primary

Cellular Markers

The investigators will use participants' peripheral blood derived CD34+ cells looking at number, function, and gene expression. Post Linagliptin will be compared to pre Linagliptin measurements. Here we report fold changes in protein populations as determined by ELISA.

Time frame: Week 12 expression as a fold difference to Week 0

Arm	Measure	Group	Value (MEAN)	Dispersion
Placebo	Cellular Markers	VEGFA	1.43 Fold Change	Standard Deviation 1.2
Placebo	Cellular Markers	SOD2	1.40 Fold Change	Standard Deviation 1.34
Placebo	Cellular Markers	SOD3	1.13 Fold Change	Standard Deviation 0.81
Placebo	Cellular Markers	GPX3	1.59 Fold Change	Standard Deviation 1.4
Placebo	Cellular Markers	PECAM	1.48 Fold Change	Standard Deviation 1.11
Linagliptin	Cellular Markers	GPX3	1.36 Fold Change	Standard Deviation 1.32
Linagliptin	Cellular Markers	PECAM	2.48 Fold Change	Standard Deviation 2.8
Linagliptin	Cellular Markers	VEGFA	2.4 Fold Change	Standard Deviation 2.91
Linagliptin	Cellular Markers	SOD3	1.15 Fold Change	Standard Deviation 0.86
Linagliptin	Cellular Markers	SOD2	2.47 Fold Change	Standard Deviation 4.27

Primary