Linagliptin's Effect on CD34+ Stem Cells

Sponsor

George Washington University (Other)

Overall Status

Completed

CT.gov ID

NCT02467478

Collaborator

Boehringer Ingelheim (Industry)

Enrollment

Location

Arms

Actual Duration (Months)

0.6

Patients Per Site Per Month

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Impaired Renal Function	Drug: Linagliptin Drug: Placebo	Phase 4

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).

Study Design

Study Type:

Interventional

Actual Enrollment :

31 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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.

Actual Study Start Date :

Apr 1, 2015

Actual Primary Completion Date :

Apr 1, 2019

Actual Study Completion Date :

Dec 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Matching placebo 1 pill daily for 12 weeks	Drug: Placebo 1 tablet daily for 12 weeks
Active Comparator: Linagliptin Linagliptin 5mg once daily for 12 weeks	Drug: Linagliptin 5 mg tablet once daily for 12 weeks Other Names: TRADJENTA

Arm

Intervention/Treatment

Placebo Comparator: Placebo

Matching placebo 1 pill daily for 12 weeks

Drug: Placebo

1 tablet daily for 12 weeks

Active Comparator: Linagliptin

Linagliptin 5mg once daily for 12 weeks

Drug: Linagliptin

5 mg tablet once daily for 12 weeks

Other Names:

TRADJENTA

Outcome Measures

Primary Outcome Measures

Cellular Markers [Up to 12 weeks post Linagliptin]
The investigators will use participants' peripheral blood derived CD34+ cells looking at number, function, and gene expression. This will be correlated to improvement in 24hr urinary protein estimation and creatinine clearance. Post Linagliptin will be compared to pre Linagliptin measurements.
Urinary Function Marker in CKD [6 to 12 weeks post Linagliptin]
We measure using microalbumin/creatinine ratio provided from a random spot urine sample.

Secondary Outcome Measures

Serum Endothelial Inflammatory Markers [6 to 12 weeks post Linagliptin]
Serum endothelial inflammatory markers will include: high sensitivity C-reactive protein (hs-CRP), IL-6, and TNF-alpha
Fasting lipid profile [6 to 12 weeks post Linagliptin]
Measured through serum biochemistry Lipid Panel
Glycemic control [6 to 12 weeks post Linagliptin]
Glycemic control is evaluated by measuring fasting blood glucose, insulin, and HbA1c levels and assessing insulin resistance using homeostatic model assessment insulin resistance (HOMA-IR)
Adiposity [6 to 12 weeks post Linagliptin]
Measured using the Tanita Body Composition Analyzer scale, measured as percentage body fat.
Estimation of Creatinine clearance [6 to 12 weeks post Linagliptin]
Measured via blood biochemistry eGFR, and spot urine urine microalbumin/creatinine ratio
Vessel Health [6 to 12 weeks post Linagliptin]
Vessel health is assessed by looking at systolic and diastolic blood pressure, Arterial stiffness, and central and aortic blood pressure (which are assessed using Vascular Flow and wave measurement equipment, SphygmoCor Central Pressure system from AtCor).
Resting Metabolic Rate (RMR) [6 to 12 weeks post Linagliptin]
(RMR, similar to Resting Energy expenditure measurement) at baseline and post therapy.

Eligibility Criteria

Criteria

Ages Eligible for Study:

30 Years to 70 Years

Sexes Eligible for Study:

All

Accepts 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.