Linagliptin's Effect on CD34+ Stem Cells
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|ClinicalTrials.gov Identifier: NCT02467478|
Recruitment Status : Recruiting
First Posted : June 10, 2015
Last Update Posted : August 7, 2018
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|
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 Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||40 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|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 :||April 2015|
|Estimated Primary Completion Date :||April 2019|
|Estimated Study Completion Date :||December 2019|
Placebo Comparator: Placebo
Matching placebo 1 pill daily for 12 weeks
1 tablet daily for 12 weeks
Active Comparator: Linagliptin
Linagliptin 5mg once daily for 12 weeks
5 mg tablet once daily for 12 weeks
Other Name: TRADJENTA
- Cellular Markers [ Time Frame: 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 [ Time Frame: 6 to 12 weeks post Linagliptin ]We measure using microalbumin/creatinine ratio provided from a random spot urine sample.
- Serum Endothelial Inflammatory Markers [ Time Frame: 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 [ Time Frame: 6 to 12 weeks post Linagliptin ]Measured through serum biochemistry Lipid Panel
- Glycemic control [ Time Frame: 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 [ Time Frame: 6 to 12 weeks post Linagliptin ]Measured using the Tanita Body Composition Analyzer scale, measured as percentage body fat.
- Estimation of Creatinine clearance [ Time Frame: 6 to 12 weeks post Linagliptin ]Measured via blood biochemistry eGFR, and spot urine urine microalbumin/creatinine ratio
- Vessel Health [ Time Frame: 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) [ Time Frame: 6 to 12 weeks post Linagliptin ](RMR, similar to Resting Energy expenditure measurement) at baseline and post therapy.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02467478
|Contact: Fiona Dore, BSemail@example.com|
|Contact: Nicole Swanson, MSfirstname.lastname@example.org|
|United States, District of Columbia|
|The George Washington University Medical Faculty Associates||Recruiting|
|Washington, District of Columbia, United States, 20037|
|Contact: Fiona Dore, BS 202-741-2342 email@example.com|
|Principal Investigator:||Sabyasachi Sen, MD, PhD||Medical Faculty Associates|