A Phase 4 interventional study of Linagliptin and Placebo in Type 2 Diabetes and Impaired Renal Function, sponsored by George Washington University. Completed at 1 site in United States. Open to participants aged 30 Years to 70 Years. Per ClinicalTrials.gov, last updated 2023-01-19.
Sponsored by George Washington University · Phase 4, Interventional, and Treatment
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
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).
1,995 studies on the registry are indexed under Renal Insufficiency; 173 are open to participants now.
This study's enrollment of 31 is below the median of 43 across 1,504 interventional studies indexed under Renal Insufficiency.
Browse Renal Insufficiency studies →George Washington University is the lead sponsor of 187 studies on the registry; 34 are open to participants now.
Of its 13 completed or terminated interventional studies of FDA-regulated products, 11 (85%) have results posted.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
Matching placebo 1 pill daily for 12 weeks
Drug: Placebo
Linagliptin 5mg once daily for 12 weeks
Drug: Linagliptin
5 mg tablet once daily for 12 weeks
Also known as: TRADJENTA
1 tablet daily for 12 weeks
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
Urinary Function Marker in CKD
We measure using microalbumin/creatinine ratio provided from a random spot urine sample.
Time frame: 12 weeks post beginning Linagliptin or placebo treatment
Serum Endothelial Inflammatory Markers
Serum endothelial inflammatory markers included here: high sensitivity C-reactive protein (hs-CRP)
Time frame: 12 weeks post Linagliptin or Placebo treatment
Serum Endothelial Inflammatory Markers
Serum endothelial inflammatory markers included here: Interleukin 6 (IL-6)
Time frame: 12 weeks post Linagliptin or Placebo treatment
Fasting Lipid Profile
Measured through serum biochemistry Lipid Panel
Time frame: 12 weeks post beginning Linagliptin or placebo treatment
Glycemic Control
Glycemic control is evaluated by measuring HbA1c levels to gauge changes in blood sugar control over last \~90 days
Time frame: 12 weeks post beginning Linagliptin or placebo treatment
Glycemic Control: Fasting Glucose
Glycemic control is evaluated by measuring fasting blood glucose at time of measurement
Time frame: 12 weeks post beginning Linagliptin or placebo treatment
Glycemic Control: Insulin
Glycemic control is evaluated by measuring insulin levels at the time of the visit
Time frame: 12 weeks post beginning Linagliptin or placebo treatment
Adiposity
Measured using the Tanita Body Composition Analyzer scale, measured as percentage body fat.
Time frame: 12 weeks post beginning Linagliptin or placebo treatment
Estimation of Creatinine Clearance
Measured via blood biochemistry eGFR, an alternative measurement to spot urine urine microalbumin/creatinine ratio presented above
Time frame: 12 weeks post beginning Linagliptin or placebo treatment
Pulse Wave Analysis
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.
Time frame: 12 weeks post beginning Linagliptin or placebo treatment
Pulse Wave Velocity
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.
Time frame: 12 weeks post beginning Linagliptin or placebo treatment
Resting Metabolic Rate (RMR)
(RMR, similar to Resting Energy expenditure measurement): Evaluation of changes in Basal Metabolic Rate
Time frame: 12 weeks post beginning Linagliptin or placebo treatment
| Milestone | Placebo | Linagliptin |
|---|---|---|
| Started | 17 | 14 |
| Completed | 17 | 14 |
| Not completed | 0 | 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.
| Fold Change | Placebo | Linagliptin |
|---|---|---|
| PECAM | 1.48 ± 1.11 | 2.48 ± 2.80 |
| VEGFA | 1.43 ± 1.2 | 2.4 ± 2.91 |
| SOD3 | 1.13 ± 0.81 | 1.15 ± 0.86 |
| SOD2 | 1.40 ± 1.34 | 2.47 ± 4.27 |
| GPX3 | 1.59 ± 1.40 | 1.36 ± 1.32 |
We measure using microalbumin/creatinine ratio provided from a random spot urine sample.
| ratio | Placebo | Linagliptin |
|---|---|---|
| Urinary Function Marker in CKD | 51.12 ± 99.55 | 39.70 ± 68.92 |
Serum endothelial inflammatory markers included here: high sensitivity C-reactive protein (hs-CRP)
| mg/L | Placebo | Linagliptin |
|---|---|---|
| Serum Endothelial Inflammatory Markers | 3.08 ± 3.41 | 5.17 ± 6.54 |
Serum endothelial inflammatory markers included here: Interleukin 6 (IL-6)
| pg/mL | Placebo | Linagliptin |
|---|---|---|
| Serum Endothelial Inflammatory Markers | 2.18 ± 1.45 | 5.09 ± 6.08 |
Measured through serum biochemistry Lipid Panel
| mg/dl | Placebo | Linagliptin |
|---|---|---|
| Cholesterol | 171.45 ± 48.49 | 159.69 ± 48.53 |
| Triglycerides | 127.76 ± 79.04 | 124.31 ± 50.67 |
Glycemic control is evaluated by measuring HbA1c levels to gauge changes in blood sugar control over last \~90 days
| percentage of hemoglobin | Placebo | Linagliptin |
|---|---|---|
| Glycemic Control | 7.27 ± 0.73 | 6.66 ± 0.40 |
Glycemic control is evaluated by measuring fasting blood glucose at time of measurement
| mg/dL | Placebo | Linagliptin |
|---|---|---|
| Glycemic Control: Fasting Glucose | 129.68 ± 46.78 | 109.93 ± 16.81 |
Glycemic control is evaluated by measuring insulin levels at the time of the visit
| mIU/L | Placebo | Linagliptin |
|---|---|---|
| Glycemic Control: Insulin | 20.82 ± 12.6 | 20.52 ± 19.7 |
Measured using the Tanita Body Composition Analyzer scale, measured as percentage body fat.
| percentage of body fat | Placebo | Linagliptin |
|---|---|---|
| Adiposity | 30.6 ± 2.9 | 31.2 ± 4.4 |
Measured via blood biochemistry eGFR, an alternative measurement to spot urine urine microalbumin/creatinine ratio presented above
| mL/min/1.73m^2 | Placebo | Linagliptin |
|---|---|---|
| Estimation of Creatinine Clearance | 84.12 ± 19.81 | 79.46 ± 19.9 |
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.
| Percentage (of pulse pressure) | Placebo | Linagliptin |
|---|---|---|
| Augmentation Index 75 | 21.37 ± 11.49 | 22.33 ± 12 |
| Augmentation Index | 24.17 ± 12.93 | 24.93 ± 14.37 |
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.
| m/s | Placebo | Linagliptin |
|---|---|---|
| Pulse Wave Velocity | 10.23 ± 8.65 | 10.53 ± 8.58 |
(RMR, similar to Resting Energy expenditure measurement): Evaluation of changes in Basal Metabolic Rate
| Calories/day | Placebo | Linagliptin |
|---|---|---|
| Resting Metabolic Rate (RMR) | 1650.07 ± 428.52 | 1657.6 ± 445.45 |
Collected over Adverse event data was collected from signing of informed consent to 30 days post final visit (approximately 16 weeks). Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Placebo | 0/17 (0%) | 1/17 (5.9%) | 0/17 (0%) |
| Linagliptin | 0/14 (0%) | 1/14 (7.1%) | 0/14 (0%) |
| Event | Placebo | Linagliptin |
|---|---|---|
| Kidney StoneRenal and urinary disorders | 1/17 | 1/14 |
| Bacterial AbscessSkin and subcutaneous tissue disorders | 1/17 | 1/14 |
| Age, Customized(years) | Placebo | Linagliptin | Total |
|---|---|---|---|
| Mean | 63 ± 6 | 61 ± 5 | 62.09 ± 1.4 |
| Sex: Female, Male(Participants) | Placebo | Linagliptin | Total |
|---|---|---|---|
| Female | 10 | 3 | 13 |
| Male | 7 | 11 | 18 |
| Race (NIH/OMB)(Participants) | Placebo | Linagliptin | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 12 | 8 | 20 |
| White | 4 | 3 | 7 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 1 | 3 | 4 |
| BMI(kg/m^2) | Placebo | Linagliptin | Total |
|---|---|---|---|
| Mean | 30.6 ± 2.9 | 31.2 ± 4.4 | 30.8 ± .42 |
| HbA1c(percentage of hemoglobin) | Placebo | Linagliptin | Total |
|---|---|---|---|
| Mean | 7.4 ± 1 | 7.1 ± 0.7 | 7.26 ± .21 |
| Required to be on stable dose of Metformin and/or Insulin(participants) | Placebo | Linagliptin | Total |
|---|---|---|---|
| Metformin | 14 | 12 | 26 |
| Insulin | 6 | 4 | 10 |
| BP(mmHg) | Placebo | Linagliptin | Total |
|---|---|---|---|
| Systolic | 133 ± 18 | 128 ± 10 | 131 ± 14 |
| Diastolic | 77 ± 7 | 81 ± 7 | 79 ± 7 |
| Percent Fat(percentage) | Placebo | Linagliptin | Total |
|---|---|---|---|
| Mean | 38 ± 10 | 30 ± 10 | 34 ± 10 |
6 further baseline measures are reported on the registry.
Documents are hosted by the registry — open the source record to download them.
Plan to share: No — There is no current plan to share IPD with other researchers.
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