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Rapid Effects Linagliptin on Monocyte Polarization and Endothelial Progenitor Cells in Type 2 Diabetes

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ClinicalTrials.gov Identifier: NCT01617824
Recruitment Status : Completed
First Posted : June 12, 2012
Last Update Posted : December 19, 2014
Sponsor:
Information provided by (Responsible Party):
University of Padova

Tracking Information
First Submitted Date  ICMJE June 3, 2012
First Posted Date  ICMJE June 12, 2012
Last Update Posted Date December 19, 2014
Study Start Date  ICMJE September 2012
Actual Primary Completion Date December 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 18, 2014)
M1/M2 polarization balance [ Time Frame: day 5 ]
Evaluate whether 4-days Linagliptin treatment, compared to placebo, significantly reduces the M1/M2 ratio in type 2 diabetic patients. In this cross-over design trial, Linagliptin and placebo will be administered once daily for 4 consecutive days to 30 type 2 diabetic patients with or without renal failure with a 2 week washout period in between.
Original Primary Outcome Measures  ICMJE
 (submitted: June 9, 2012)
M1/M2 polarization balance [ Time Frame: 4 days ]
Evaluate whether 5-days Linagliptin treatment, compared to placebo, significantly reduces the M1/M2 ratio in type 2 diabetic patients. In this cross-over design trial, Linagliptin and placebo will be administered once daily for 4 consecutive days to 30 type 2 diabetic patients with or without renal failure with a 2 week washout period in between.
Change History Complete list of historical versions of study NCT01617824 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 18, 2014)
  • Cytokine and chemokine concentrations [ Time Frame: day 5 ]
    Evaluate whether 4-days Linagliptin treatment, compared to placebo, significantly modifies the concentrations of selected cytokines and chemokines (MCP-1, RANTES, SDF-1a, IL-1, IL-6, TNF-a, IL-10, TGF-beta, CCL22, fraktalkine) in type 2 diabetic patients. In this cross-over design trial, Linagliptin and placebo will be administered once daily for 4 consecutive days to 30 type 2 diabetic patients with and without renal failure with a 2 week washout period in between. As the number of measures is high and there is no adjustment for multiple testing, this outcome is to be considered exploratory.
  • Endothelial progenitor cell levels [ Time Frame: day 5 ]
    Evaluate whether 4-days Linagliptin treatment, compared to placebo, significantly modifies the levels of CD34+KDR+ EPCs (outcome added in course)
Original Secondary Outcome Measures  ICMJE
 (submitted: June 9, 2012)
Cytokine and chemokine concentrations [ Time Frame: 4 days ]
Evaluate whether 5-days Linagliptin treatment, compared to placebo, significantly modifies the concentrations of selected cytokines and chemokines (MCP-1, RANTES, SDF-1a, IL-1, IL-6, TNF-a, IL-10, TGF-beta, CCL22, fraktalkine) in type 2 diabetic patients. In this cross-over design trial, Linagliptin and placebo will be administered once daily for 4 consecutive days to 30 type 2 diabetic patients with and without renal failure with a 2 week washout period in between. As the number of measures is high and there is no adjustment for multiple testing, this outcome is to be considered exploratory.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Rapid Effects Linagliptin on Monocyte Polarization and Endothelial Progenitor Cells in Type 2 Diabetes
Official Title  ICMJE Rapid Effects of the DPP-4 Inhibitor Linagliptin on Monocyte Polarization and Endothelial Progenitor Cells in Type 2 Diabetic Patients With and Without Chronic Renal Failure. A Randomized Cross-over Trial Versus Placebo
Brief Summary

Diabetes mellitus is characterized by chronic low grade inflammation, which is worsened by the co-existence of renal failure.

One key aspect of chronic inflammatory diseases is the alteration in the polarization profile of circulating monocyte-macrophage cells.

Namely, monocytes-macrophages can exist in a pro-inflammatory (M1) polarized form or an anti-inflammatory (M2) polarized state. Alterations in the M1/M2 balance is thought to contribute to inflammation within atherosclerotic lesions and visceral adipose tissue which, in turn, can worsen cardiovascular disease and metabolic features in type 2 diabetic patients.

M1 and M2 are regulated by a complex interplay of soluble signaling molecules, many of which are substrate of the enzyme DPP-4 (dipeptidyl peptidase-4). Therefore, inhibition of DPP-4 can affect the M1/M2 polarization balance.

In this clinical trial, the investigators will test whether the DPP-4 inhibitor Linagliptin, compared to placebo, modifies the M1/M2 balance in type 2 diabetic patients with and without chronic renal failure.

In addition, we will test whether DPP-4 inhibition with Linagliptin acutely affects endothelial progenitor cells (EPCs), which are vasculoprotective cells implicated in the pathobiology of diabetic complications.

Detailed Description

Type 2 diabetes is associated with chronic sterile low-grade inflammation, usually caused by hyperglycemia and associated biochemical abnormalities, as well as by overweight/obesity. The co-existence of chronic renal failure further exacerbates inflammation in diabetic patients, and this contributes to the exceedingly high morbidity and mortality of this category of patients. One key element of this type of inflammation is the pro- versus anti-inflammatory polarization of circulating monocytes and tissue macrophages. Diabetes indeed causes an imbalance of this polarization, in favour of the pro-inflammatory (M1) monocytes at the expenses of anti-inflammatory (M2) monocytes. Cells belonging to the monocyte/macrophage lineage are of great importance in diabetes pathophysiology, as they are involved in atherosclerosis and adipose tissue biology, both of which determine diabetes outcomes. It is recognized that M1/M2 polarization relies on the expression of chemokines/cytokines and their respective receptors. Interestingly, among non-incretin substrates of DPP-4 are several chemokines (e.g. MCP-1 and -2, RANTES and SDF-1a), which may regulate M1/M2 polarization. Linagliptin (terminal half-life >100 hours, and effective half-life for accumulation approximately 12 hours) can be safely used in type 2 diabetic patients with renal impairment without dose adjusting, because the drug is excreted >90% with feces and has a minor renal excretion. The possibility to modulate the M1/M2 inflammatory pathway with the DPP-4 inhibitor linagliptin entails a hitherto unappreciated opportunity for protecting diabetic patients with renal disease from the detrimental consequences of chronic inflammation on vascular and adipose tissue biology. We have set up a protocol to assess M1/M2 polarization of circulating monocyte/macrophage cells by flow cytometry. Our preliminary data indicate that diabetes is associated with an imbalance in M1/M2 polarization versus non diabetic controls, in favour of M1 cells in diabetic patients. Hyperglycemia per se may affect M1/M2 polarization and it is expected that any effect of linagliptin on monocytes can be detected as soon as DPP-4 inhibition reaches steady-state. Therefore, in order to provide a proof-of-concept for the effect of linagliptin on M1/M2 polarization and to avoid the confounding of improved glucose control, the time point of the study will be very short (4 days). Our preliminary data in cell cultures indicate that a few days of treatment with a stimulus is sufficient to modulate monocyte/macrophage polarization. This will provide valuable information on the direct effects of the drug on this inflammatory pathway.

Endothelial progenitor cells (EPCs) are vasculoprotective cells released from the bone marrow (BM) in response to ischemia, hypoxia and tissue injury. Once in the bloodstream, EPCs home to damaged tissues and help restoring a healthy and functional vasculature, by means of endothelial repair and angiogenesis. In steady-state conditions, CD34+KDR+ EPCs circulate in peripheral blood (PB) at very low levels and their release from the BM is coordinated by the sympathetic nervous system. It has been demonstrated that levels of EPC and generic CD34+ PC are predictors of future cardiovascular events, cardiovascular death and all-cause mortality. We have previously shown that Sitagliptin raised EPCs levels in 4 weeks. Herein, we aim to confirm those findings using Linagliptin, with a shorter time point.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Participant)
Primary Purpose: Prevention
Condition  ICMJE
  • Type 2 Diabetes
  • Chronic Renal Failure
Intervention  ICMJE
  • Drug: Linagliptin
    Linagliptin 5 mg tablets for 4 days
    Other Name: Trajenta 5 mg
  • Drug: Placebo
    Placebo tablets for 4 days
Study Arms  ICMJE
  • Experimental: Linagliptin
    Linagliptin 5 mg tablets daily for 4 days
    Intervention: Drug: Linagliptin
  • Placebo Comparator: Placebo
    Placebo tablets 1 daily for 4 days
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 18, 2014)
45
Original Estimated Enrollment  ICMJE
 (submitted: June 9, 2012)
60
Actual Study Completion Date  ICMJE December 2014
Actual Primary Completion Date December 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Type 2 diabetes
  • eGFR > 60 mL/min/1.73 mq (for the patients without renal failure)
  • eGFR 10-60 mL/min/1.73 mq (for the patients with renal failure)

Exclusion Criteria:

  • Type 1 diabetes
  • Hypersensitivity to Linagliptin or excipients
  • Intolerance to other DPP-4 inhibitors
  • Terminal renal failure (eGFR < 10 mL/min/1.73 mq)
  • Use of GLP-1 analogs or other DPP-4 inhibitors
  • Recent (within 1 month) trauma or surgery or acute diseases
  • Any acute or chronic inflammatory condition
  • Immunosuppression or organ transplantation
  • Pregnancy or lactation
  • Inability to provide informed consent.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 35 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Italy
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01617824
Other Study ID Numbers  ICMJE 2588P
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University of Padova
Study Sponsor  ICMJE University of Padova
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Angelo Avogaro, M.D. Ph.D. University of Padova
Principal Investigator: Gian Paolo Fadini, M.D. University of Padova
PRS Account University of Padova
Verification Date December 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP