Rapid Effects Linagliptin on Monocyte Polarization in Type 2 Diabetes

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2013 by University of Padova
Sponsor:
Information provided by (Responsible Party):
University of Padova
ClinicalTrials.gov Identifier:
NCT01617824
First received: June 3, 2012
Last updated: December 9, 2013
Last verified: December 2013
  Purpose

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.


Condition Intervention Phase
Type 2 Diabetes
Chronic Renal Failure
Drug: Linagliptin
Drug: Placebo
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Single Blind (Subject)
Primary Purpose: Prevention
Official Title: Rapid Effects of the DPP-4 Inhibitor Linagliptin on Monocyte Polarization in Type 2 Diabetic Patients With and Without Chronic Renal Failure. A Randomized Cross-over Trial Versus Placebo

Resource links provided by NLM:


Further study details as provided by University of Padova:

Primary Outcome Measures:
  • M1/M2 polarization balance [ Time Frame: 4 days ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Cytokine and chemokine concentrations [ Time Frame: 4 days ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 60
Study Start Date: September 2012
Estimated Study Completion Date: October 2014
Estimated Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Linagliptin
Linagliptin 5 mg tablets daily for 4 days
Drug: Linagliptin
Linagliptin 5 mg tablets for 4 days
Other Name: Trajenta 5 mg
Placebo Comparator: Placebo
Placebo tablets 1 daily for 4 days
Drug: Placebo
Placebo tablets for 4 days

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.

  Eligibility

Ages Eligible for Study:   35 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Type 2 diabetes
  • eGFR > 60 mL/min/1.73 mq (for the 30 patients without rnal failure)
  • eGFR 10-60 mL/min/1.73 mq (for the 30 patients with rnal 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01617824

Contacts
Contact: Angelo Avogaro, M.D. Ph.D. +39 049 8212178 angelo.avogaro@unipd.it
Contact: Gian Paolo Fadini, M.D. +39 049 8214318 gianpaolo.fadini@unipd.it

Locations
Italy
University Hospital Diabetes Outpatient Clinic Recruiting
Padova, Italy, 35100
Contact: Angelo Avogaro, M.D. Ph.D.    +39 049 8213066    angelo.avogaro@unipd.it   
Contact: Gian Paolo Fadini, M.D.    +39 049 8214318    gianpaolo.fadini@unipd.it   
Principal Investigator: Angelo Avogaro, M.D. Ph.D.         
Sub-Investigator: Gian Paolo Fadini, M.D.         
Sponsors and Collaborators
University of Padova
Investigators
Study Chair: Angelo Avogaro, M.D. Ph.D. University of Padova
Principal Investigator: Gian Paolo Fadini, M.D. University of Padova
  More Information

No publications provided

Responsible Party: University of Padova
ClinicalTrials.gov Identifier: NCT01617824     History of Changes
Other Study ID Numbers: 2588P
Study First Received: June 3, 2012
Last Updated: December 9, 2013
Health Authority: Italy: Ministry of Health

Keywords provided by University of Padova:
Diabetes
Kidney
Inflammation
Metabolism

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Kidney Failure, Chronic
Renal Insufficiency
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Renal Insufficiency, Chronic
Kidney Diseases
Urologic Diseases
BI 1356
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Hypoglycemic Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on July 20, 2014