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

NCT ID: NCT01617824

Last Updated: 2014-12-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 45 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-09-30
• Study Completion Date: 2014-12-31

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.

Conditions

Type 2 Diabetes; Chronic Renal Failure

Keywords

Diabetes; Kidney; Inflammation; Metabolism

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: PREVENTION
• Blinding Strategy: SINGLE

Study Groups

Linagliptin

Linagliptin 5 mg tablets daily for 4 days

Group Type: EXPERIMENTAL

Linagliptin

Intervention Type: DRUG

Linagliptin 5 mg tablets for 4 days

Placebo

Placebo tablets 1 daily for 4 days

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo tablets for 4 days

Interventions

Linagliptin

Linagliptin 5 mg tablets for 4 days

Intervention Type: DRUG

Placebo

Placebo tablets for 4 days

Intervention Type: DRUG

Other Intervention Names

Trajenta 5 mg

Eligibility Criteria

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.

• Minimum Eligible Age: 35 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Padova

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Angelo Avogaro, M.D. Ph.D.

Role: STUDY_CHAIR

University of Padova

Gian Paolo Fadini, M.D.

Role: PRINCIPAL_INVESTIGATOR

University of Padova

Locations

University Hospital Diabetes Outpatient Clinic

Padua, , Italy

Countries

Italy

References

Fadini GP, Bonora BM, Albiero M, Zaninotto M, Plebani M, Avogaro A. DPP-4 inhibition has no acute effect on BNP and its N-terminal pro-hormone measured by commercial immune-assays. A randomized cross-over trial in patients with type 2 diabetes. Cardiovasc Diabetol. 2017 Feb 10;16(1):22. doi: 10.1186/s12933-017-0507-9.

Reference Type: DERIVED

PMID: 28183314 (View on PubMed)

Fadini GP, Bonora BM, Cappellari R, Menegazzo L, Vedovato M, Iori E, Marescotti MC, Albiero M, Avogaro A. Acute Effects of Linagliptin on Progenitor Cells, Monocyte Phenotypes, and Soluble Mediators in Type 2 Diabetes. J Clin Endocrinol Metab. 2016 Feb;101(2):748-56. doi: 10.1210/jc.2015-3716. Epub 2015 Dec 22.

Reference Type: DERIVED

PMID: 26695864 (View on PubMed)

Other Identifiers

2588P

Identifier Type: -

Identifier Source: org_study_id