Rapid Effects Linagliptin on Monocyte Polarization and Endothelial Progenitor Cells in Type 2 Diabetes
Condition: Type 2 Diabetes; Chronic Renal Failure
MeSH terms: Renal Insufficiency; Kidney Failure, Chronic; Renal Insufficiency, Chronic; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): Linagliptin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Linagliptin 5 mg tablets for 4 days; Placebo tablets for 4 days
Other intervention name(s): Trajenta 5 mg
Intervention MeSH terms: Linagliptin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Primary purpose: Prevention
Keywords: Diabetes; Kidney; Inflammation; Metabolism