The Effect of Uric Acid Lowering in Type 1 Diabetes
Condition: Type 1 Diabetes Mellitus
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1
Study type: Interventional
Phase: Phase 4

Summary: 
      Patients with type 1 diabetes mellitus (T1DM) are at high risk of developing kidney
      complications potentially leading to end stage renal disease. Uric acid (UA), the end product
      of purine metabolism, emerged as an important determinant of renal and vascular injury due to
      its ability activate the renin-angiotensin-aldosterone system (RAAS) and increase production
      of harmful reactive oxygen species (ROS). ROS cause progressive endothelial cell dysfunction,
      inflammation, tissue fibrosis and eventually cell death. These processes are enhanced in DM
      because of the effect of hyperglycemia.

      Since existing preventive drug therapies fail to completely prevent kidney damage, an
      examination of the effect of UA lowering against initiation and progression of renal and
      vascular complications is therefore of the utmost importance. The purpose of this study is to
      examine the effect of UA lowering with febuxostat on renal and systemic vascular function in
      patients with uncomplicated T1DM. It was hypothesized that UA lowering will improve kidney
      and systemic vascular function through effects on blood vessel function and anti-inflammatory
      effect.

      Kidney and blood vessel function will be assessed under conditions of normal and high blood
      sugar levels before and after 8 weeks of treatment with the UA lowering drug febuxostat in
      patients with diabetes and during normoglycemia only in health controls.

      Current treatment for renal and vascular complications in DM patients includes blockade of
      the RAAS. Unfortunately, angiotensin converting enzyme inhibitors (ACEi) and angiotensin II
      (AngII) receptor blockers (ARBs) lead to incomplete RAAS suppression, and do not completely
      prevent renal or vascular complications. Moreover, dual RAAS blockade increases renal and
      cardiovascular risk. Recent experimental work suggests that UA lowering therapies can block
      the RAAS, suppress inflammation and promote renal and systemic vascular protection.
      Therefore, our study is critical in determining the possible role of early UA lowering on
      renal and systemic hemodynamic dysfunction in young patients with T1DM.
    

Detailed description: 
      Uric acid (UA) was recently suggested to exert deleterious effects on blood pressure and
      renal function, even when baseline UA levels are within the normal range. UA activates the
      renin angiotensin-aldosterone system (RAAS), increases oxidative stress and promotes
      inflammation. As a consequence, higher UA levels are associated with metabolic abnormalities
      (insulin resistance, hyperglycemia), cardiovascular disease (hypertension, endothelial
      dysfunction, arterial stiffness, cardiac diastolic dysfunction) and kidney function
      abnormalities (hyperfiltration - a marker for intraglomerular hypertension, proteinuria).
      Thus pharmacologic UA lowering may promote renal and cardiovascular protection. The
      mechanisms underlying these protective effects in humans, prior to the onset of clinical
      disease, remain unknown.

      This study is focused on the prevention of complications in young, normotensive type 1
      diabetes mellitus (T1DM) patients with normal renal function and UA levels. The study will
      examine the effect of UA lowering with febuxostat (FBX) on renal hemodynamic function,
      vascular function and urinary inflammatory biomarkers. Based on substantial supportive
      pre-clinical and epidemiological data, we hypothesize that lowering UA levels that are within
      normal range at baseline will: 1) ameliorate hemodynamic abnormalities characteristic of
      T1DM, and reduce renal and systemic hypertensive responses to hyperglycemia; 2) ameliorate
      endothelial function abnormalities characteristic of T1DM; 3) reduce urinary inflammatory
      cytokines/chemokine excretion.
    

Intervention name(s): Febuxostat
Intervention type(s): Drug
Intervention description(s): Oral tablet, 80mg, OD, 8 weeks
Other intervention name(s): Trade name Uloric®
Intervention MeSH terms: Febuxostat
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Diabetic Nephropathy; Diabetes Mellitus; Diabetes Complications; Uric Acid; Febuxostat; Uloric; Glomerular Filtration Rate; Kidney Disease; Vascular Disease; Cardiovascular Diseases; Endothelial Function; Arterial Stiffness; Pharmacologic Actions; Gout Suppressants; Therapeutic Uses; Free Radical Scavengers; Antioxidants; Protective Agents; Physiological Effects of Drugs; Angiotensin II Infusion; Flow-mediated Dilation; Flow-mediated Constriction; Nitroglycerin; Hyperglycemia; Renin-angiotensin-aldosterone System; Nitric Oxide; cGMP; Oxidative Stress; Renal Haemodynamic Function; Inulin Clearance; PAH Clearance; Skin Biopsy; T1R mRNA Expression; Cytokines; Chemokines