Cardiovascular Effects of Chronic Sildenafil in Men With Type 2 Diabetes
Condition: Diabetes Mellitus, Type 2; Endothelial Dysfunction
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 4

Summary: 
      Type 2 Diabetes Mellitus (T2DM) represents a model of endothelial dysfunction, where chronic
      nitric oxide deprivation, hyperglycaemia and hyperinsulinemia and fibrogenic mediators lead
      to cardiovascular remodelling associated with diabetic cardiomyopathy and in consequence to
      secondary complications of diabetes. Specific anti-oxidative and anti-fibrotic therapies are
      not currently available. Sildenafil (Viagra) has demonstrated the capability of significantly
      improving endothelial dysfunction and cardiac fibrosis in experimental animal models.

      The purpose of the present study is performed to establish the effect of chronic high dose
      sildenafil treatment on heart performance in diabetic subjects.
    

Detailed description: 
      Type 2 Diabetes Mellitus (T2DM) represents a model of endothelial dysfunction at central and
      peripheral levels, where chronic nitric oxide deprivation, due to hyperglycaemia, leads to a
      loss of vascular endothelium-relaxant function and ischaemia-reperfusion ventricular damage.
      Since haemodynamic and oxidative stress could trigger a pro-inflammatory process of the
      intracardiac vasculature, endothelial cells activated in turns can produce fibrogenic
      mediators and induce fibroblast activation and myocardial fibrosis. Moreover, the increase of
      insulin levels of T2DM induces cardiotoxicity increasing the expression of ventricular
      angiotensin II type 1 receptor (AT1). All these mechanisms lead to cardiovascular remodelling
      associated with diabetic cardiomyopathy that is characterized by an impairment of heart
      diastolic performance with a ventricular hypertrophy and a dilatation and an increase of
      heart torsion.

      Specific anti-oxidative and anti-fibrotic therapies are not currently available.
      Phosphodiesterase 5 inhibitors (PDE5i) work to improve endothelial dysfunction by preventing
      the breakdown of cyclic guanosine monophosphate (cGMP), resulting in increased cellular
      content and consequent relaxation of smooth muscle cells of all systemic arteries and veins.
      PDE5i have therefore the potential to impact the cardiovascular performance, acting on all
      these mechanisms.

      The aim of the study is to evaluate the cardiovascular effects of the chronic (3 months) high
      dose (100 mg daily) sildenafil treatment in patient with type 2 diabetes. We will analyze the
      changes in parameters of endothelial dysfunction and heart remodelling and in metabolic
      indices. We will evaluate the outcomes at day 90. Moreover we will estimate if the changes in
      endothelial function will be sustained 30 days after discontinuing treatment.

      This is designed as a phase IV study on chronic treatment with a cohort size of 30 patients
      randomized to receive Sildenafil and 20 patients randomized to placebo. Accounting for a 15%
      drop off, a total enrollment of 60 patients is planned. Patients will begin a washout from
      PDE5i in the first visit (4 weeks before the beginning of the treatment). Evaluation of
      potential toxicity will be monitored throughout the course of treatment. Follow-up visits
      will take place at days + 30, +60, +90 (end of treatment) and +120. Plasma and serum
      monitoring of basal and postprandial glycaemia and insulinemia, hematochemical routine, VEGF,
      hormones and others cytokines and albuminuria will be made prior to treatment, at days 30,
      60, 90, 120. Measurements of cine-MRI, FMD and blood pressure Holter 24h will be made at time
      0 and at days 90.

      The long-term objective is to identify a safe and easily administered treatment that improves
      functional outcome in diabetic patients.
    

Intervention name(s): Sildenafil; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 100 mg daily (3 capsules/day); Placebo 100 mg (3 capsules/day)
Other intervention name(s): - Viagra 25 mg; - Viagra 50 mg
Intervention MeSH terms: Sildenafil Citrate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Type 2 diabetes mellitus; Endothelial dysfunction; Sildenafil