Diabetes Mellitus, Type 2 Clinical Trial
Official title:
Cardiovascular Effects of Chronic Sildenafil (Viagra) Treatment in Diabetic Subjects With Endothelial Dysfunction.
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.
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.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Outcomes Assessor), Primary Purpose: Treatment
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