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.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: January 2009

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(s) in this Clinical Trial

• Drug: Sildenafil
  • 100 mg daily (3 capsules/day)
• Drug: Placebo
  • Placebo 100 mg (3 capsules/day)

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: 1
  • Sildenafil 100 mg
• Placebo Comparator: 2
  • Placebo 100 mg

Primary Measures

• Changes of cardiac performance, measured by cine-Magnetic Resonance Imaging (MRI) analysis of left ventricular torsion, before and after three months of treatment with 100 mg Sildenafil daily.
  • Time Frame: 0 and + 3 months
    Safety Issue?: Yes

Secondary Measures

• MRI: Left ventricular volume, Fibrosis area, Ejection fraction; blood pressure (holter 24 h); flow mediated dilatation of the brachial artery; VEGF levels, HOMA index, eGFR, Albuminuria (24 h), Oxidative stress markers
  • Time Frame: 0 and + 3 months
    Safety Issue?: Yes

Inclusion Criteria:

• Patients with type 2 diabetes mellitus
• Patients age 35-75
• Metabolic control of diabetes by diet or oral treatment (unmodified in the last 3 months)
• Blood pressure <160/100 mmHg, including subjects with controlled hypertension, treated with ACE-inhibitors/sartans, unmodified in the last 3 months

Exclusion Criteria:

• Participation in another study with an investigational drug or device
• HbA1c >12%
• Alterations during ECG stress examination
• Current use of nitrate agents
• Proliferative retinopathy
• Patients with history of cardiovascular and malignant disease
• Psychosocial disturbance
• Alcohol or drug dependence
• Allergy or hypersensitivity to sildenafil or other Phosphodiesterase inhibitors.

Gender Eligibility for this Clinical Trial: Male

Minimum Age for this Clinical Trial: 35 Years

Maximum Age for this Clinical Trial: 75 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: University of Roma La Sapienza

Overall Clinical Trial Officials and Contacts

Andrea Lenzi, MD, PhD Principal Investigator University of Roma La Sapienza  

Overall Contact: Andrea M Isidori, MD, PhD 39-06-4997-0540 andrea.isidori@uniroma1.it

Information obtained from ClinicalTrials.gov on October 10, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00692237

Study ID Number: 746/07

ClinicalTrials.gov Identifier: NCT00692237

Health Authority: Italy: Ethics Committee

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