Cardiovascular Effects of Chronic Sildenafil in Men With Type 2 Diabetes (CECSID)

May 5, 2013 updated by: Andrea M. Isidori, University of Roma La Sapienza

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 Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

59

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Rome, Italy, 00161
        • Dipartimento di Fisiopatologia Medica - Policlinico Umberto I

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

35 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: 1
Sildenafil 100 mg
Drug: Sildenafil
100 mg daily (3 capsules/day)
Other Names:
  • - Viagra 25 mg
  • - Viagra 50 mg
Placebo Comparator: 2
Placebo 100 mg
Drug: Placebo
Placebo 100 mg (3 capsules/day)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Left Ventricular Torsion Defined as Change in Ventricular Mid-wall Rotation (°) Measured by Cine-Cardiac Magnetic Resonance (CMR) Imaging With Tagging, Before and After Three Months of Treatment With Sildenafil and Placebo (100 mg/Day).
Time Frame: 0 and + 3 months
Diabetic cardiomyopathy and hypertrophy are characterized by an increase in cardiac torsion Normal value of rotation are < 12°; in hypertrophic heart such values can raise up to 20-25°. A reduction in left ventricular wall rotation is a sign of improvement after removal of known causes of hypertrophy (for example after surgical repair of aortic stenosis). Based on previous studies a reduction of 3 degrees (°) is considered clinically significant.
0 and + 3 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Ejection Fraction (EF) Defined as the Volume of Blood Ejected With Each Beat Was Measured on Cine-Cardiac Magnetic Resonance (CMR) Images Before and After Three Months Treatment With Sildenafil and Placebo (100 mg/Day).
Time Frame: 0 and + 3 months
The volume of blood within a ventricle immediately before a contraction is known as the end-diastolic volume; the volume of blood left in a ventricle at the end of contraction is end-systolic volume. The difference between end-diastolic volume and end-systolic volumes is the volume of blood ejected with each beat. Ejection fraction (Ef) is the fraction of the end-diastolic volume that is ejected with each beat; expressed as percentage of EDV. This is a measure of cardiac performance that can be deteriorated in diabetic cardiomyopathy.
0 and + 3 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Roma La Sapienza

Investigators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2008

Primary Completion (Actual)

September 1, 2009

Study Completion (Actual)

December 1, 2009

Study Registration Dates

First Submitted

June 4, 2008

First Submitted That Met QC Criteria

June 5, 2008

First Posted (Estimate)

June 6, 2008

Study Record Updates

Last Update Posted (Estimate)

May 8, 2013

Last Update Submitted That Met QC Criteria

May 5, 2013

Last Verified

May 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 746/07

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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