A Phase 4 interventional study of Sildenafil and Placebo in Diabetes Mellitus, Type 2 and Endothelial Dysfunction, sponsored by University of Roma La Sapienza. Completed at 1 site in Italy. Open to male participants aged 35 Years to 75 Years. Per ClinicalTrials.gov, last updated 2013-05-08.
Sponsored by University of Roma La Sapienza · Phase 4, Interventional, and Treatment
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.
10,925 studies on the registry are indexed under Diabetes Mellitus; 1,319 are open to participants now.
This study's enrollment of 59 is below the median of 80 across 8,367 interventional studies indexed under Diabetes Mellitus.
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Exclusion Criteria:
Sildenafil 100 mg
Drug: Sildenafil
Placebo 100 mg
Drug: Placebo
100 mg daily (3 capsules/day)
Also known as: - Viagra 25 mg, - Viagra 50 mg
Placebo 100 mg (3 capsules/day)
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).
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.
Time frame: 0 and + 3 months
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).
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.
Time frame: 0 and + 3 months
Eligible men were recruited from the outpatient clinics of Policlinico Umberto I - Sapienza University Hospital of Rome between 2008 and 2009.
| Milestone | Sildenafil | Placebo |
|---|---|---|
| Started | 30 | 29 |
| Completed | 29 | 25 |
| Not completed | 1 | 4 |
| Withdrew: Withdrawal by subject | 1 | 3 |
| Withdrew: Adverse event | 0 | 1 |
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.
| Degree angle (delta) | Sildenafil | Placebo |
|---|---|---|
| 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). | -3.89 ± 3.11 | 2.13 ± 2.35 |
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.
| Percentage % of volume (delta) | Sildenafil | Placebo |
|---|---|---|
| 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). | 2.77 ± 4.36 | 3.14 ± 5.87 |
Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Sildenafil | — | 0/30 (0%) | 0/30 (0%) |
| Placebo | — | 1/29 (3.4%) | 0/29 (0%) |
| Event | Sildenafil | Placebo |
|---|---|---|
| Portal Vein ThrombosisBlood and lymphatic system disorders | 0/30 | 1/29 |
| Age, Categorical(Participants) | Sildenafil | Placebo | Total |
|---|---|---|---|
| <=18 years | 0 | 0 | 0 |
| Between 18 and 65 years | 20 | 20 | 40 |
| >=65 years | 10 | 9 | 19 |
| Age Continuous(years) | Sildenafil | Placebo | Total |
|---|---|---|---|
| Mean | 61 ± 7 | 59 ± 7 | 60 ± 7 |
| Sex: Female, Male(Participants) | Sildenafil | Placebo | Total |
|---|---|---|---|
| Female | 0 | 0 | 0 |
| Male | 30 | 29 | 59 |
| Region of Enrollment(participants) | Sildenafil | Placebo | Total |
|---|---|---|---|
| Italy | 30 | 29 | 59 |
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University of Roma La Sapienza