Clinical trial NCT00692237: Cardiovascular Effects of Chronic Sildenafil in Men With Type 2 Diabetes
Official title: Cardiovascular Effects of Chronic Sildenafil (Viagra) Treatment in Diabetic Subjects With Endothelial Dysfunction.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Diabetes Mellitus, Type 2
Endothelial Dysfunction
Keywords: Type 2 diabetes mellitus
Endothelial dysfunction
Sildenafil
Lead sponsor: University of Roma La Sapienza
Sponsor class: OTHER
First posted: 2008-06-06
Enrollment: 59
Sex: MALE
Minimum age (years): 35
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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).
timeFrame: 0 and + 3 months
Secondary outcomes:
measure: 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).
timeFrame: 0 and + 3 months
Other outcomes:
Locations:
city: Rome
country: Italy
facility: Dipartimento di Fisiopatologia Medica - Policlinico Umberto I
Study officials:
affiliation: University of Roma La Sapienza
name: Andrea Lenzi, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Giannetta E, Isidori AM, Galea N, Carbone I, Mandosi E, Vizza CD, Naro F, Morano S, Fedele F, Lenzi A. Chronic Inhibition of cGMP phosphodiesterase 5A improves diabetic cardiomyopathy: a randomized, controlled clinical trial using magnetic resonance imaging with myocardial tagging. Circulation. 2012 May 15;125(19):2323-33. doi: 10.1161/CIRCULATIONAHA.111.063412. Epub 2012 Apr 11.
citation: Pofi R, Giannetta E, Galea N, Francone M, Campolo F, Barbagallo F, Gianfrilli D, Venneri MA, Filardi T, Cristini C, Antonini G, Badagliacca R, Frati G, Lenzi A, Carbone I, Isidori AM. Diabetic Cardiomiopathy Progression is Triggered by miR122-5p and Involves Extracellular Matrix: A 5-Year Prospective Study. JACC Cardiovasc Imaging. 2021 Jun;14(6):1130-1142. doi: 10.1016/j.jcmg.2020.10.009. Epub 2020 Nov 18.
citation: Venneri MA, Barbagallo F, Fiore D, De Gaetano R, Giannetta E, Sbardella E, Pozza C, Campolo F, Naro F, Lenzi A, Isidori AM. PDE5 Inhibition Stimulates Tie2-Expressing Monocytes and Angiopoietin-1 Restoring Angiogenic Homeostasis in Diabetes. J Clin Endocrinol Metab. 2019 Jul 1;104(7):2623-2636. doi: 10.1210/jc.2018-02525.
citation: Mandosi E, Giannetta E, Filardi T, Lococo M, Bertolini C, Fallarino M, Gianfrilli D, Venneri MA, Lenti L, Lenzi A, Morano S. Endothelial dysfunction markers as a therapeutic target for Sildenafil treatment and effects on metabolic control in type 2 diabetes. Expert Opin Ther Targets. 2015;19(12):1617-22. doi: 10.1517/14728222.2015.1066337. Epub 2015 Jul 15.