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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 1 | Active Comparator | Sildenafil 100 mg |
|
| 2 | Placebo Comparator | Placebo 100 mg |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sildenafil | Drug | 100 mg daily (3 capsules/day) |
|
|
| 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). | 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 |
| 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). | 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Andrea Lenzi, MD, PhD | University of Roma La Sapienza | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Dipartimento di Fisiopatologia Medica - Policlinico Umberto I | Rome | 00161 | Italy |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22496161 | Result | 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. | |
| 33221242 |
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Overall 66 patients were eligible and enrolled; Seven were then excluded due to evidence of aneurysm of ascending aorta (1) on stress-Echo and of ischemic heart disease (6) at the first CMR. Fifty-nine patients were randomized.
Eligible men were recruited from the outpatient clinics of Policlinico Umberto I - Sapienza University Hospital of Rome between 2008 and 2009.
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| ID | Title | Description |
|---|---|---|
| FG000 | Sildenafil | Sildenafil citrate 100 mg/day (50+25+25) |
| FG001 | Placebo | Placebo 100 mg/day (50 + 25 + 25) |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Sildenafil | Sildenafil citrate 100 mg/day (50+25+25) |
| BG001 | Placebo | Placebo 100 mg/day (50 + 25 + 25) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | An overall sample size of 32 subjects (16 for each group) would thus have given a 90% power to detect the specified minimum detectable difference (3°) at a 2-sided significance level of 0.01; 59 patients were enrolled: 29 randomized to Sildenafil and 25 randomized to Placebo completed the trial. Analysis was per primary efficacy outcome (LV-q). | Posted | Mean | Standard Deviation | Degree angle (delta) | 0 and + 3 months |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Sildenafil | Sildenafil citrate 100 mg/day (50+25+25) |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Portal Vein Thrombosis | Blood and lymphatic system disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr Andrea Isidori | Sapienza University of Rome | +39 0649970540 | andrea.isidori@uniroma1.it |
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| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D000068677 | Sildenafil Citrate |
| ID | Term |
|---|---|
| D013449 | Sulfonamides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D013450 | Sulfones |
| D013457 |
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| Placebo | Drug | Placebo 100 mg (3 capsules/day) |
|
| 0 and + 3 months |
| Derived |
| 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. |
| 31102457 | Derived | 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. |
| 26178526 | Derived | 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. |
| BG002 |
| Total |
Total of all reporting groups |
| Participants |
|
| Age Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG000 | Sildenafil | Patients randomized to receive sildenafil were instructed to take 3 capsules per day (25 mg at 8.00 a.m. + 25 mg at 4.00 p.m. + 50 mg at 10.00 p.m.) that were identical-looking to placebo capsules, for a duration of 3 months (12 weeks). The allocation list was produced using dedicated software by permuted-block randomization with 1:1 allocation using randomly sized blocks (4 to 8). The study was double-blinded. |
| OG001 | Placebo | Patients randomized to receive placebo were instructed to take 3 capsules per day (1 at 8.00 a.m. + 1 at 4.00 p.m. + 1 at 10.00 p.m.) that were identical-looking to sildenafil capsules, for a duration of 3 months (12 weeks). The allocation list was produced using dedicated software by permuted-block randomization with 1:1 allocation using randomly sized blocks (4 to 8). The study was double-blinded. |
|
|
| Secondary | 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. | We included in this analysis all the patients that concluded the study (Sildenafil group = 29; Placebo group = 25). The 4 randomized patients who discontinued, did not perform the second after-treatment CMR evaluation. Analysis was "per protocol". | Posted | Mean | Standard Deviation | Percentage % of volume (delta) | 0 and + 3 months |
|
|
|
| 0 |
| 30 |
| 0 |
| 30 |
| EG001 | Placebo | Placebo 100 mg/day (50 + 25 + 25) | 1 | 29 | 0 | 29 |
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| D004700 | Endocrine System Diseases |
| Sulfur Compounds |
| D010879 | Piperazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |