Renin-Angiotensin and Fibrinolysis in Humans: Effect of Long-Term PDE5 Inhibition on Glucose Homeostasis

Study Overview
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Brief Summary
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The purpose of this study is to determine the effect of chronic PDE5 inhibitor therapy on glucose metabolism in persons with prediabetes.

Conditions
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Impaired Glucose Tolerance

Intervention / Treatment
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* Drug: Sildenafil
* Drug: Placebo
* Diagnostic Test: Hyperglycemic clamp
* Diagnostic Test: Euglycemic clamp


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Age > 18 years and BMI > 25 kg/M2 (> 23 kg/M2 among Asian Americans) Elevated fasting plasma glucose (100-125 mg/dL) IGT (2 hour plasma glucose 140-199 mg/dL) OR metabolic syndrome and/or hemoglobin A1c 5.7-6.4% Exclusion criteria: Diabetes type 1 or type 2, as defined by a fasting glucose of 126 mg/dL or greater, a two hour plasma glucose of 200 mg/dL or greater, or the use of anti-diabetic medication. The use of nitrates or any disease that might require the use of nitrates. The use of any potent CYP3A4 inhibitor. subjects who have participated in a weight-reduction program during the last 6 month or whose weight has increased or decreased more than 2 kg over the preceding 6 months. Pregnancy. Women of child-bearing potential will be required to have undergone tubal ligation or to be using barrier methods of birth control. Breast-feeding. Cardiovascular disease such as myocardial infarction within 6 months prior to enrollment, presence of angina pectoris, significant arrhythmia, congestive heart failure (LV hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis or hypertrophic cardiomyopathy. Treatment with anticoagulants. Treatment with metformin. History of serious neurologic disease such as cerebral hemorrhage, stroke, or transient ischemic attack. History or presence of immunological or hematological disorders. Diagnosis of asthma. Clinically significant gastrointestinal impairment that could interfere with drug absorption. Impaired hepatic function (aspartate amino transaminase [AST] and/or alanine amino. transaminase [ALT] >1.5 x upper limit of normal range) Impaired renal function (serum creatinine >1.5 mg/dl). Hematocrit <35%. Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult. Treatment with chronic systemic glucocorticoid therapy (more than 7 consecutive days in 1 month). Treatment with lithium salts. History of alcohol or drug abuse. Treatment with any investigational drug in the 1 month preceding the study. Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study. Inability to comply with the protocol, e.g. uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: sildenafil Aim 1<br>sildenafil 25 mg p.o. tid | Drug: Sildenafil<br>* Sildenafil 25 mg by mouth three times a day for three months<br>Diagnostic Test: Hyperglycemic clamp<br>* Subjects with prediabetes will have a baseline hyperglycemic clamp (Aim 1) and then receive sildenafil or placebo for 3 months. Another hyperglycemic clamp will be performed followed by another 3 months off drug and an oral glucose tolerance test.<br>|
| Placebo Comparator: placebo Aim 1<br>matching placebo p.o. tid | Drug: Placebo<br>* Matching placebo three times a day for three months<br>Diagnostic Test: Hyperglycemic clamp<br>* Subjects with prediabetes will have a baseline hyperglycemic clamp (Aim 1) and then receive sildenafil or placebo for 3 months. Another hyperglycemic clamp will be performed followed by another 3 months off drug and an oral glucose tolerance test.<br>|
| Experimental: sildenafil Aim 2<br>sildenafil 25 mg p.o. tid | Drug: Sildenafil<br>* Sildenafil 25 mg by mouth three times a day for three months<br>Diagnostic Test: Euglycemic clamp<br>* Subjects with prediabetes will have a baseline euglycemic clamp (Aim 2) and then receive sildenafil or placebo for 3 months. Another euglycemic clamp will be performed followed by another 3 months off drug and an oral glucose tolerance test.<br>|
| Placebo Comparator: placebo Aim 2<br>matching placebo p.o. tid | Drug: Placebo<br>* Matching placebo three times a day for three months<br>Diagnostic Test: Euglycemic clamp<br>* Subjects with prediabetes will have a baseline euglycemic clamp (Aim 2) and then receive sildenafil or placebo for 3 months. Another euglycemic clamp will be performed followed by another 3 months off drug and an oral glucose tolerance test.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin Secretion | in the group of subjects undergoing hyperglycemic clamp (Aim 1) | 2.5 hours after 3 months of therapy | 
| Index of Tissue Sensitivity to Insulin | in the group of subjects undergoing hyperglycemic clamp (Aim 1), calculated by dividing the average glucose infusion rate during the last hour of the clamp by the average plasma insulin concentration during the same interval | 2.5 hours after 3 months of therapy | 
| Glucose Infusion Rate | In the group of subjects undergoing euglycemic clamp (Aim 2) | 2.5 hours after 3 months of therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fasting Plasma Glucose |  | 3 months | 
| Blood Pressure | Systolic blood pressure | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BMI greater than 25, Elevated fasting blood sugar (100-125mg/dL)