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

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

Study Overview

• Status: Terminated
• Conditions: Impaired Glucose Tolerance
• Intervention / Treatment: Drug: Sildenafil; Diagnostic test: Hyperglycemic clamp; Drug: Placebo; Diagnostic test: Euglycemic clamp

• Study Type: Interventional
• Enrollment (Actual): 78
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: sildenafil Aim 1; sildenafil 25 mg p.o. tid	Drug: Sildenafil; Sildenafil 25 mg by mouth three times a day for three months; Diagnostic test: Hyperglycemic clamp; 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.
Placebo Comparator: placebo Aim 1; matching placebo p.o. tid	Diagnostic test: Hyperglycemic clamp; 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.; Drug: Placebo; Matching placebo three times a day for three months
Experimental: sildenafil Aim 2; sildenafil 25 mg p.o. tid	Drug: Sildenafil; Sildenafil 25 mg by mouth three times a day for three months; Diagnostic test: Euglycemic clamp; 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.
Placebo Comparator: placebo Aim 2; matching placebo p.o. tid	Drug: Placebo; Matching placebo three times a day for three months; Diagnostic test: Euglycemic clamp; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Vanderbilt University
• Investigators: Principal Investigator: Nancy J Brown, MD, Vanderbilt University

Publications and helpful links

General Publications

• Ramirez CE, Nian H, Yu C, Gamboa JL, Luther JM, Brown NJ, Shibao CA. Treatment with Sildenafil Improves Insulin Sensitivity in Prediabetes: A Randomized, Controlled Trial. J Clin Endocrinol Metab. 2015 Dec;100(12):4533-40. doi: 10.1210/jc.2015-3415. Epub 2015 Nov 18.
• Ramirez CE, Shuey MM, Milne GL, Gilbert K, Hui N, Yu C, Luther JM, Brown NJ. Arg287Gln variant of EPHX2 and epoxyeicosatrienoic acids are associated with insulin sensitivity in humans. Prostaglandins Other Lipid Mediat. 2014 Oct;113-115:38-44. doi: 10.1016/j.prostaglandins.2014.08.001. Epub 2014 Aug 28.

Study record dates

Study Major Dates

• Study Start: August 1, 2011
• Primary Completion (Actual): November 1, 2016
• Study Completion (Actual): November 1, 2016

Study Registration Dates

• First Submitted: July 11, 2011
• First Submitted That Met QC Criteria: August 2, 2011
• First Posted (Estimate): August 4, 2011

Study Record Updates

• Last Update Posted (Actual): April 17, 2017
• Last Update Submitted That Met QC Criteria: March 3, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: BMI greater than 25; Elevated fasting blood sugar (100-125mg/dL)
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperglycemia; Glucose Intolerance; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate
• Other Study ID Numbers: 110206