Impaired Glucose Tolerance
Conditions
Keywords
BMI greater than 25, Elevated fasting blood sugar (100-125mg/dL)
Brief summary
The purpose of this study is to determine the effect of chronic PDE5 inhibitor therapy on glucose metabolism in persons with prediabetes.
Interventions
DRUGSildenafil
Sildenafil 25 mg by mouth three times a day for three months
DRUGPlacebo
Matching placebo three times a day for three months
DIAGNOSTIC_TESTHyperglycemic 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.
DIAGNOSTIC_TESTEuglycemic 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.
Sponsors
Vanderbilt University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Secretion | 2.5 hours after 3 months of therapy | in the group of subjects undergoing hyperglycemic clamp (Aim 1) |
| Index of Tissue Sensitivity to Insulin | 2.5 hours after 3 months of therapy | 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 |
| Glucose Infusion Rate | 2.5 hours after 3 months of therapy | In the group of subjects undergoing euglycemic clamp (Aim 2) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fasting Plasma Glucose | 3 months | — |
| Blood Pressure | 3 months | Systolic blood pressure |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sildenafil sildenafil 25 mg p.o. tid
Administration of sildenafil: Subjects with prediabetes will have a baseline hyperglycemic (Aim 1) or a euglycemic (Aim 2) clamp and then receive sildenafil for 3 months. Another hyperglycemic or euglycemic clamp will be performed followed by another 3 months off drug and an oral glucose tolerance test. | 39 |
| Placebo matching placebo p.o. tid
Administration of placebo: Subjects with prediabetes will have a baseline hyperglycemic (Aim 1) or a euglycemic (Aim 2) clamp and then receive sildenafil or placebo for 3 months. Another hyperglycemic or euglycemic clamp will be performed followed by another 3 months off drug and an oral glucose tolerance test. | 39 |
| Total | 78 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 4 | 3 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 4 |
Baseline characteristics
| Characteristic | Sildenafil | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 48.4 years STANDARD_DEVIATION 10.6 | 49.58 years STANDARD_DEVIATION 10.8 | 51.0 years STANDARD_DEVIATION 10.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 16 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 29 Participants | 61 Participants | 32 Participants |
| Region of Enrollment United States | 39 participants | 78 participants | 39 participants |
| Sex: Female, Male Female | 24 Participants | 50 Participants | 26 Participants |
| Sex: Female, Male Male | 15 Participants | 28 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 32 / 39 | 25 / 39 |
| serious Total, serious adverse events | 1 / 39 | 0 / 39 |
Outcome results
Primary
Glucose Infusion Rate
In the group of subjects undergoing euglycemic clamp (Aim 2)
Time frame: 2.5 hours after 3 months of therapy
Population: one subject in the sildenafil Aim 2 arm has incomplete data from the three-month clamp due to infusion dysfunction
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil Aim 1 | Glucose Infusion Rate | 140.45 mL/hr | Standard Deviation 38.38 |
| Placebo Aim 1 | Glucose Infusion Rate | 162.61 mL/hr | Standard Deviation 64.49 |
Primary
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
Time frame: 2.5 hours after 3 months of therapy
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil Aim 1 | Index of Tissue Sensitivity to Insulin | 6.45 (mg/kg/min per microU/mL)*100 | Standard Error 0.661 |
| Placebo Aim 1 | Index of Tissue Sensitivity to Insulin | 4.66 (mg/kg/min per microU/mL)*100 | Standard Error 0.661 |
Primary
Insulin Secretion
in the group of subjects undergoing hyperglycemic clamp (Aim 1)
Time frame: 2.5 hours after 3 months of therapy
Population: Glucose-stimulated insulin secretion from 90 to 120 minutes of hyperglycemic clamp
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil Aim 1 | Insulin Secretion | 109.4 microU/mL | Standard Error 85 |
| Placebo Aim 1 | Insulin Secretion | 103.1 microU/mL | Standard Error 67.7 |
Secondary
Blood Pressure
Systolic blood pressure
Time frame: 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil Aim 1 | Blood Pressure | 122 mmHg | Standard Deviation 17.2 |
| Placebo Aim 1 | Blood Pressure | 123.1 mmHg | Standard Deviation 14.6 |
| Sildenafil Aim 2 | Blood Pressure | 114.3 mmHg | Standard Deviation 11.6 |
| Placebo Aim 2 | Blood Pressure | 112.5 mmHg | Standard Deviation 22.6 |
Secondary
Fasting Plasma Glucose
Time frame: 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil Aim 1 | Fasting Plasma Glucose | 98.6 mg/dL | Standard Deviation 11.7 |
| Placebo Aim 1 | Fasting Plasma Glucose | 96.9 mg/dL | Standard Deviation 7.6 |
| Sildenafil Aim 2 | Fasting Plasma Glucose | 98.8 mg/dL | Standard Deviation 6.5 |
| Placebo Aim 2 | Fasting Plasma Glucose | 97.5 mg/dL | Standard Deviation 11.1 |