Back to resultsEffect of DPP4 Inhibition on Growth Hormone Secretion
Primary Purpose
Obesity
Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Sitagliptin
Pegvisomant
Placebo
L-NMMA
Exendin 9-39
Sponsored by
About this trial
This is an interventional other trial for Obesity focused on measuring obesity, growth hormone
Eligibility Criteria
Inclusion Criteria:
- Age 18 to 40 years inclusive
- BMI ≤ 25 kg/m2
- For female subjects:
Status-post surgical sterilization, or If of child-bearing potential, utilization of a barrier method of birth control following negative serum pregnancy test at screening visit and on every study day
Exclusion Criteria:
- Smoking
- Type 1 or Type 2 Diabetes Mellitus, as defined by a fasting glucose of 126 mg/dL or greater at the time of screening visit or the use of anti-diabetic medication
- Hypertension, as defined by an untreated seated systolic blood pressure (SBP) greater than 140 mmHg and/or an untreated diastolic blood pressure (DBP) greater than 90 mmHg at the time of screening visit or the use of anti-hypertensive medication
- History of reported or recorded hypoglycemia (plasma glucose < 70 mg/dL)
- Pregnancy and/or Breast-Feeding
- Use of any medication other than multivitamin, including use of transdermal as well as oral hormone replacement therapy or use of oral contraceptive therapy
- Anemia defined as hematocrit <35% at screening visit
- Cardiovascular or cerebrovascular disease, including history of myocardial infarction, history of congestive heart failure, history of stroke
- Pulmonary Hypertension
- Abnormal thyroid hormone levels (TSH) at the time of screening visit
- Abnormal serum insulin like growth factor-1 (IGF-1) at the time of screening visit
- Impaired renal function, defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m^2
- Impaired hepatic function (alanine or aspartate transaminase > 2 X upper limit of normal range)
- Treatment with an investigational drug in the 1 month preceding the study
Sites / Locations
- Vanderbilt University Medical Center
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Other
Other
Other
Arm Label
Group A (14 healthy subjects)
Group B (14 healthy subjects)
Group C (14 healthy subjects)
Arm Description
In Aim 1: Healthy Lean adults are randomized in a double-blinded cross over fashion to sitagliptin versus placebo. In Aim 2: Healthy Lean adults receive sitagliptin and are randomized in a double-blinded cross over fashion to pre-treatment with either LNMMA (L-N-Monomethyl-arginine) versus placebo.
In Aim 1: Healthy Lean adults are randomized in a double-blinded cross over fashion to sitagliptin versus placebo. In Aim 2: Healthy Lean adults receive sitagliptin and are randomized in a double-blinded cross over fashion to pre-treatment with either pegvisomant versus placebo.
In Aim 1: Healthy Lean adults are randomized in a double-blinded cross over fashion to sitagliptin versus placebo. In Aim 2: Healthy Lean adults receive sitagliptin and are randomized in a double-blinded cross over fashion to pre-treatment with either Exendin 9-39 versus placebo.
Outcomes
Primary Outcome Measures
Aim 1: Stimulated Peak Growth Hormone Level
Subjects underwent two study days separated by a washout period. On one study day they will receive sitagliptin and on another placebo, in a randomized double-blind fashion. Growth hormone secretion was stimulated using arginine (30 grams i.v. over 30 minutes) on each study day. Growth hormone levels were assessed during a 3 hour period following arginine stimulation.
Aim 1: Percent Change From Baseline in Forearm Vascular Resistance
Forearm blood flow was determined by strain gauge plethysmography. Forearm vascular resistance was then calculated by dividing this into mean arterial pressure. The percent change from baseline was determined at each timepoint.
Aim 1: Percent Change From Baseline in Forearm Blood Flow
Forearm blood flow was determined by strain gauge plethysmography. The percent change from baseline was determined at each timepoint.
Aim 2: Percent Change From Baseline in Forearm Blood Flow
Subjects undergo two study days separated by a washout period. On one study day they received sitagliptin plus another study drug and on another sitagliptin plus placebo, in a randomized double-blind fashion. Forearm blood flow was assessed at each visit.
Aim 2: Percent Change From Baseline in Forearm Vascular Resistance
Subjects undergo two study days separated by a washout period. On one study day they will receive sitagliptin plus another study drug and on another sitagliptin plus placebo, in a randomized double-blind fashion. Forearm blood flow was assessed at each visit every 30 minutes for 3 hours. This was divided into mean arterial pressure to determine forearm vascular resistance.
Secondary Outcome Measures
Aim 1: Venous Blood Sampling for Tissue Plasminogen Activator (TPA) Activity Levels
In Aim 1 subjects underwent two study days separated by a washout period. On one study day they received study drug and on another placebo, in a randomized double-blind fashion. Venous blood samples were obtained at each visit.
Aim 2: Venous Blood Sampling for Tissue Plasminogen Activator (TPA) Activity Levels
Subjects undergo two study days separated by a washout period. On one study day they received sitagliptin plus pegvisomant and on another sitagliptin plus placebo, in a randomized double-blind fashion. Tissue plasminogen activator activity (tPA) was assessed at each visit.
Aim 2: Measurement of Growth Hormone (GH) Levels
Subjects undergo two study days separated by a washout period. On one study day they received sitagliptin plus pegvisomant and on another sitagliptin plus placebo, in a randomized double-blind fashion. Growth hormone secretion following arginine stimulation was assessed at each visit. Growth hormone levels were determined using an assay that is not subject to interference by pegvisomant.
Full Information
NCT ID
NCT01701973
First Posted
October 3, 2012
Last Updated
May 25, 2018
Sponsor
Vanderbilt University
Collaborators
National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI)
1. Study Identification
Unique Protocol Identification Number
NCT01701973
Brief Title
Effect of DPP4 Inhibition on Growth Hormone Secretion
Official Title
The Effect of Dipeptidyl Peptidase IV Inhibition on Growth Hormone-Mediated Vasodilation
Study Type
Interventional
2. Study Status
Record Verification Date
May 2018
Overall Recruitment Status
Completed
Study Start Date
January 2013 (undefined)
Primary Completion Date
May 2017 (Actual)
Study Completion Date
May 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Vanderbilt University
Collaborators
National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI)
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This study tests the following hypotheses:
Aim 1: Test the hypothesis that acute dipeptidyl peptidase 4 (DPP4) inhibition with the currently available anti-diabetic drug, sitagliptin, will increase stimulated growth hormone (GH) secretion in healthy lean adults by decreasing the degradation of growth hormone releasing hormone (GHRH).
Aim 2: Test the hypothesis that decreased degradation of GHRH during acute DPP4 inhibition will result in an increase in endothelium-dependent vasodilation mediated by GH and independent from GLP1 (glucagon like peptide-1) in healthy lean adults.
This study promises to provide novel data regarding how this increasingly used class of anti-diabetic drugs affects the pituitary GH axis and could affect blood vessel relaxation. Growth hormone levels are low in the setting of obesity and pre-diabetes. A further study may evaluate the effect of chronic DPP4 inhibitor therapy in a population of patients with obesity and pre-diabetes.
Detailed Description
Growth hormone secretion is low in patients with obesity, insulin resistance, and hyperlipidemia. GH therapy in these populations and others has been limited by side effects which include hyperglycemia. Another strategy to increase GH secretion is to enhance pulsatile GH secretion by growth hormone releasing hormone. Growth hormone releasing hormone (GHRH) has a half life of 5 minutes due to its rapid inactivation by DPP4. An alternative strategy to increase endogenous GH secretion is by inhibiting degradation of GHRH by DPP4. DPP4 inhibitors are currently approved therapies for the treatment of hyperglycemia in patients with type 2 diabetes mellitus. They additionally cause blood vessel relaxation. We therefore propose to test the hypothesis that DPP4 inhibition simultaneously enhances GH secretion while improving blood glucoses and vascular function in patient populations with low GH and increased cardiovascular risk. These preliminary aims serve primarily as a novel "proof of concept" study to define the effect of acute pharmacologic DPPIV inhibition on stimulated GH secretion.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Obesity
Keywords
obesity, growth hormone
7. Study Design
Primary Purpose
Other
Study Phase
Phase 4
Interventional Study Model
Crossover Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
44 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Group A (14 healthy subjects)
Arm Type
Other
Arm Description
In Aim 1: Healthy Lean adults are randomized in a double-blinded cross over fashion to sitagliptin versus placebo.
In Aim 2: Healthy Lean adults receive sitagliptin and are randomized in a double-blinded cross over fashion to pre-treatment with either LNMMA (L-N-Monomethyl-arginine) versus placebo.
Arm Title
Group B (14 healthy subjects)
Arm Type
Other
Arm Description
In Aim 1: Healthy Lean adults are randomized in a double-blinded cross over fashion to sitagliptin versus placebo.
In Aim 2: Healthy Lean adults receive sitagliptin and are randomized in a double-blinded cross over fashion to pre-treatment with either pegvisomant versus placebo.
Arm Title
Group C (14 healthy subjects)
Arm Type
Other
Arm Description
In Aim 1: Healthy Lean adults are randomized in a double-blinded cross over fashion to sitagliptin versus placebo.
In Aim 2: Healthy Lean adults receive sitagliptin and are randomized in a double-blinded cross over fashion to pre-treatment with either Exendin 9-39 versus placebo.
Intervention Type
Drug
Intervention Name(s)
Sitagliptin
Other Intervention Name(s)
Januvia
Intervention Description
During Aim 1, given on one of two study days (other study day subjects receive placebo.) During Aim 2, given during both of two study days.
Intervention Type
Drug
Intervention Name(s)
Pegvisomant
Other Intervention Name(s)
Somavert
Intervention Description
During Aim 2, given 72 hours prior to one of two study days (Group B subjects only)
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
sugar pill
Intervention Description
During Aim 1, given on one of two study days (other study day subjects receive sitagliptin.) During Aim 2, given on one of two study days (other study day subjects receive either L-NMMA, pegvisomant, or Exendin 9-39 pending their group assignment)
Intervention Type
Drug
Intervention Name(s)
L-NMMA
Other Intervention Name(s)
L-N-Monomethyl-arginine
Intervention Description
During Aim 2, given during one of two study days (Group A subjects only)
Intervention Type
Drug
Intervention Name(s)
Exendin 9-39
Intervention Description
During Aim 2, given during one of two study days (Group C subjects only)
Primary Outcome Measure Information:
Title
Aim 1: Stimulated Peak Growth Hormone Level
Description
Subjects underwent two study days separated by a washout period. On one study day they will receive sitagliptin and on another placebo, in a randomized double-blind fashion. Growth hormone secretion was stimulated using arginine (30 grams i.v. over 30 minutes) on each study day. Growth hormone levels were assessed during a 3 hour period following arginine stimulation.
Time Frame
Growth Hormone Level at 30 minutes (i.e. at completion of arginine infusion), 45 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes
Title
Aim 1: Percent Change From Baseline in Forearm Vascular Resistance
Description
Forearm blood flow was determined by strain gauge plethysmography. Forearm vascular resistance was then calculated by dividing this into mean arterial pressure. The percent change from baseline was determined at each timepoint.
Time Frame
Percent change from baseline in forearm vascular resistance at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes
Title
Aim 1: Percent Change From Baseline in Forearm Blood Flow
Description
Forearm blood flow was determined by strain gauge plethysmography. The percent change from baseline was determined at each timepoint.
Time Frame
Percent change from baseline in forearm blood flow at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes.
Title
Aim 2: Percent Change From Baseline in Forearm Blood Flow
Description
Subjects undergo two study days separated by a washout period. On one study day they received sitagliptin plus another study drug and on another sitagliptin plus placebo, in a randomized double-blind fashion. Forearm blood flow was assessed at each visit.
Time Frame
Percent change from baseline in forearm blood flow at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes.
Title
Aim 2: Percent Change From Baseline in Forearm Vascular Resistance
Description
Subjects undergo two study days separated by a washout period. On one study day they will receive sitagliptin plus another study drug and on another sitagliptin plus placebo, in a randomized double-blind fashion. Forearm blood flow was assessed at each visit every 30 minutes for 3 hours. This was divided into mean arterial pressure to determine forearm vascular resistance.
Time Frame
Percent change from baseline in forearm vascular resistance at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes
Secondary Outcome Measure Information:
Title
Aim 1: Venous Blood Sampling for Tissue Plasminogen Activator (TPA) Activity Levels
Description
In Aim 1 subjects underwent two study days separated by a washout period. On one study day they received study drug and on another placebo, in a randomized double-blind fashion. Venous blood samples were obtained at each visit.
Time Frame
baseline and every 30 minutes for 180 minutes
Title
Aim 2: Venous Blood Sampling for Tissue Plasminogen Activator (TPA) Activity Levels
Description
Subjects undergo two study days separated by a washout period. On one study day they received sitagliptin plus pegvisomant and on another sitagliptin plus placebo, in a randomized double-blind fashion. Tissue plasminogen activator activity (tPA) was assessed at each visit.
Time Frame
baseline and every 30 minutes until 180 minutes
Title
Aim 2: Measurement of Growth Hormone (GH) Levels
Description
Subjects undergo two study days separated by a washout period. On one study day they received sitagliptin plus pegvisomant and on another sitagliptin plus placebo, in a randomized double-blind fashion. Growth hormone secretion following arginine stimulation was assessed at each visit. Growth hormone levels were determined using an assay that is not subject to interference by pegvisomant.
Time Frame
baseline and every 30 minutes until 180 minutes
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Age 18 to 40 years inclusive
BMI ≤ 25 kg/m2
For female subjects:
Status-post surgical sterilization, or If of child-bearing potential, utilization of a barrier method of birth control following negative serum pregnancy test at screening visit and on every study day
Exclusion Criteria:
Smoking
Type 1 or Type 2 Diabetes Mellitus, as defined by a fasting glucose of 126 mg/dL or greater at the time of screening visit or the use of anti-diabetic medication
Hypertension, as defined by an untreated seated systolic blood pressure (SBP) greater than 140 mmHg and/or an untreated diastolic blood pressure (DBP) greater than 90 mmHg at the time of screening visit or the use of anti-hypertensive medication
History of reported or recorded hypoglycemia (plasma glucose < 70 mg/dL)
Pregnancy and/or Breast-Feeding
Use of any medication other than multivitamin, including use of transdermal as well as oral hormone replacement therapy or use of oral contraceptive therapy
Anemia defined as hematocrit <35% at screening visit
Cardiovascular or cerebrovascular disease, including history of myocardial infarction, history of congestive heart failure, history of stroke
Pulmonary Hypertension
Abnormal thyroid hormone levels (TSH) at the time of screening visit
Abnormal serum insulin like growth factor-1 (IGF-1) at the time of screening visit
Impaired renal function, defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m^2
Impaired hepatic function (alanine or aspartate transaminase > 2 X upper limit of normal range)
Treatment with an investigational drug in the 1 month preceding the study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jessica K Devin, MD, MSCI
Organizational Affiliation
Vanderbilt University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Vanderbilt University Medical Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
29478970
Citation
Wilson JR, Brown NJ, Nian H, Yu C, Bidlingmaier M, Devin JK. Dipeptidyl Peptidase-4 Inhibition Potentiates Stimulated Growth Hormone Secretion and Vasodilation in Women. J Am Heart Assoc. 2018 Feb 25;7(5):e008000. doi: 10.1161/JAHA.117.008000.
Results Reference
derived
Learn more about this trial
Effect of DPP4 Inhibition on Growth Hormone Secretion
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