Effect of DPP4 Inhibition on Growth Hormone Secretion

• Sponsor: Vanderbilt University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01701973
• Collaborator: National Institutes of Health (NIH) (NIH), National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 44
• Location: 1
• Arms: 3
• Duration (Months): 51.9
• Patients Per Site Per Month: 0.8

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Obesity	Drug: Sitagliptin; Drug: Pegvisomant; Drug: Placebo; Drug: L-NMMA; Drug: Exendin 9-39	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 44 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Other
• Official Title: The Effect of Dipeptidyl Peptidase IV Inhibition on Growth Hormone-Mediated Vasodilation
• Study Start Date: Jan 1, 2013
• Actual Primary Completion Date: May 1, 2017
• Actual Study Completion Date: May 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Other: Group A (14 healthy subjects) 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.	Drug: Sitagliptin; 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.; Other Names: Januvia ; Drug: Placebo; 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); Other Names: sugar pill ; Drug: L-NMMA; During Aim 2, given during one of two study days (Group A subjects only); Other Names: L-N-Monomethyl-arginine
Other: Group B (14 healthy subjects) 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.	Drug: Sitagliptin; 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.; Other Names: Januvia ; Drug: Pegvisomant; During Aim 2, given 72 hours prior to one of two study days (Group B subjects only); Other Names: Somavert ; Drug: Placebo; 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); Other Names: sugar pill
Other: Group C (14 healthy subjects) 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.	Drug: Sitagliptin; 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.; Other Names: Januvia ; Drug: Placebo; 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); Other Names: sugar pill ; Drug: Exendin 9-39; During Aim 2, given during one of two study days (Group C subjects only)

Outcome Measures

Primary Outcome Measures

1. Aim 1: Stimulated Peak Growth Hormone Level [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]

   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.

2. Aim 1: Percent Change From Baseline in Forearm Vascular Resistance [Percent change from baseline in forearm vascular resistance at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes]

   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.

3. Aim 1: Percent Change From Baseline in Forearm Blood Flow [Percent change from baseline in forearm blood flow at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes.]

   Forearm blood flow was determined by strain gauge plethysmography. The percent change from baseline was determined at each timepoint.

4. Aim 2: Percent Change From Baseline in Forearm Blood Flow [Percent change from baseline in forearm blood flow at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes.]

   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.

5. Aim 2: Percent Change From Baseline in Forearm Vascular Resistance [Percent change from baseline in forearm vascular resistance at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes]

   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

1. Aim 1: Venous Blood Sampling for Tissue Plasminogen Activator (TPA) Activity Levels [baseline and every 30 minutes for 180 minutes]

   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.

2. Aim 2: Venous Blood Sampling for Tissue Plasminogen Activator (TPA) Activity Levels [baseline and every 30 minutes until 180 minutes]

   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.

3. Aim 2: Measurement of Growth Hormone (GH) Levels [baseline and every 30 minutes until 180 minutes]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 40 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232

Sponsors and Collaborators

• Vanderbilt University
• National Institutes of Health (NIH)
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Jessica K Devin, MD, MSCI, Vanderbilt University Medical Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 8, 2016

More Information

Publications

None provided.

• Responsible Party: Jessica Koch Devin, Assistant Professor, Vanderbilt University
• ClinicalTrials.gov Identifier: NCT01701973
• Other Study ID Numbers: 120078; 1K23HL119602
• First Posted: Oct 5, 2012
• Last Update Posted: May 29, 2018
• Last Verified: May 1, 2018

• Keywords provided by Jessica Koch Devin, Assistant Professor, Vanderbilt University: obesity; growth hormone
• Additional relevant MeSH terms: Obesity; Sitagliptin Phosphate

Study Results

Participant Flow

Recruitment Details	Healthy Lean Adults are randomized to two cross-over studies (Aim 1 and Aim 2).
Pre-assignment Detail	In Aim 1, Healthy adults were randomized in a double-blinded cross-over fashion to sitagliptin vs placebo. A minimum 8 week wash-out separated Aims 1 & 2. 23 of the same adults who completed Aim 1 participated in Aim 2. In Aim 2, these adults were divided into three subgroups and randomized to sitagliptin+placebo vs. sitagliptin+antagonist.

Arm/Group Title	Aim 1: Sitagliptin, Then Placebo	Aim 1: Placebo, Then Sitagliptin	Aim 2: Sitagliptin + Placebo,Then Sitagliptin + LNMMA	Aim 2:Sitagliptin + LNMMA, Then Sitagliptin + Placebo	Aim 2: Sitagliptin + Placebo, Then Sitagliptin + Pegvisomant	Aim 2: Sitagliptin + Pegvisomant, Then Sitagliptin + Placebo	Aim 2: Sitagliptin + Placebo, Then Sitagliptin + Exendin 9-39	Aim 2: Sitagliptin + Exendin 9-39, Then Sitagliptin + Placebo
Arm/Group Description	In Aim 1: Healthy Lean adults are randomized in a double-blinded cross over fashion to sitagliptin 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 L-NMMA (L-N-Monomethyl-arginine) 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 L-NMMA (L-N-Monomethyl-arginine) 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 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 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.	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.
Period Title: Aim 1: First Intervention (1 Day)
STARTED	23	21	0	0	0	0	0	0
COMPLETED	23	20	0	0	0	0	0	0
NOT COMPLETED	0	1	0	0	0	0	0	0
Period Title: Aim 1: First Intervention (1 Day)
STARTED	22	17	0	0	0	0	0	0
COMPLETED	22	17	0	0	0	0	0	0
NOT COMPLETED	0	0	0	0	0	0	0	0
Period Title: Aim 1: First Intervention (1 Day)
STARTED	0	0	5	4	2	3	5	4
COMPLETED	0	0	5	4	2	3	5	4
NOT COMPLETED	0	0	0	0	0	0	0	0
Period Title: Aim 1: First Intervention (1 Day)
STARTED	0	0	5	4	2	3	5	3
COMPLETED	0	0	5	4	2	3	5	3
NOT COMPLETED	0	0	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Participants From All Groups
Arm/Group Description	Data was collected as one group
Overall Participants	39
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	25 (5)
Sex: Female, Male (Count of Participants)
Female	29 74.4%
Male	10 25.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 10.3%
Not Hispanic or Latino	35 89.7%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 5.1%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 5.1%
White	35 89.7%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	39 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Data from all subjects who completed both study days in Aim 1 were analyzed. Subjects represented young, healthy adults without any chronic medical conditions and who did not take any medications. Oral birth control use was not permitted.

Arm/Group Title	Aim 1: Sitagliptin,Female Participants	Aim 1: Placebo, Female Participants	Aim 1: Sitagliptin, Male Participants	Aim 1: Placebo, Male Participants
Arm/Group Description	Subjects underwent two study days separated by a washout period. On one study day they received sitagliptin and on another placebo, in a randomized double-blind fashion. Growth hormone secretion was stimulated using arginine on each study day. Growth hormone levels were assessed during a 3 hour period following arginine stimulation.	Subjects underwent two study days separated by a washout period. On one study day they received sitagliptin and on another placebo, in a randomized double-blind fashion. Growth hormone secretion was stimulated using arginine on each study day. Growth hormone levels were assessed during a 3 hour period following arginine stimulation.	Subjects underwent two study days separated by a washout period. On one study day they received sitagliptin and on another placebo, in a randomized double-blind fashion. Growth hormone secretion was stimulated using arginine on each study day. Growth hormone levels were assessed during a 3 hour period following arginine stimulation.	Subjects underwent two study days separated by a washout period. On one study day they received sitagliptin and on another placebo, in a randomized double-blind fashion. Growth hormone secretion was stimulated using arginine on each study day. Growth hormone levels were assessed during a 3 hour period following arginine stimulation.
Measure Participants	29	29	10	10
30 minutes	5.2 (4.2)	3.1 (3.3)	1.9 (1.9)	2.0 (2.3)
45 minutes	9.5 (6.1)	6.6 (5.0)	3.4 (3.5)	3.9 (3.3)
60 minutes	9.4 (6.4)	7.0 (6.0)	3.0 (3.6)	3.3 (2.3)
90 minutes	5.0 (3.4)	6.4 (4.8)	1.1 (1.00)	2.1 (2.0)
120 minutes	2.7 (2.1)	4.2 (3.4)	1.5 (3.1)	0.9 (0.8)
150 minutes	1.8 (2.5)	2.4 (2.1)	2.2 (4.3)	1.8 (3.3)
180 minutes	0.9 (0.9)	1.3 (1.9)	1.0 (1.9)	1.0 (1.8)

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aim 1: Sitagliptin,Female Participants	Aim 1: Placebo, Female Participants	Aim 1: Sitagliptin, Male Participants	Aim 1: Placebo, Male Participants
Arm/Group Description	Subjects underwent two study days separated by a washout period. On one study day they received sitagliptin and on another placebo, in a randomized double-blind fashion. Growth hormone secretion was stimulated using arginine on each study day. Forearm vascular resistance (FVR) was assessed during a 3 hour period following arginine stimulation.	Subjects underwent two study days separated by a washout period. On one study day they received sitagliptin and on another placebo, in a randomized double-blind fashion. Growth hormone secretion was stimulated using arginine on each study day. Forearm vascular resistance (FVR) was assessed during a 3 hour period following arginine stimulation.	Subjects underwent two study days separated by a washout period. On one study day they received sitagliptin and on another placebo, in a randomized double-blind fashion. Growth hormone secretion was stimulated using arginine on each study day. Forearm vascular resistance (FVR) was assessed during a 3 hour period following arginine stimulation.	Subjects underwent two study days separated by a washout period. On one study day they received sitagliptin and on another placebo, in a randomized double-blind fashion. Growth hormone secretion was stimulated using arginine on each study day. Forearm vascular resistance (FVR) was assessed during a 3 hour period following arginine stimulation.
Measure Participants	29	29	10	10
30 minutes	-5.0677 (18.56794)	-5.3498 (19.60881)	1.4929 (21.57596)	-11.2235 (13.60628)
60 minutes	-5.1365 (16.61555)	-1.0195 (22.62776)	6.7355 (23.96889)	4.6875 (31.77169)
90 minutes	-10.1867 (22.00489)	-1.6694 (31.84989)	1.0144 (28.50393)	-3.8029 (35.33295)
120 minutes	-12.5192 (31.29272)	-5.0763 (26.06546)	-10.3674 (32.22945)	-2.7449 (31.52281)
150 minutes	-24.1962 (23.92090)	-11.8335 (27.88447)	-9.7129 (30.40280)	-7.1590 (30.41909)
180 minutes	-22.4043 (27.60020)	-16.5358 (32.22119)	-11.9609 (20.50786)	-15.0591 (25.33331)

3. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

Data from all subjects who completed both study days in Aim 1 were analyzed. Subjects represented young, healthy adults without any chronic medical conditions and who did not take any medications. Oral birth control use was not permitted.

Arm/Group Title	Aim 1: Sitagliptin,Female Participants	Aim 1: Placebo, Female Participants	Aim 1: Sitagliptin, Male Participants	Aim 1: Placebo, Male Participants
Arm/Group Description	Subjects underwent two study days separated by a washout period. On one study day they received sitagliptin and on another placebo, in a randomized double-blind fashion. Growth hormone secretion was stimulated using arginine on each study day. Forearm blood flow was assessed during a 3 hour period following arginine stimulation.	Subjects underwent two study days separated by a washout period. On one study day they received sitagliptin and on another placebo, in a randomized double-blind fashion. Growth hormone secretion was stimulated using arginine on each study day. Forearm blood flow was assessed during a 3 hour period following arginine stimulation.	Subjects underwent two study days separated by a washout period. On one study day they received sitagliptin and on another placebo, in a randomized double-blind fashion. Growth hormone secretion was stimulated using arginine on each study day. Forearm blood flow was assessed during a 3 hour period following arginine stimulation.	Subjects underwent two study days separated by a washout period. On one study day they received sitagliptin and on another placebo, in a randomized double-blind fashion. Growth hormone secretion was stimulated using arginine on each study day. Forearm blood flow was assessed during a 3 hour period following arginine stimulation.
Measure Participants	29	29	10	10
30 minutes	0.4835 (19.44436)	1.6458 (19.42502)	-.0238 (23.86278)	9.2597 (14.60368)
60 minutes	5.3416 (21.33943)	4.9101 (37.42841)	-2.8869 (25.79685)	0.6789 (24.91588)
90 minutes	15.9192 (36.11077)	11.7285 (47.44341)	1.5212 (30.57639)	13.5358 (37.76659)
120 minutes	23.2248 (40.83970)	10.3081 (28.31870)	20.1185 (38.89402)	9.9379 (28.93967)
150 minutes	39.9269 (45.00577)	19.7355 (30.90766)	21.6011 (42.67343)	15.0944 (34.56449)
180 minutes	40.6354 (50.48606)	30.0924 (36.51124)	16.8489 (24.95539)	26.1772 (34.75120)

4. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

19 of the original 29 females in Aim 1 returned to complete two more study days (Aim 2) in which they received sitagliptin + double-blinded study drug vs. sitagliptin plus placebo in a cross-over study. Three men from Aim 1 also returned to complete two more study days (Aim 2).

Arm/Group Title	Aim 2: Sitagliptin and LNMMA, Female Participants	Aim 2: Sitagliptin and Placebo, Females in LNMMA Group	Aim 2: Sitagliptin and LNMMA, Male Participants	Aim 2: Sitagliptin and Placebo, Males in LNMMA Group	Aim 2: Sitagliptin and Pegvisomant, Female Participants	Aim 2: Sitagliptin & Placebo, Females in Pegvisomant Group	Aim 2: Sitagliptin and Exendin 9-39, Female Participants	Aim 2: Sitagliptin and Placebo, Females in Exendin 9-39 Group	Aim 2: Sitagliptin and Exendin 9-39, Male Participant	Aim 2: Sitagliptin and Placebo, Male in Exendin 9-39 Group
Arm/Group Description	Seven of the original 29 women returned for an additional two study days separated by a wash-out period. On one study day they received sitagliptin plus L-N-monomethylarginine (LNMMA) and on another sitagliptin plus placebo, in a randomized cross-over fashion.	Seven of the original 29 women returned for an additional two study days separated by a wash-out period. On one study day they received sitagliptin plus L-N-monomethylarginine (LNMMA) and on another sitagliptin plus placebo, in a randomized cross-over fashion.	Two of the men in Aim 1 returned for an additional two study days separated by a wash-out period. On one study day they received sitagliptin plus L-N-monomethylarginine (LNMMA) and on another sitagliptin plus placebo, in a randomized cross-over fashion.	Two of the men in Aim 1 returned for an additional two study days separated by a wash-out period. On one study day they received sitagliptin plus L-N-monomethylarginine (LNMMA) and on another sitagliptin plus placebo, in a randomized cross-over fashion.	Five of the original 29 women returned for an additional two study days separated by a wash-out period. On one study day they received sitagliptin plus pegvisomant and on another sitagliptin plus placebo, in a randomized cross-over fashion. The protocol specified a priori not to study men further if the first seven men randomized to sitagliptin vs. placebo in Aim 1 showed no effect of sitagliptin in men.	Five of the original 29 women returned for an additional two study days separated by a wash-out period. On one study day they received sitagliptin plus pegvisomant and on another sitagliptin plus placebo, in a randomized cross-over fashion. The protocol specified a priori not to study men further if the first seven men randomized to sitagliptin vs. placebo in Aim 1 showed no effect of sitagliptin in men.	Seven of the original 29 women returned for an additional two study days separated by a wash-out period. On one study day they received sitagliptin plus Exendin 9-39 and on another sitagliptin plus placebo, in a randomized cross-over fashion.	Seven of the original 29 women returned for an additional two study days separated by a wash-out period. On one study day they received sitagliptin plus Exendin 9-39 and on another sitagliptin plus placebo, in a randomized cross-over fashion.	One of the men from Aim 1 returned for an additional two study days separated by a wash-out period. On one study day they received sitagliptin plus Exendin 9-39 and on another sitagliptin plus placebo, in a randomized cross-over fashion.	One of the men from Aim 1 returned for an additional two study days separated by a wash-out period. On one study day they received sitagliptin plus Exendin 9-39 and on another sitagliptin plus placebo, in a randomized cross-over fashion.
Measure Participants	7	7	2	2	5	5	7	7	1	1
30 minutes	-0.71 (6.75)	-9.34 (8.60)	5.17 (4.27)	14.78 (14.78)	15.64 (5.06)	0.39 (8.93)	-7.33 (8.66)	-0.98 (12.08)	-7.59 (NA)	-22.67 (NA)
60 minutes	-3.64 (12.68)	-17.06 (12.93)	7.05 (4.06)	4.56 (0.97)	6.58 (10.16)	16.10 (12.79)	-10.54 (8.53)	6.95 (9.53)	9.37 (NA)	-13.00 (NA)
90 minutes	3.24 (10.02)	-6.35 (16.60)	25.69 (6.25)	20.32 (12.83)	36.96 (14.71)	16.67 (33.39)	2.23 (8.69)	2.08 (11.60)	5.36 (NA)	-18.33 (NA)
120 minutes	4.22 (12.54)	9.80 (18.23)	32.92 (0.97)	56.26 (55.06)	54.10 (21.87)	41.97 (31.29)	31.10 (9.04)	22.24 (11.14)	16.52 (NA)	-22.00 (NA)
150 minutes	16.09 (13.00)	11.26 (28.45)	26.27 (13.73)	71.51 (76.00)	59.08 (32.36)	26.87 (17.56)	29.48 (8.22)	15.59 (8.26)	45.98 (NA)	1.33 (NA)
180 minutes	14.80 (15.85)	17.12 (20.53)	29.24 (35.21)	65.31 (80.28)	51.21 (26.07)	43.51 (26.31)	30.76 (8.88)	27.11 (12.21)	54.91 (NA)	-1.67 (NA)

5. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

19 of the original 29 females who participated in Aim 1 returned to complete an additional two study days (Aim 2) in which they received sitagliptin + double-blinded study drug vs. sitagliptin plus placebo in a cross-over study. Three men from Aim 1 also returned to complete two more study days (Aim 2).

Arm/Group Title	Aim 2: Sitagliptin and LNMMA, Female Participants	Aim 2: Sitagliptin and Placebo, Females in LNMMA Group	Aim 2: Sitagliptin and LNMMA, Male Participants	Aim 2: Sitagliptin and Placebo, Males in LNMMA Group	Aim 2: Sitagliptin and Pegvisomant, Female Participants	Aim 2: Sitagliptin & Placebo,Females in Pegvisomant Group	Aim 2: Sitagliptin and Exendin 9-39, Female Participants	Aim 2: Sitagliptin and Placebo, Females in Exendin 9-39 Group	Aim 2: Sitagliptin and Exendin 9-39, Male Participant	Aim 2: Sitagliptin and Placebo, Male in Exendin 9-39 Group
Arm/Group Description	Seven of the original 29 women returned for an additional two study days separated by a wash-out period. On one study day they received sitagliptin plus LNMMA and on another sitagliptin plus placebo, in a randomized cross-over fashion.	Seven of the original 29 women returned for an additional two study days separated by a wash-out period. On one study day they received sitagliptin plus LNMMA and on another sitagliptin plus placebo, in a randomized cross-over fashion.	Two of the men in Aim 1 returned for an additional two study days separated by a wash-out period. On one study day they received sitagliptin plus L-N-monomethylarginine (LNMMA) and on another sitagliptin plus placebo, in a randomized cross-over fashion.	Two of the men in Aim 1 returned for an additional two study days separated by a wash-out period. On one study day they received sitagliptin plus L-N-monomethylarginine (LNMMA) and on another sitagliptin plus placebo, in a randomized cross-over fashion.	Five of the original 29 women returned for an additional two study days separated by a wash-out period. On one study day they received sitagliptin plus pegvisomant and on another sitagliptin plus placebo, in a randomized cross-over fashion. The protocol specified a priori not to study men further if the first seven men randomized to sitagliptin vs. placebo in Aim 1 showed no effect of sitagliptin in men.	Five of the original 29 women returned for an additional two study days separated by a wash-out period. On one study day they received sitagliptin plus pegvisomant and on another sitagliptin plus placebo, in a randomized cross-over fashion. The protocol specified a priori not to study men further if the first seven men randomized to sitagliptin vs. placebo in Aim 1 showed no effect of sitagliptin in men.	Seven of the original 29 women returned for an additional two study days separated by a wash-out period. On one study day they received sitagliptin plus Exendin 9-39 and on another sitagliptin plus placebo, in a randomized cross-over fashion.	Seven of the original 29 women returned for an additional two study days separated by a wash-out period. On one study day they received sitagliptin plus Exendin 9-39 and on another sitagliptin plus placebo, in a randomized cross-over fashion.	One of the men in Aim 1 returned for an additional two study days separated by a wash-out period. On one study day they received sitagliptin plus Exendin 9-39 and on another sitagliptin plus placebo, in a randomized cross-over fashion.	One of the men in Aim 1 returned for an additional two study days separated by a wash-out period. On one study day they received sitagliptin plus Exendin 9-39 and on another sitagliptin plus placebo, in a randomized cross-over fashion.
Measure Participants	7	7	2	2	5	5	7	7	1	1
30 minutes	-8.67 (9.66)	8.98 (12.07)	-9.87 (0.82)	-14.60 (12.22)	-20.00 (3.67)	-3.75 (12.43)	5.30 (8.19)	4.53 (12.62)	0.57 (NA)	27.77 (NA)
60 minutes	8.77 (17.03)	51.82 (36.73)	-9.75 (2.28)	-2.42 (3.34)	-4.05 (10.67)	-10.97 (11.64)	14.46 (11.08)	-4.26 (7.26)	-11.80 (NA)	6.73 (NA)
90 minutes	-4.89 (8.93)	39.24 (35.45)	-23.34 (8.00)	-16.75 (4.25)	-25.28 (7.02)	3.79 (19.09)	1.76 (8.96)	4.82 (16.53)	-14.02 (NA)	22.45 (NA)
120 minutes	0.99 (11.00)	21.98 (35.57)	-24.81 (1.18)	-28.34 (21.27)	-32.39 (8.90)	-14.57 (18.78)	-22.37 (6.11)	-13.16 (10.34)	-16.20 (NA)	26.68 (NA)
150 minutes	-13.25 (8.49)	42.27 (44.03)	-20.62 (6.34)	-32.11 (24.34)	-30.12 (11.10)	-14.25 (13.15)	-20.92 (5.30)	-8.49 (9.03)	-32.30 (NA)	-1.32 (NA)
180 minutes	-10.25 (10.76)	5.28 (19.22)	-22.56 (13.90)	-19.52 (37.12)	-25.00 (11.92)	-17.97 (15.66)	-22.58 (5.82)	-16.76 (8.94)	-34.69 (NA)	1.69 (NA)

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Data from the first 14 subjects (7 men and 7 women) who completed both study days in Aim 1 were analyzed. We do not report tPA results from the remaining participants as the manufacturer changed the tPA assay standard and results were not comparable.

Arm/Group Title	Aim 1: Sitagliptin,Female Participants	Aim 1: Placebo, Female Participants	Aim 1: Sitagliptin, Male Participants	Aim 1: Placebo, Male Participants
Arm/Group Description	Subjects undergo two study days separated by a washout period. On one study day they received sitagliptin and on another placebo, in a randomized double-blind fashion. Growth hormone secretion was stimulated using arginine on each study day. tPA levels were assessed during a 3 hour period following arginine stimulation.	Subjects underwent two study days separated by a washout period. On one study day they received sitagliptin and on another placebo, in a randomized double-blind fashion. Growth hormone secretion was stimulated using arginine on each study day. tPA levels were assessed during a 3 hour period following arginine stimulation.	Subjects underwent two study days separated by a washout period. On one study day they received sitagliptin and on another placebo, in a randomized double-blind fashion. Growth hormone secretion was stimulated using arginine on each study day. tPA levels were assessed during a 3 hour period following arginine stimulation.	Subjects underwent two study days separated by a washout period. On one study day they received sitagliptin and on another placebo, in a randomized double-blind fashion. Growth hormone secretion was stimulated using arginine on each study day. tPA levels were assessed during a 3 hour period following arginine stimulation.
Measure Participants	7	7	7	7
Baseline prior to Arginine	0.30 (0.05)	0.28 (0.05)	0.44 (0.14)	0.22 (0.07)
30 minutes	0.40 (0.04)	0.32 (0.04)	0.28 (0.08)	0.25 (0.07)
45 minutes	0.43 (0.04)	0.35 (0.04)	0.40 (0.10)	0.32 (0.08)
60 minutes	0.40 (0.06)	0.32 (0.05)	0.37 (0.09)	0.34 (0.08)
90 minutes	0.39 (0.07)	0.35 (0.06)	0.34 (0.09)	0.27 (0.07)
120 minutes	0.40 (0.07)	0.35 (0.04)	0.38 (0.12)	0.28 (0.07)
150 minutes	0.44 (0.04)	0.41 (0.04)	0.42 (0.12)	0.37 (0.08)
180 minutes	0.55 (0.06)	0.50 (0.05)	0.51 (0.12)	0.45 (0.09)

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Five of the original 29 women returned for two more study days separated by a wash-out. As pre-specified in the protocol, men did not complete this portion of the study. We do not report tPA results from participants who received LNMMA and Exendin 9-39 in this table as the manufacturer changed the tPA assay standard and results were not comparable.

Arm/Group Title	Aim 2: Sitagliptin and Placebo, Females in Pegvisomant Group	Aim 2: Sitagliptin and Pegvisomant, Female Participants
Arm/Group Description	Five of the original 29 women returned for an additional two study days separated by a wash-out period. On one study day they received sitagliptin plus pegvisomant and on another sitagliptin plus placebo, in a randomized cross-over fashion.	Five of the original 29 women returned for an additional two study days separated by a wash-out period. On one study day they received sitagliptin plus pegvisomant and on another sitagliptin plus placebo, in a randomized cross-over fashion.
Measure Participants	5	5
Baseline prior to Arginine	0.24 (0.05)	0.10 (0.03)
30 minutes	0.26 (0.04)	0.15 (0.05)
45 minutes	0.33 (0.06)	0.17 (0.06)
60 minutes	0.27 (0.08)	0.14 (0.04)
90 minutes	0.26 (0.07)	0.16 (0.05)
120 minutes	0.28 (0.08)	0.16 (0.05)
150 minutes	0.31 (0.07)	0.20 (0.05)
180 minutes	0.35 (0.06)	0.23 (0.05)

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Five of the original 29 women returned for an additional two study days separated by a wash-out period. As pre-specified in the protocol, men did not complete this portion of the study. We did not measure GH levels in participants who received LNMMA or Exendin 9-39 as these drugs are not known to influence GH secretion.

Arm/Group Title	Aim 2: Sitagliptin and Placebo, Females in Pegvisomant Group	Aim 2: Sitagliptin and Pegvisomant, Female Participants
Arm/Group Description	Five of the original 29 women returned for an additional two study days separated by a wash-out period. On one study day they received sitagliptin plus pegvisomant and on another sitagliptin plus placebo, in a randomized cross-over fashion.	Five of the original 29 women returned for an additional two study days separated by a wash-out period. On one study day they received sitagliptin plus pegvisomant and on another sitagliptin plus placebo, in a randomized cross-over fashion.
Measure Participants	5	5
30 minutes	2.99 (1.60)	4.27 (2.19)
60 minutes	5.92 (2.37)	7.00 (2.20)
90 minutes	6.05 (2.39)	11.53 (4.67)
120 minutes	4.06 (2.18)	6.17 (1.21)
150 minutes	1.83 (0.83)	4.09 (1.33)
180 minutes	1.57 (0.82)	1.77 (0.32)

Adverse Events

Time Frame	The first subject started drug 2/11/13 and the last completed 2/10/2017. In Aim 1, each subject took oral study drug (placebo vs. sitagliptin). Adverse event data was collected over a one month period for each subject. In Aim 2, each subject took oral sitagliptin and also received a single dose of LNMMA, Exendin 9-39 or Pegvisomant based upon their subgroup assigment. Adverse event data was collected over a 6 week period for each subject.
Arm/Group Title	Sitagliptin		Placebo		Sitagliptin Plus Pegvisomant		Sitagliptin Plus LNMMA		Sitagliptin Plus Exendin 9-39
Arm/Group Description	Healthy lean adults completed a double blinded cross over study in which they took sitagliptin vs. placebo separated by a wash-out.		Healthy lean adults completed a double blinded cross over study in which they took sitagliptin vs. placebo separated by a wash-out.		Five women from Aim 1 returned for an additional two study days in which they were randomized to sitagliptin plus placebo vs. sitagliptin plus pre-treatment with pegvisomant.		9 participants from Aim 1 returned for an additional two study days in which they were randomized to sitagliptin plus placebo vs. sitagliptin plus L-N-mono-methylarginine (LNMMA).		8 participants from Aim 1 returned for an additional two study days in which they were randomized to sitagliptin plus placebo vs. sitagliptin plus Exendin 9-39.
All Cause Mortality
	Sitagliptin		Placebo		Sitagliptin Plus Pegvisomant		Sitagliptin Plus LNMMA		Sitagliptin Plus Exendin 9-39
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/40 (0%)		0/43 (0%)		0/5 (0%)		0/9 (0%)		0/8 (0%)
Serious Adverse Events
	Sitagliptin		Placebo		Sitagliptin Plus Pegvisomant		Sitagliptin Plus LNMMA		Sitagliptin Plus Exendin 9-39
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/40 (0%)		0/43 (0%)		0/5 (0%)		0/9 (0%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Sitagliptin		Placebo		Sitagliptin Plus Pegvisomant		Sitagliptin Plus LNMMA		Sitagliptin Plus Exendin 9-39
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/40 (17.5%)		1/43 (2.3%)		2/5 (40%)		0/9 (0%)		0/8 (0%)
Cardiac disorders
Palpitations	1/40 (2.5%)		0/43 (0%)		0/5 (0%)		0/9 (0%)		0/8 (0%)
Ear and labyrinth disorders
Nasal congestion	1/40 (2.5%)		0/43 (0%)		0/5 (0%)		0/9 (0%)		0/8 (0%)
Gastrointestinal disorders
Nausea	3/40 (7.5%)		1/43 (2.3%)		0/5 (0%)		0/9 (0%)		0/8 (0%)
Reflux	1/40 (2.5%)		0/43 (0%)		0/5 (0%)		0/9 (0%)		0/8 (0%)
Abdominal cramping and diarrhea	0/40 (0%)		0/43 (0%)		1/5 (20%)		0/9 (0%)		0/8 (0%)
Nervous system disorders
Dizziness and paresthesias during arginine infusion	0/40 (0%)		0/43 (0%)		1/5 (20%)		0/9 (0%)		0/8 (0%)
Skin and subcutaneous tissue disorders
Bruising related to placement of intravenous catheter	3/40 (7.5%)		0/43 (0%)		0/5 (0%)		0/9 (0%)		0/8 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.