Effect of DPP4 Inhibition on Growth Hormone Secretion

• ClinicalTrials.gov Identifier: NCT01701973
• Recruitment Status: Completed
• First Posted: October 5, 2012
• Results First Posted: May 29, 2018
• Last Update Posted: May 29, 2018
• Sponsor: Vanderbilt University
• Collaborators: National Institutes of Health (NIH); National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Jessica Koch Devin, Vanderbilt University

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 (Clinical Trial)
• 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: January 2013
• Actual Primary Completion Date: May 2017
• Actual Study Completion Date: May 2017

Arms and Interventions

Arm	Intervention/treatment
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 Name: 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 Name: sugar pill; Drug: L-NMMA; During Aim 2, given during one of two study days (Group A subjects only); Other Name: L-N-Monomethyl-arginine
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 Name: Januvia; Drug: Pegvisomant; During Aim 2, given 72 hours prior to one of two study days (Group B subjects only); Other Name: 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 Name: sugar pill
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 Name: 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 Name: 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 [ 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 ]
   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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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

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

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

Contacts and Locations

Locations

United States, Tennessee

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)

Documents provided by Jessica Koch Devin, Vanderbilt University:

Study Protocol and Statistical Analysis Plan  [PDF] September 8, 2016

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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). pii: e008000. doi: 10.1161/JAHA.117.008000.

• Responsible Party: Jessica Koch Devin, Assistant Professor, Vanderbilt University
• ClinicalTrials.gov Identifier: NCT01701973
• Other Study ID Numbers: 120078; 1K23HL119602 ( U.S. NIH Grant/Contract )
• First Posted: October 5, 2012
• Results First Posted: May 29, 2018
• Last Update Posted: May 29, 2018
• Last Verified: May 2018

Keywords provided by Jessica Koch Devin, Vanderbilt University:

obesity; growth hormone

Additional relevant MeSH terms:

Obesity; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Sitagliptin Phosphate; Hypoglycemic Agents; Physiological Effects of Drugs; Incretins; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Dipeptidyl-Peptidase IV Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action