Effect of DPP4 Inhibition on Growth Hormone Secretion

NCT01701973 | Completed Phase 4 Results DMC

• 2 other identifiers: 1200781K23HL119602
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 1

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.

Conditions

Obesity

Keywords

obesity; growth hormone

Outcome Measures

Primary Outcomes (5)

• 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.

  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

• 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.

  Percent change from baseline in forearm vascular resistance at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes

• 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.

  Percent change from baseline in forearm blood flow at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes.

• 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.

  Percent change from baseline in forearm blood flow at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes.

• 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.

  Percent change from baseline in forearm vascular resistance at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes

Secondary Outcomes (3)

• Aim 1: Venous Blood Sampling for Tissue Plasminogen Activator (TPA) Activity Levels

  baseline and every 30 minutes for 180 minutes

• Aim 2: Venous Blood Sampling for Tissue Plasminogen Activator (TPA) Activity Levels

  baseline and every 30 minutes until 180 minutes

• Aim 2: Measurement of Growth Hormone (GH) Levels

  baseline and every 30 minutes until 180 minutes

Study Arms (3)

Group A (14 healthy subjects)

OTHER

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; Drug: Placebo; Drug: L-NMMA

Group B (14 healthy subjects)

OTHER

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; Drug: Pegvisomant; Drug: Placebo

Group C (14 healthy subjects)

OTHER

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; Drug: Placebo; Drug: Exendin 9-39

Interventions

Sitagliptin DRUG

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.

Also known as: Januvia

Group A (14 healthy subjects); Group B (14 healthy subjects); Group C (14 healthy subjects)

Pegvisomant DRUG

During Aim 2, given 72 hours prior to one of two study days (Group B subjects only)

Also known as: Somavert

Group B (14 healthy subjects)

Placebo DRUG

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)

Also known as: sugar pill

Group A (14 healthy subjects); Group B (14 healthy subjects); Group C (14 healthy subjects)

L-NMMA DRUG

During Aim 2, given during one of two study days (Group A subjects only)

Also known as: L-N-Monomethyl-arginine

Group A (14 healthy subjects)

Exendin 9-39 DRUG

During Aim 2, given during one of two study days (Group C subjects only)

Group C (14 healthy subjects)

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

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

Study Sites (1)

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

Related Publications (1)

• 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.

  PMID: 29478970 DERIVED

MeSH Terms

Conditions

Obesity

Interventions

Sitagliptin Phosphate; pegvisomant; Sugars; omega-N-Methylarginine; exendin (9-39)

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrazines; Carbohydrates; Arginine; Amino Acids, Basic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Diamino; Amino Acids, Essential

Results Point of Contact

• Title: Dr. Jessica Devin
• Organization: Vanderbilt University Medical Center

jessica.devin@vanderbilt.edu

6159361665

Study Officials

• Jessica K Devin, MD, MSCI

  Vanderbilt University Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: October 3, 2012
• First Posted: October 5, 2012
• Study Start: January 1, 2013
• Primary Completion: May 1, 2017
• Study Completion: May 1, 2017
• Last Updated: May 29, 2018
• Results First Posted: May 29, 2018

Record last verified: 2018-05

Locations

US (1)