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Effect of DPP4 Inhibition on Growth Hormone Secretion

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ClinicalTrials.gov Identifier: NCT01701973
Recruitment Status : Completed
First Posted : October 5, 2012
Results First Posted : May 28, 2018
Last Update Posted : May 28, 2018
Sponsor:
Collaborators:
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Jessica Koch Devin, Vanderbilt University

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 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

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hormones
Drug Information available for: Sitagliptin

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)




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.



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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01701973


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:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Jessica Koch Devin, Assistant Professor, Vanderbilt University
ClinicalTrials.gov Identifier: NCT01701973     History of Changes
Other Study ID Numbers: 120078
1K23HL119602 ( U.S. NIH Grant/Contract )
First Posted: October 5, 2012    Key Record Dates
Results First Posted: May 28, 2018
Last Update Posted: May 28, 2018
Last Verified: May 2018

Keywords provided by Jessica Koch Devin, Vanderbilt University:
obesity
growth hormone

Additional relevant MeSH terms:
Hormones
Sitagliptin Phosphate
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Hypoglycemic Agents
Incretins
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action