Effect of DPP4 Inhibition on Growth Hormone Secretion - Full Text View

Purpose

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 GLP-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	Intervention	Phase
Obesity	Drug: Sitagliptin Drug: Pegvisomant Drug: Placebo Drug: L-NMMA Drug: Exendin 9-39	Phase 4


Study Type:	Interventional
Study Design:	Allocation: Randomized Intervention Model: Crossover Assignment Masking: Double Blind (Subject, Investigator)
Official Title:	The Effect of Dipeptidyl Peptidase IV Inhibition on Growth Hormone-Mediated Vasodilation

Resource links provided by NLM:

MedlinePlus related topics: Hormones

Drug Information available for: Pegvisomant Sitagliptin Sitagliptin phosphate

U.S. FDA Resources

Further study details as provided by Vanderbilt University:

Primary Outcome Measures:

Aim 1: stimulated peak growth hormone level [ Time Frame: Change from Baseline in Growth Hormone level ] [ Designated as safety issue: No ]
Subjects undergo two study days separated by a washout period. On one study day they will receive study drug and on another placebo, in a randomized double-blind fashion. Growth hormone level will be stimulated using arginine on each study day. Growth hormone levels will be assessed during a 3 hour period following arginine stimulation. The peak Growth Hormone level will be obtained.
Aim 2: forearm blood flow [ Time Frame: Change from Baseline in Forearm Blood Flow ] [ Designated as safety issue: No ]
Subjects undergo two study days separated by a washout period. On one study day they will receive study drug and on another placebo, in a randomized double-blind fashion. Forearm blood flow will be assessed at each visit.

Secondary Outcome Measures:

Venous Blood Sampling [ Time Frame: Change from Baseline in Venous Blood Samples ] [ Designated as safety issue: No ]
In Aim 1 and 2, subjects undergo two study days separated by a washout period. On one study day they will receive study drug and on another placebo, in a randomized double-blind fashion. Venous blood samples will be obtained at each visit. These samples will be analyzed for markers of cardiovascular and metabolic risk.


Estimated Enrollment:	42
Study Start Date:	January 2013
Estimated Study Completion Date:	August 2016
Estimated Primary Completion Date:	July 2016 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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 L-NMMA 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: NG-Monomethyl-L-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)

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.

Eligibility


Ages Eligible for Study:	18 Years to 40 Years (Adult)
Genders Eligible for Study:	Both
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 β-HCG 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 SBP greater than 140 mmHg and/or an untreated 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 IGF-1 at the time of screening visit
Impaired renal function, defined as eGFR <60 mL/min/1.73M2
Impaired hepatic function (AST or ALT > 2 X upper limit of normal range)
Treatment with an investigational drug in the 1 month preceding the study

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01701973

Locations


United States, Tennessee
Vanderbilt University Medical Center	Recruiting
Nashville, Tennessee, United States, 37232
Contact: Patricia Wright, RN 615-322-8837 patricia.wright@vanderbilt.edu
Principal Investigator: Jessica K Devin, MD, MSCI

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

More Information


Responsible Party:	Jessica Koch Devin, Assistant Professor, Vanderbilt University
ClinicalTrials.gov Identifier:	NCT01701973 History of Changes
Other Study ID Numbers:	120078 1K23HL119602
Study First Received:	October 3, 2012
Last Updated:	April 29, 2016
Health Authority:	United States: Institutional Review Board United States: Food and Drug Administration

Keywords provided by Vanderbilt University:


obesity growth hormone

Additional relevant MeSH terms:


Hormones Sitagliptin Phosphate Omega-N-Methylarginine 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

ClinicalTrials.gov processed this record on September 30, 2016