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The Effect of Dipeptidyl Peptidase 4 Inhibition on Growth Hormone Secretion in Women With Polycystic Ovarian Syndrome

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02122380
Recruitment Status : Completed
First Posted : April 24, 2014
Results First Posted : May 8, 2020
Last Update Posted : May 8, 2020
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Jessica Koch Devin, Vanderbilt University

Brief Summary:
Adults with abdominal obesity are at high risk for cardiovascular disease and also exhibit diminished growth hormone (GH) secretion; the latter further contributes to the development of visceral adiposity, impaired fibrinolysis and inflammation.Growth hormone releasing hormone (GHRH), the primary stimulus for endogenous GH secretion, is a substrate of dipeptidyl peptidase 4 (DPP4); inhibition of DPP4 with the currently available anti-diabetic therapy, sitagliptin, may therefore increase GH secretion by decreasing the degradation of GHRH. The proposed research will test the hypothesis that chronic sitagliptin therapy will enhance GH secretion and vascular function while improving glucose tolerance in patients with impaired GH secretion who are at risk for the development of diabetes mellitus and cardiovascular disease, specifically obese women with polycystic ovary syndrome.

Condition or disease Intervention/treatment Phase
Polycystic Ovary Syndrome Drug: Sitagliptin Drug: Placebo Phase 4

Detailed Description:

Thirty-four obese (BMI ≥ 30 kg/m2) females (18-40 years old) with polycystic ovarian syndrome (PCOS) will participate in this randomized, double-blind, placebo-controlled crossover study. The use of oral contraceptives or metformin will be discontinued at least 30 days prior. In females experiencing monthly cycles, the outpatient visit will take place during the mid-luteal phase of the participant's menstrual cycle and the inpatient visit will take place during the late follicular phase.

Subjects will be randomized to treatment order (sitagliptin 100 mg daily vs placebo) using a block randomization algorithm with a block size of two. The dose of sitagliptin was chosen as it is currently the FDA-recommended dose of sitagliptin for type 2 diabetic patients with unimpaired renal function. Subjects will receive standardized dietary counseling throughout the study; visits will be standardized to the menstrual cycle when possible. Subjects will take each therapy for one month; a minimum one month wash-out will separate study treatments. Side effects and compliance with study medication will be assessed at each visit in the clinical research center (CRC).

Each subject will undergo one outpatient visit and one inpatient visit during each treatment. On each study day, subjects will report fasting to the CRC in the morning having abstained from exercise that morning. On each study day, subjects will receive an intravenous catheter. Subjects will undergo an oral glucose tolerance test (OGTT) during the outpatient study visit. During the inpatient study visit, endothelium-dependent and -independent vasodilation will be assessed using flow-mediated dilation technique with ultrasound. Standardized meals will be provided at lunch and dinner. Body composition will be determined in the afternoon. At 8 PM overnight frequent sampling for venous GH will begin every 10 minutes for 12 hours to determine overnight GH secretion.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 23 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Other
Official Title: The Effect of Dipeptidyl Peptidase 4 Inhibition on Growth Hormone Secretion in Women With Polycystic Ovarian Syndrome
Study Start Date : February 2016
Actual Primary Completion Date : August 1, 2019
Actual Study Completion Date : August 1, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Sitagliptin, then Placebo
Sitagliptin 100 mg by mouth daily for 30 days followed by Placebo daily for 30 days
Drug: Sitagliptin
Sitagliptin 100 mg by mouth daily for 30 Days
Other Name: Januvia

Drug: Placebo
1 placebo pill by mouth per day for 30 days

Experimental: Placebo, then Sitagliptin
Placebo daily for 30 days followed by Sitagliptin 100 mg daily for 30 days
Drug: Sitagliptin
Sitagliptin 100 mg by mouth daily for 30 Days
Other Name: Januvia

Drug: Placebo
1 placebo pill by mouth per day for 30 days




Primary Outcome Measures :
  1. Mean Overnight Growth Hormone Levels [ Time Frame: At completion of 30 days of placebo treatment and at completion of 30 days of sitagliptin treatment; every 10 minutes from 8 PM until 8 AM. ]
    Growth hormone levels were determined every 10 minutes from 8 PM until 8 AM during the inpatient visit on the last day of each treatment. A mean of the GH levels was calculated for each participant, and then the value from each participant was averaged across all participants.


Secondary Outcome Measures :
  1. Early Insulin Secretion During Oral Glucose Tolerance Test [ Time Frame: During Outpatient Visit (after 2 weeks of therapy) during placebo and sitagliptin treatment periods. Insulin levels were obtained at time 0, 15 and 30 minutes following 75 gram glucose ingestion. ]
    Oral glucose tolerance testing was performed with 75 grams of glucose solution. Baseline venous blood samples of insulin were obtained prior to ingestion of oral glucose solution (time 0). Insulin levels were then obtained through a peripheral IV line every 15 minutes for 270 minutes after glucose solution is swallowed. Early insulin secretion was determined by calculating area under the curve using data (i.e. insulin levels) obtained at baseline (time 0), 15 minutes and 30 minutes.

  2. Area Under the Curve (AUC) for Blood Glucoses During 75 Gram Oral Glucose Tolerance Test [ Time Frame: During Outpatient Visit (after 2 weeks of therapy) during placebo and sitagliptin treatment periods. Every 15 minutes from time 0 to 120 minutes after oral glucose ingestion. ]
    Oral glucose tolerance testing was performed with 75 grams of glucose solution. Baseline blood glucose was obtained prior to ingestion of oral glucose solution (time 0). Blood glucose levels were then obtained through a peripheral IV line every 15 minutes from timepoint 0 until 120 minutes to calculate the area under the curve.

  3. Visceral Adipose Tissue [ Time Frame: At completion of 30 days of placebo treatment and at completion of 30 days of sitagliptin treatment. ]
    During the inpatient visit of each treatment (placebo and sitagliptin), visceral adipose tissue was determined by a certified densitometrist using dual-energy x-ray absorptiometry with enCore software (v. 13.6)

  4. Vascular Function (Endothelium-dependent Vasodilation) [ Time Frame: Vascular function was determined by measuring brachial artery diameter at rest and during reactive hyperemia and calculating percent change. This was determined after 30 days of placebo treatment and after 30 days of sitagliptin treatment. ]
    Endothelium-dependent vasodilation was evaluated by measuring the diameter of the brachial artery under basal (i.e. rest) condition and during reactive hyperemia. The percentage change in diameter (i.e. endothelium-dependent vasodilation) was calculated as percent change=[(peak diameter-baseline diameter)/baseline diameter]*100. Endothelium-dependent vasodilation was determined twice during the study: at completion of 30 days of placebo treatment and at completion of 30 days of sitagliptin treatment.



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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Females, age 18-40 years
  • BMI ≥ 30 kg/m2
  • Diagnosis of polycystic ovary syndrome defined by 2003 Rotterdam criteria as meeting two out of the three below criteria :

    • Oligomenorrhea or amenorrhea
    • clinical or biochemical evidence of hyperandrogenism (hirsutism and/or documented upper normal or elevated serum testosterone in the absence of exogenous hormone therapy or Metformin)
    • documented history of polycystic ovaries on ultrasound examination

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 150 mmHg and/or an untreated diastolic blood pressure (DBP) greater than 95 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 (Negative serum pregnancy test will be confirmed at screening visit and every study visit.)
  • Surgical menopause, defined as s/p total hysterectomy including bilateral salpingo-oophorectomy
  • Use of transdermal or oral contraceptive therapy. The use of these contraceptives must be discontinued at least 8 weeks prior to study initiation.
  • The use of insulin sensitizers, specifically Metformin or thiazolidinediones must be discontinued 8 weeks prior to study initiation.
  • 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), prolactin, or morning 17 hydroxyprogesterone at the time of screening visit
  • Impaired renal function, defined as estimated glomerular filtration rate (eGFR) <60
  • 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
  • Allergy to any of the medications used in this protocol
  • Regular work of a night-shift or unusual schedule which may disrupt circadian rhythm.
  • Personal or Family History (defined as first degree relative) of Pancreatic Cancer
  • Personal history of Pancreatitis or known pancreatic lesions
  • Coagulopathy as defined by history
  • Regular NSAID use, including but not limited to, naproxen, ibuprofen, and aspirin
  • Mental conditions rendering the subject unable to understand the nature, scope, and possible consequences of the study
  • Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study
  • Any underlying or acute disease requiring regular medication that could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult

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): NCT02122380


Locations
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United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Vanderbilt University
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
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Principal Investigator: Jessica 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):
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Responsible Party: Jessica Koch Devin, Principal Investigator, Vanderbilt University
ClinicalTrials.gov Identifier: NCT02122380    
Other Study ID Numbers: 131969
K23HL119602-01A1 ( U.S. NIH Grant/Contract )
First Posted: April 24, 2014    Key Record Dates
Results First Posted: May 8, 2020
Last Update Posted: May 8, 2020
Last Verified: April 2020
Keywords provided by Jessica Koch Devin, Vanderbilt University:
Growth Hormone
Dipeptidyl Peptidase 4
Polycystic Ovary Syndrome
Additional relevant MeSH terms:
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Polycystic Ovary Syndrome
Syndrome
Disease
Pathologic Processes
Ovarian Cysts
Cysts
Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Gonadal Disorders
Endocrine System Diseases
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