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

Primary Purpose

Polycystic Ovary Syndrome

Status

Completed

Phase

Phase 4

Locations

United States

Study Type

Interventional

Intervention

Sitagliptin

Placebo

About this trial

This is an interventional other trial for Polycystic Ovary Syndrome focused on measuring Growth Hormone, Dipeptidyl Peptidase 4, Polycystic Ovary Syndrome

Eligibility Criteria

18 Years - 40 Years (Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

Vanderbilt University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Sitagliptin, then Placebo

Placebo, then Sitagliptin

Arm Description

Sitagliptin 100 mg by mouth daily for 30 days followed by Placebo daily for 30 days

Placebo daily for 30 days followed by Sitagliptin 100 mg daily for 30 days

Outcomes

Primary Outcome Measures

Mean Overnight Growth Hormone Levels

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

Early Insulin Secretion During Oral Glucose Tolerance Test

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.

Area Under the Curve (AUC) for Blood Glucoses During 75 Gram Oral Glucose Tolerance Test

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.

Visceral Adipose Tissue

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)

Vascular Function (Endothelium-dependent Vasodilation)

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.

Full Information

NCT ID

NCT02122380

First Posted

April 14, 2014

Last Updated

April 30, 2020

Sponsor

Vanderbilt University

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

1. Study Identification

Unique Protocol Identification Number

NCT02122380

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

April 2020

Overall Recruitment Status

Completed

Study Start Date

February 2016 (undefined)

Primary Completion Date

August 1, 2019 (Actual)

Study Completion Date

August 1, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Vanderbilt University

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Polycystic Ovary Syndrome

Keywords

Growth Hormone, Dipeptidyl Peptidase 4, Polycystic Ovary Syndrome

7. Study Design

Primary Purpose

Other

Study Phase

Phase 4

Interventional Study Model

Crossover Assignment

Masking

ParticipantInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

23 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Sitagliptin, then Placebo

Arm Type

Experimental

Arm Description

Sitagliptin 100 mg by mouth daily for 30 days followed by Placebo daily for 30 days

Arm Title

Placebo, then Sitagliptin

Arm Type

Experimental

Arm Description

Placebo daily for 30 days followed by Sitagliptin 100 mg daily for 30 days

Intervention Type

Drug

Intervention Name(s)

Sitagliptin

Other Intervention Name(s)

Januvia

Intervention Description

Sitagliptin 100 mg by mouth daily for 30 Days

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

1 placebo pill by mouth per day for 30 days

Primary Outcome Measure Information:

Title

Mean Overnight Growth Hormone Levels

Description

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.

Secondary Outcome Measure Information:

Title

Early Insulin Secretion During Oral Glucose Tolerance Test

Description

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.

Title

Area Under the Curve (AUC) for Blood Glucoses During 75 Gram Oral Glucose Tolerance Test

Description

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.

Title

Visceral Adipose Tissue

Description

Time Frame

At completion of 30 days of placebo treatment and at completion of 30 days of sitagliptin treatment.

Title

Vascular Function (Endothelium-dependent Vasodilation)

Description

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.

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

40 Years

Accepts Healthy Volunteers

Eligibility 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jessica Devin, MD MSCI

Organizational Affiliation

Vanderbilt University Medical Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

Vanderbilt University Medical Center

City

Nashville

State/Province

Tennessee

ZIP/Postal Code

37232

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

31529097

Citation

Devin JK, Nian H, Celedonio JE, Wright P, Brown NJ. Sitagliptin Decreases Visceral Fat and Blood Glucose in Women With Polycystic Ovarian Syndrome. J Clin Endocrinol Metab. 2020 Jan 1;105(1):136-51. doi: 10.1210/clinem/dgz028.

Results Reference

derived

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

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