Clinical trial NCT02122380: 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
Overall status: COMPLETED
Phase: PHASE4
Conditions: Polycystic Ovary Syndrome
Keywords: Growth Hormone
Dipeptidyl Peptidase 4
Polycystic Ovary Syndrome
Lead sponsor: Vanderbilt University Medical Center
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2014-04-24
Enrollment: 23
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: OTHER

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.

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

Primary outcomes:
measure: Mean Overnight Growth Hormone Levels
timeFrame: 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 outcomes:
measure: Early Insulin Secretion During Oral Glucose Tolerance Test
timeFrame: 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.
measure: Area Under the Curve (AUC) for Blood Glucoses During 75 Gram Oral Glucose Tolerance Test
timeFrame: 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.
measure: Visceral Adipose Tissue
timeFrame: At completion of 30 days of placebo treatment and at completion of 30 days of sitagliptin treatment.
measure: Vascular Function (Endothelium-dependent Vasodilation)
timeFrame: 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.
Other outcomes:
Locations:
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
Study officials:
affiliation: Vanderbilt University Medical Center
name: Jessica Devin, MD MSCI
role: PRINCIPAL_INVESTIGATOR
References:
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.