Polycystic Ovary Syndrome
Conditions
Keywords
Growth Hormone, Dipeptidyl Peptidase 4, Polycystic Ovary Syndrome
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.
Interventions
DRUGSitagliptin
Sitagliptin 100 mg by mouth daily for 30 Days
DRUGPlacebo
1 placebo pill by mouth per day for 30 days
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Vanderbilt University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 40 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Overnight Growth Hormone Levels | 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
| Measure | Time frame | Description |
|---|---|---|
| Early Insulin Secretion During Oral Glucose Tolerance Test | 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. |
| Area Under the Curve (AUC) for Blood Glucoses During 75 Gram Oral Glucose Tolerance Test | 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. |
| Visceral Adipose Tissue | 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) |
| Vascular Function (Endothelium-dependent Vasodilation) | 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. |
Countries
United States
Participant flow
Recruitment details
55 patients were screened for eligibility at Vanderbilt University Medical Center.
Pre-assignment details
23 out of 55 participants were randomized. Of those not randomized, 23 were did not meet inclusion criteria and 9 declined to participate.
Participants by arm
| Arm | Count |
|---|---|
| Sitagliptin Then Placebo Participants first received sitagliptin 100 mg by mouth daily for 30 days. After an 8 week washout period, they then received Placebo daily for 30 days. | 11 |
| Placebo Then Sitagliptin Participants first received Placebo daily for 30 days. After an 8 week washout period, they then received Sitagliptin 100 mg daily for 30 days. | 12 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (30 Days) | Adverse Event | 1 | 0 |
| First Intervention (30 Days) | Physician Decision | 0 | 1 |
| Second Intervention (30 Days) | 2 did not complete all of inpatient day | 0 | 2 |
| Washout (8 Weeks) | Lost to Follow-up | 1 | 0 |
| Washout (8 Weeks) | No Longer Met Inclusion Criteria | 0 | 2 |
Baseline characteristics
| Characteristic | Placebo Then Sitagliptin | Total | Sitagliptin Then Placebo |
|---|---|---|---|
| Age, Continuous | 30.3 years STANDARD_DEVIATION 4.3 | 30.3 years STANDARD_DEVIATION 4.3 | 30.4 years STANDARD_DEVIATION 4.3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 16 Participants | 8 Participants |
| Sex: Female, Male Female | 12 Participants | 23 Participants | 11 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 21 |
| other Total, other adverse events | 5 / 20 | 9 / 21 |
| serious Total, serious adverse events | 1 / 20 | 0 / 21 |
Outcome results
Primary
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.
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.
Population: All participants who received both interventions and completed both inpatient visits were included in the analysis. (1 participant was unable to complete their 2nd inpatient visit due to a family emergency. A 2nd participant was unable to complete the overnight portion of the inpatient visit due to illness in a family member.)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Overnight Growth Hormone Levels | 0.85 ng/mL | Standard Deviation 0.54 |
| Sitagliptin | Mean Overnight Growth Hormone Levels | 0.84 ng/mL | Standard Deviation 0.51 |
Comparison: Null hypothesis is that there was no difference in change of mean growth hormone (GH) levels between sitagliptin and placebo. The test was performed with a significance level of 0.05 (two sided). A sample size of 16 participants was needed to provide 93% power to detect a difference in GH means of 0.5 mcg/L.p-value: 0.918Wilcoxon (Mann-Whitney)
Secondary
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.
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.
Population: All participants who received both interventions and completed both outpatient study visits were included in analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Area Under the Curve (AUC) for Blood Glucoses During 75 Gram Oral Glucose Tolerance Test | 15353.8 mg*minutes/dL | Standard Deviation 2708.6 |
| Sitagliptin | Area Under the Curve (AUC) for Blood Glucoses During 75 Gram Oral Glucose Tolerance Test | 13877.5 mg*minutes/dL | Standard Deviation 2486.3 |
Comparison: Null hypothesis is that there was no difference in blood glucose levels between sitagliptin and placebo. The test was performed with a significance level of 0.05 (two sided).p-value: 0.009Wilcoxon (Mann-Whitney)
Secondary
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.
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.
Population: All participants who received both interventions and completed both outpatient study visits were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Early Insulin Secretion During Oral Glucose Tolerance Test | 1522.1 microU*minutes/mL | Standard Deviation 792.3 |
| Sitagliptin | Early Insulin Secretion During Oral Glucose Tolerance Test | 1871.3 microU*minutes/mL | Standard Deviation 843.6 |
Comparison: Null hypothesis is that there was no difference in change of early insulin secretion between sitagliptin and placebo. The test was performed with a significance level of 0.05 (two sided).p-value: 0.054Wilcoxon (Mann-Whitney)
Secondary
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.
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.
Population: All participants who received both interventions and completed all study protocols during the daytime portion of the inpatient visits were included in the analysis. (1 participant was unable to complete their 2nd inpatient visit due to a family emergency.)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Vascular Function (Endothelium-dependent Vasodilation) | 13.63 percent change | Standard Deviation 5.27 |
| Sitagliptin | Vascular Function (Endothelium-dependent Vasodilation) | 13.00 percent change | Standard Deviation 5.34 |
Comparison: Null hypothesis is that there was no difference in vascular function between sitagliptin and placebo treatments. The test was performed with a significance level of 0.05 (two sided).p-value: 0.943Wilcoxon (Mann-Whitney)
Secondary
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)
Time frame: At completion of 30 days of placebo treatment and at completion of 30 days of sitagliptin treatment.
Population: All participants who received both interventions and completed all study protocols during the daytime portion of the inpatient visits were included in the analysis. (1 participant was unable to complete their 2nd inpatient visit due to a family emergency.)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Visceral Adipose Tissue | 1141.9 grams | Standard Deviation 700.7 |
| Sitagliptin | Visceral Adipose Tissue | 1055.1 grams | Standard Deviation 710.1 |
Comparison: Null hypothesis is that there was no difference in the mass of visceral adipose tissue after sitagliptin vs. placebo. The test was performed with a significance level of 0.05 (two sided).p-value: 0.022Wilcoxon (Mann-Whitney)