A Phase 4 interventional study of Sitagliptin and Placebo in Polycystic Ovary Syndrome, sponsored by Vanderbilt University. Completed at 1 site in United States. Open to female participants aged 18 Years to 40 Years. Per ClinicalTrials.gov, last updated 2020-05-08.
Sponsored by Vanderbilt University · Phase 4, Interventional, and Other
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.
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.
944 studies on the registry are indexed under Polycystic Ovary Syndrome; 174 are open to participants now.
This study's enrollment of 23 is below the median of 70 across 685 interventional studies indexed under Polycystic Ovary Syndrome.
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Of its 7 completed or terminated interventional studies of FDA-regulated products, 5 (71%) have results posted.
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Diagnosis of polycystic ovary syndrome defined by 2003 Rotterdam criteria as meeting two out of the three below criteria :
Exclusion Criteria:
Sitagliptin 100 mg by mouth daily for 30 days followed by Placebo daily for 30 days
Drug: Sitagliptin · Drug: Placebo
Placebo daily for 30 days followed by Sitagliptin 100 mg daily for 30 days
Drug: Sitagliptin · Drug: Placebo
Sitagliptin 100 mg by mouth daily for 30 Days
Also known as: Januvia
1 placebo pill by mouth per day for 30 days
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.
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.
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.
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.
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.
55 patients were screened for eligibility at Vanderbilt University Medical Center.
| Milestone | Sitagliptin Then Placebo | Placebo Then Sitagliptin |
|---|---|---|
| Started | 11 | 12 |
| Completed | 10 | 11 |
| Not completed | 1 | 1 |
| Withdrew: Adverse event | 1 | 0 |
| Withdrew: Physician decision | 0 | 1 |
| Milestone | Sitagliptin Then Placebo | Placebo Then Sitagliptin |
|---|---|---|
| Started | 10 | 11 |
| Completed | 9 | 9 |
| Not completed | 1 | 2 |
| Withdrew: Lost to follow-up | 1 | 0 |
| Withdrew: No longer met inclusion criteria | 0 | 2 |
| Milestone | Sitagliptin Then Placebo | Placebo Then Sitagliptin |
|---|---|---|
| Started | 9 | 9 |
| Completed | 9 | 7 |
| Not completed | 0 | 2 |
| Withdrew: 2 did not complete all of inpatient day | 0 | 2 |
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.
| ng/mL | Placebo | Sitagliptin |
|---|---|---|
| Mean Overnight Growth Hormone Levels | 0.85 ± 0.54 | 0.84 ± 0.51 |
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.
| microU*minutes/mL | Placebo | Sitagliptin |
|---|---|---|
| Early Insulin Secretion During Oral Glucose Tolerance Test | 1522.1 ± 792.3 | 1871.3 ± 843.6 |
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.
| mg*minutes/dL | Placebo | Sitagliptin |
|---|---|---|
| Area Under the Curve (AUC) for Blood Glucoses During 75 Gram Oral Glucose Tolerance Test | 15353.8 ± 2708.6 | 13877.5 ± 2486.3 |
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)
| grams | Placebo | Sitagliptin |
|---|---|---|
| Visceral Adipose Tissue | 1141.9 ± 700.7 | 1055.1 ± 710.1 |
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.
| percent change | Placebo | Sitagliptin |
|---|---|---|
| Vascular Function (Endothelium-dependent Vasodilation) | 13.63 ± 5.27 | 13.00 ± 5.34 |
Collected over 30 days for each intervention.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Sitagliptin | 0/20 (0%) | 1/20 (5%) | 5/20 (25%) |
| Placebo | 0/21 (0%) | 0/21 (0%) | 9/21 (42.9%) |
| Event | Sitagliptin | Placebo |
|---|---|---|
| PancreatitisGastrointestinal disorders | 1/20 | 0/21 |
| Event | Sitagliptin | Placebo |
|---|---|---|
| Abdominal Pain, NauseaGastrointestinal disorders | 2/20 | 4/21 |
| DizzinessNervous system disorders | 2/20 | 3/21 |
| HeadacheNervous system disorders | 1/20 | 0/21 |
| EmesisGastrointestinal disorders | 0/20 | 1/21 |
| Shingles InfectionInfections and infestations | 0/20 | 1/21 |
All participants randomized to an intervention are included.
| Age, Continuous(years) | Sitagliptin Then Placebo | Placebo Then Sitagliptin | Total |
|---|---|---|---|
| Mean | 30.4 ± 4.3 | 30.3 ± 4.3 | 30.3 ± 4.3 |
| Sex: Female, Male(Participants) | Sitagliptin Then Placebo | Placebo Then Sitagliptin | Total |
|---|---|---|---|
| Female | 11 | 12 | 23 |
| Male | 0 | 0 | 0 |
| Race (NIH/OMB)(Participants) | Sitagliptin Then Placebo | Placebo Then Sitagliptin | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 1 | 1 | 2 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 2 | 3 | 5 |
| White | 8 | 8 | 16 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 |
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Vanderbilt University