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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

Sitagliptin 100 mg by mouth daily for 30 Days

Sitagliptin

1 placebo pill by mouth per day for 30 days

Placebo

Jessica Devin, MD MSCI

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.

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

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.

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.

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.

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)

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.

National Heart, Lung, and Blood Institute (NHLBI)

Vanderbilt University

Principal Investigator

Safety population included all participants who received at least one dose of intervention.

Participants received Sitagliptin 100 mg by mouth daily for up to 30 days.

Participants received Placebo daily for up to 30 days.

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.

Sitagliptin Then Placebo

Participants first received Placebo daily for 30 days. After an 8 week washout period, they then received Sitagliptin 100 mg daily for 30 days.

Placebo Then Sitagliptin

Total

Age, Continuous

Only Females were included in this study because Polycystic Ovarian Syndrome is a disorder limited to women.

Sex: Female, Male

Race (NIH/OMB)

All participants randomized to an intervention are included.

Dr. Jessica Devin

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.

Participants who received Placebo tablet each morning in either the first 30 days or last 30 days of the study.

Participants who received Sitagliptin 100 mg daily each morning in either the first 30 days or last 30 days of the study.

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.)

Mean Overnight Growth Hormone Levels

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).

All participants who received both interventions and completed both outpatient study visits were included in the analysis.

Early Insulin Secretion During Oral Glucose Tolerance Test

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).

All participants who received both interventions and completed both outpatient study visits were included in analysis.

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

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).

Participants who received Sitagliptin 100 mg each morning in either the first 30 days or last 30 days of the study.

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.)

Visceral Adipose Tissue

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).

Vascular Function (Endothelium-dependent Vasodilation)

Participants first received sitagliptin 100 mg by mouth daily for 30 days. After a washout period of 8 weeks, then then received Placebo daily for 30 days

Participants first received Placebo daily for 30 days. After a washout period of 8 weeks, they then received Sitagliptin 100 mg daily for 30 days

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
The Effect of Dipeptidyl Peptidase 4 Inhibition on Growth Hormone Secretion in Women With Polycystic Ovarian Syndrome	NCT02122380	Polycystic Ovar...	Sitagliptin Placebo	18 Years - 40 Years	Vanderbilt University Medical Center
The Effect of Dipeptidyl Peptidase 4 Inhibition on Growth Hormone Secretion in Women With Polycystic Ovarian Syndrome	NCT02122380	Polycystic Ovar...	Sitagliptin Placebo	18 Years - 40 Years	Vanderbilt University Medical Center

Spots Global Cancer Trial Database for dipeptidyl peptidase 4