Effect of Sitagliptin on Short-Term Metabolic Dysregulation of Oral Glucocorticoid Therapy

Study Overview
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Brief Summary
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The investigators hypothesize that sitagliptin will significantly reduce impairments in insulin secretion and insulin resistance resulting from short-term oral glucocorticoid therapy.

Detailed Description
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The investigators plan to conduct a prospective, randomized, double-blind, placebo-controlled parallel arm crossover study comparing insulin secretion and insulin resistance in subjects with impaired fasting glucose on oral glucocorticoid therapy + placebo versus subjects on oral glucocorticoid therapy + sitagliptin. For the oral glucocorticoid therapy, we plan to use dexamethasone (dex) 2.5 mg daily. We chose dex for known glycemic effects, improved compliance, and once daily dosing. Previous studies have shown that in humans, glucocorticoid-induced insulin resistance develops within 4 hours with infused drug at high dose (methylprednisolone 500 mg x single infusion) and does not change with duration of drug therapy of up to 3 months.10 Furthermore, more modest doses over a short duration (dex 2.0 mg orally daily x 2 days) have been shown to decrease insulin-mediated glucose disposal.11 12 Thus, studying acute effects of oral dex at 2.5 mg daily x 7 days should be more than adequate to achieve impaired glucose-mediated insulin secretion and impaired insulin-mediated glucose disposal. In order for sitagliptin to have the desired effect, drug should be administered for at least 7 days (5 half-lives plus 40% more for margin of error). We plan to study subjects with impaired fasting glucose or impaired glucose tolerance as they would likely be candidates for DPP-IV therapy in the future and would be likely to have impaired insulin secretion and impaired glucose disposal amenable to DPP-IV therapy. A total of 10 participants were enrolled in this study. Participants were given 2.5 mg dexamethasone daily plus either placebo tablet or sitagliptin daily for 8 days with a washout period prior to crossover. The order of study drug administration was randomized. Participants underwent blood sampling, mixed meal testing (MMT), and intravenous glucose tolerance testing (IVGTT) before and after each study period.

Official Title
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Effect of Sitagliptin on Short-Term Metabolic Dysregulation of Oral Glucocorticoid Therapy

Conditions
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Pre-diabetes, Impaired Fasting Glucose, Impaired Glucose Tolerance

Intervention / Treatment
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* Drug: Dexamethasone 2.5 mg and Sitagliptin 100 mg
* Drug: Dexamethasone 2.5 mg and placebo tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women impaired fasting glucose We will stratify for weight and age. Exclusion Criteria: Known Type 2 DM Severe disease preventing participation in study On chronic steroids for any reason Already taking DPP-4 inhibitor

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Double blind, placebo controlled crossover study
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dexamethasone 2.5mg and Sitagliptin100mg<br>Participants received Dexamethasone 2.5 mg plus Sitagliptin 100 mg daily for 8 days | Drug: Dexamethasone 2.5 mg and Sitagliptin 100 mg<br>* Participants received Dexamethasone 2.5mg plus Sitaliptin 100mg daily for 8 days<br>* Other names: Sitagliptin;Drug: Dexamethasone 2.5 mg and placebo tablet<br>* Participants rececived Dexamethasone 2.5 mg plus placebo tablet daily for 8 days<br>* Other names: Placebo;|
| Placebo Comparator: Dexamethasone 2.5mg and placebo tablet<br>Participants received Dexamethasone 2.5 mg plus Sitagliptin-matched placebo tablet daily for 8 days. | Drug: Dexamethasone 2.5 mg and Sitagliptin 100 mg<br>* Participants received Dexamethasone 2.5mg plus Sitaliptin 100mg daily for 8 days<br>* Other names: Sitagliptin;Drug: Dexamethasone 2.5 mg and placebo tablet<br>* Participants rececived Dexamethasone 2.5 mg plus placebo tablet daily for 8 days<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin Sensitivity | Insulin Sensitivity measured at the end of each treatment period. The primary outcome variable was the difference in the disposition index (DI) determined as the product of the acute insulin response to glucose (AIRg) x the insulin sensitivity index (SI) in subjects during IVGTT on the 8th day (after 7 days) of on dex + placebo, then a after a washout of approximately 4 weeks, participants crossed over to dex + sitagliptin 100 mg x 7 days. Subjects were randomized to order of medication. The primary analyses will be an ANCOVA, including baseline responses as a covariate. | Measured on day #8 (after 8 days of sitagliptin or placebo) followed by a 4 week washout then measured again on day #8 (after 8 days of crossover treatment). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Active GIP | We had planned to measure the difference or change in active GIP in response to the MTT between the 2 study drug periods: on sitagliptin versus on placebo. However, when other measures were negative, we opted not to pursue this lab assay for cost and time. We did not perform measures of GIP. | Active GIP would have been measured during MTT after 1 week of dex + sitagliptin and again after 1 week of dex + placebo, but we did not measure active GIP | 
| Change in Active GLP-1 | As with GIP, we had planned to measure the difference or change in active GLP-1 in response to the MTT between the 2 study drug periods: on sitagliptin versus on placebo. We had hypothesized that GIP and GLP-1 would be elevated while on the DPP4 inhibitor compared to placebo as this is the mechanism of action of the drug sitagliptin. When other measures were negative, we elected not to pursue this due to time and cost. | Active GLP-1 would have been measured during MTT after 1 week of dex + sitagliptin and again after 1 week of dex + placebo, but we did not measure active GLP-1 | 
| Change in Glucose Response | Change in glucose response during the MTT. This was the Si (insulin sensitivity). We sought to determine whether there was an improvement in the glucose response after a meal on the DPP4i compared to placebo in the face of steroid (dexamethasone). | measured on day #9 (after 7 days of study drug and 1 day of IVGTT) of sitagliptin during MTT, then after 4 week washout, measured again on day #9 (after 7 days of study drug + 1 day of IVGTT) of dex + placebo during MTT | 
| Change in Insulin Secretion (AIRg or Acute Insulinogenic Response to Glucose) | We measured the change in insulin secretion (AIRg or acute insulinogenic response to glucose) during the MTT and compared the insulin secretion on the DPP4 inhibitor (sitagliptin) compared to placebo. We had expected the AIRg to be greater with DPP4i compared to placebo. | measured twice: on day #8 (after 7 days of study drug and 1 day of IVGTT) of sitagliptin during MTT, then after 4 week washout, measured again on day #8 (after 7 days of study drug + 1 day of IVGTT) of dex + placebo during MTT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pre-diabetes, Impaired fasting glucose, Impaired glucose tolerance, Steroid-induced hyperglycemia