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

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ClinicalTrials.gov Identifier: NCT01488279
Recruitment Status : Completed
First Posted : December 8, 2011
Results First Posted : February 9, 2018
Last Update Posted : March 12, 2018
Sponsor:
Information provided by (Responsible Party):
Annis Marney, MD, MSCI, University of Vermont

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

Condition or disease Intervention/treatment Phase
Pre-diabetes Impaired Fasting Glucose Impaired Glucose Tolerance Drug: Dexamethasone 2.5 mg and Sitagliptin 100 mg Drug: Dexamethasone 2.5 mg and placebo tablet Not Applicable

Detailed Description:

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.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 10 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Double blind, placebo controlled crossover study
Masking: Double (Participant, Investigator)
Masking Description: Drugs were dispensed by the pharmacy with both the patient and investigator blinded
Primary Purpose: Treatment
Official Title: Effect of Sitagliptin on Short-Term Metabolic Dysregulation of Oral Glucocorticoid Therapy
Study Start Date : September 2012
Actual Primary Completion Date : July 2014
Actual Study Completion Date : December 2015


Arm Intervention/treatment
Active Comparator: Dexamethasone 2.5mg and Sitagliptin100mg
Participants received Dexamethasone 2.5 mg plus Sitagliptin 100 mg daily for 8 days
Drug: Dexamethasone 2.5 mg and Sitagliptin 100 mg
Participants received Dexamethasone 2.5mg plus Sitaliptin 100mg daily for 8 days
Other Name: Sitagliptin

Drug: Dexamethasone 2.5 mg and placebo tablet
Participants rececived Dexamethasone 2.5 mg plus placebo tablet daily for 8 days
Other Name: Placebo

Placebo Comparator: Dexamethasone 2.5mg and placebo tablet
Participants received Dexamethasone 2.5 mg plus Sitagliptin-matched placebo tablet daily for 8 days.
Drug: Dexamethasone 2.5 mg and Sitagliptin 100 mg
Participants received Dexamethasone 2.5mg plus Sitaliptin 100mg daily for 8 days
Other Name: Sitagliptin

Drug: Dexamethasone 2.5 mg and placebo tablet
Participants rececived Dexamethasone 2.5 mg plus placebo tablet daily for 8 days
Other Name: Placebo




Primary Outcome Measures :
  1. Insulin Sensitivity [ Time Frame: 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). ]
    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.


Secondary Outcome Measures :
  1. Change in Active GIP [ Time Frame: 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 ]
    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.

  2. Change in Active GLP-1 [ Time Frame: 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 ]
    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.

  3. Change in Glucose Response [ Time Frame: 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 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).

  4. Change in Insulin Secretion (AIRg or Acute Insulinogenic Response to Glucose) [ Time Frame: 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 ]
    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.



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01488279


Locations
United States, Vermont
University of Vermont Clinical Research Center
South Burlington, Vermont, United States, 05403
Sponsors and Collaborators
University of Vermont
Investigators
Principal Investigator: Annis M Marney, MD, MSCI University of Vermont

Responsible Party: Annis Marney, MD, MSCI, Assistant Professor of Medicine, University of Vermont
ClinicalTrials.gov Identifier: NCT01488279     History of Changes
Other Study ID Numbers: MISP 39681
First Posted: December 8, 2011    Key Record Dates
Results First Posted: February 9, 2018
Last Update Posted: March 12, 2018
Last Verified: February 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Annis Marney, MD, MSCI, University of Vermont:
Pre-diabetes
Impaired fasting glucose
Impaired glucose tolerance
Steroid-induced hyperglycemia

Additional relevant MeSH terms:
Glucose Intolerance
Prediabetic State
Hyperglycemia
Glucose Metabolism Disorders
Metabolic Diseases
Diabetes Mellitus
Endocrine System Diseases
Dexamethasone acetate
Dexamethasone
Glucocorticoids
Sitagliptin Phosphate
BB 1101
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Incretins
Dipeptidyl-Peptidase IV Inhibitors