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

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

Study Overview

• Status: Completed
• Conditions: Impaired Glucose Tolerance; Pre-diabetes; Impaired Fasting Glucose
• Intervention / Treatment: Drug: Dexamethasone 2.5 mg and Sitagliptin 100 mg; Drug: Dexamethasone 2.5 mg and placebo tablet

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
• Enrollment (Actual): 10
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Vermont
    • South Burlington, Vermont, United States, 05403
      • University of Vermont Clinical Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: Sitagliptin; Drug: Dexamethasone 2.5 mg and placebo tablet; Participants rececived Dexamethasone 2.5 mg plus placebo tablet daily for 8 days; Other Names: 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 Names: Sitagliptin; Drug: Dexamethasone 2.5 mg and placebo tablet; Participants rececived Dexamethasone 2.5 mg plus placebo tablet daily for 8 days; Other Names: Placebo

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Vermont
• Investigators: Principal Investigator: Annis M Marney, MD, MSCI, University of Vermont

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (Actual): July 1, 2014
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: December 5, 2011
• First Submitted That Met QC Criteria: December 6, 2011
• First Posted (Estimate): December 8, 2011

Study Record Updates

• Last Update Posted (Actual): March 12, 2018
• Last Update Submitted That Met QC Criteria: February 13, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Keywords: Pre-diabetes; Impaired fasting glucose; Impaired glucose tolerance; Steroid-induced hyperglycemia
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Hyperglycemia; Prediabetic State; Glucose Intolerance; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Dexamethasone; Dexamethasone acetate; BB 1101; Sitagliptin Phosphate
• Other Study ID Numbers: MISP 39681

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No