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

University of Vermont10 enrolled

Overview

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

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Pre-diabetes Impaired Fasting Glucose Impaired Glucose Tolerance

Interventions

Dexamethasone 2.5 mg and Sitagliptin 100 mgDRUG

Participants received Dexamethasone 2.5mg plus Sitaliptin 100mg daily for 8 days

Dexamethasone 2.5 mg and placebo tabletDRUG

Participants rececived Dexamethasone 2.5 mg plus placebo tablet daily for 8 days

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Locations (1)

University of Vermont Clinical Research Center

South Burlington, Vermont, United States

Outcomes

Primary Outcomes

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.

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).

Secondary Outcomes

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.

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

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.

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

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).

Data from ClinicalTrials.gov

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