Effect of Sitagliptin on Short-Term Metabolic Dysregulation of 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.

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