Impaired Fasting Glucose, Impaired Glucose Tolerance, Pre-diabetes
Conditions
Keywords
Pre-diabetes, Impaired fasting glucose, Impaired glucose tolerance, Steroid-induced hyperglycemia
Brief summary
The investigators hypothesize that sitagliptin will significantly reduce impairments in insulin secretion and insulin resistance resulting from short-term oral glucocorticoid therapy.
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.
Interventions
DRUGDexamethasone 2.5 mg and Sitagliptin 100 mg
Participants received Dexamethasone 2.5mg plus Sitaliptin 100mg daily for 8 days
DRUGDexamethasone 2.5 mg and placebo tablet
Participants rececived Dexamethasone 2.5 mg plus placebo tablet daily for 8 days
Sponsors
University of Vermont
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Drugs were dispensed by the pharmacy with both the patient and investigator blinded
Intervention model description
Double blind, placebo controlled crossover study
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Sensitivity | 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
| Measure | Time frame | Description |
|---|---|---|
| Change in Active 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 | 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. |
| Change in Active GLP-1 | 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. |
| Change in Glucose Response | 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). |
| Change in Insulin Secretion (AIRg or Acute Insulinogenic Response to Glucose) | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sitagliptin, Then Placebo This arm involves randomization to dexamethasone 2.5 mg + sitagliptin 100 mg daily x 7 days followed by MTT and IVGTT on subsequent days. There was a 4-6 week washout, then subjects crossed over to dex + placebo. | 5 |
| Placebo, Then Sitagliptin This arm involves randomization to dexamethasone 2.5 mg orally + placebo x 7 days followed by MTT and IVGTT on subsequent days. There was a 4-6 weeks washout, then subjects crossed over to dex + sitagliptin. | 5 |
| Total | 10 |
Baseline characteristics
| Characteristic | Sitagliptin, Then Placebo | Placebo, Then Sitagliptin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 5 Participants | 10 Participants |
| Age, Continuous | 52.5 years STANDARD_DEVIATION 5.5 | 52.5 years STANDARD_DEVIATION 5.5 | 52.5 years STANDARD_DEVIATION 5.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 5 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 5 Participants | 10 Participants |
| Region of Enrollment United States | 5 participants | 5 participants | 10 participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 5 | 0 / 5 |
| serious Total, serious adverse events | 0 / 5 | 0 / 5 |
Outcome results
Primary
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).
Population: Subjects were randomized to the order to study medication (dex + sitagliptin vs dex + placebo) by the pharmacy in order to keep double blinding
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin | Insulin Sensitivity | 1835.4 ratio without units | Standard Error 340 |
| Placebo | Insulin Sensitivity | 1846.0 ratio without units | Standard Error 340 |
Comparison: 2X2 crossover design with baseline values. To compare the means between Sitagliptin and Placebo, a sequential three step testing process used. The results of the third step, the direct treatment comparisons are presented.p-value: 0.98395% CI: [-1147.6, 1126]ANOVA
Secondary
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
Population: We did not measure GIP
Secondary
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
Population: We did not measure GLP-1
Secondary
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).
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
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin | Change in Glucose Response | 4.219 response x 10000 / minute / microUnit/ml | Standard Error 1.368 |
| Placebo | Change in Glucose Response | 4.228 response x 10000 / minute / microUnit/ml | Standard Error 1.368 |
p-value: 0.99795% CI: [-4.585, 4.568]ANOVA
Secondary
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.
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
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin | Change in Insulin Secretion (AIRg or Acute Insulinogenic Response to Glucose) | 519.6 pmol/l | Standard Error 0.46 |
| Placebo | Change in Insulin Secretion (AIRg or Acute Insulinogenic Response to Glucose) | 558.6 pmol/l | Standard Error 35.3 |
p-value: 0.4695% CI: [-156.9, 79]ANOVA