Sitagliptin Prophylaxis for Glucocorticoid-Induced Impairment of Glucose Metabolism in Males With the Metabolic Syndrome

Study Overview
=================
Brief Summary
-----------------
The investigators will assess whether the DPP-inhibitor sitagliptin will ameliorate glucocorticoid-induced impairment of glucose metabolism and beta-cell dysfunction and thus could be used as a prophylaxis for glucocorticoid-induced diabetes. Therefore the investigators will administer in males with the metabolic syndrome 30 mg prednisolone daily for two weeks and give simultaneously sitagliptin 100 mg daily. Subjects will undergo at baseline and after two weeks of treatment several tests to assess changes in glucose metabolism.

Detailed Description
-----------------
The investigators will conduct a randomized, placebo-controlled, double-blind, 2x2 factorial-designed intervention trial. The pharmacological intervention for prednisolone/prednisolone-placebo is 14 days and for sitagliptin/sitagliptin-placebo 28 days. Subjects fulfilling the IDF criteria26 for the metabolic syndrome (aged 35-65; n=60) will be randomized to one of four groups: I) prednisolone 30 mg and sitagliptin 100 mg daily; II) prednisolone 30 mg and sitagliptin-placebo daily; III) prednisolone-placebo and sitagliptin 100 mg daily; IV) prednisolone-placebo and sitagliptin-placebo daily. Before and at day 14 of treatment subjects will undergo a standardized mixed-meal test in order to assess glucose disposal and beta-cell function (by modeling analysis). During these meal tests, plasma concentrations of (total and active) GLP-1, GIP, glucagon and additional biomarkers will be assessed. A combined hyperglycemic-euglycemic clamp will be performed at baseline and at day 13 of treatment to assess insulin sensitivity and insulin secretion. During the euglycemic clamp adipose tissue and muscle biopsies will be obtained, both in fasting and under hyperinsulinemic conditions. At baseline and at day 28 of treatment, a 7-point OGTT will be performed to assess time to restoration of glycemic control. Body composition, body fat distribution and liver fat content, measured by respectively bio-impedance analysis and magnetic resonance imaging/spectroscopy (MRI/MRS), will be assessed at baseline and after 28 days of treatment. Blood pressure will be assessed at baseline and after two weeks of treatment. Microvascular function will be assessed with capillary videomicroscopy both at baseline and after two weeks of treatment.

Official Title
-----------------
Sitagliptin Prophylaxis for Glucocorticoid-Induced Impairment of Glucose Metabolism and Beta-Cell Dysfunction in Males With the Metabolic Syndrome X: A Randomized, Placebo-controlled, Double-blind Intervention Study With a 2x2 Factorial Design

Conditions
-----------------
Diabetes Mellitus, Steroid Diabetes, Glucocorticoid-induced Diabetes, Beta-cell Function

Intervention / Treatment
-----------------
* Drug: Sitagliptin 100 mg
* Drug: Prednisolone 30 mg
* Drug: Sitagliptin-placebo
* Drug: Prednisolone-placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Caucasian males Modified from IDF criteria for the metabolic syndrome: Waist circumference ≥ 94 cm And at least 2 or more of the following criteria: TG ≥ 1.7 mmol/L HDL cholesterol < 1.03 mmol/L Blood pressure >130/85 mmHg (average of three measurements) or treatment of previously diagnosed hypertension Fasting plasma glucose level (FPG) ≥ 5.6 mmol/L (but no diabetes) Exclusion Criteria: An allergic or anaphylactic reaction to prednisolone treatment in the past Clinically relevant history or presence of any medical disorder, which are mentioned in the Summary of Product Characteristics (SPC) as contraindication for the use of prednisolone Glucocorticosteroid use during the last three months prior to the first dose Participation in an investigational drug trial within 90 days prior to the first dose Donation of blood ( > 100 mL) within 90 days prior to the first dose History of or current abuse of drugs or alcohol (>14 U/week) Use of grapefruit products during the study period Recent changes in weight and/or physical activity Serious mental impairment or language problems i.e. preventing to understand the study protocol/aim Diabetes mellitus (defined as FPG ≥ 7.0 mmol/l and/or 2hPG ≥ 11.1 mmol/l) Serious pulmonary, cardiovascular, hepatic (ALT, AST more than 3x ULN) or renal disease (serum creatinine > 135 micromol/L) History of cardiovascular disease, such as myocardial infarction, cerebrovascular accident. Major psychiatric disorder, depression All diseases that induce changes in the hypothalamic-pituitary-adrenal (HPA) axis Malignant disease All other relevant medical disorders that potentially interfere with this trial. All medication interfering with study drug or interfering with study endpoints/hypotheses

Ages Eligible for Study
-----------------
Minimum Age: 35 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: I<br>prednisolone + sitagliptin | Drug: Sitagliptin 100 mg<br>* 28 days administration of 100 mg daily<br>* Other names: ATC A10BH01;Drug: Prednisolone 30 mg<br>* 14 days administration of 30 mg daily<br>* Other names: ATC H02AB06;|
| Experimental: II<br>prednisolone + sitagliptin-placebo | Drug: Prednisolone 30 mg<br>* 14 days administration of 30 mg daily<br>* Other names: ATC H02AB06;Drug: Sitagliptin-placebo<br>* 28 days administration once daily<br>|
| Experimental: III<br>prednisolone-placebo + sitagliptin | Drug: Sitagliptin 100 mg<br>* 28 days administration of 100 mg daily<br>* Other names: ATC A10BH01;Drug: Prednisolone-placebo<br>* 14 days administration once daily<br>|
| Placebo Comparator: IV<br>prednisolone-placebo + sitagliptin-placebo | Drug: Sitagliptin-placebo<br>* 28 days administration once daily<br>Drug: Prednisolone-placebo<br>* 14 days administration once daily<br>|
| No Intervention: Healthy controls<br>12 healthy men will be included to assess postprandial microvascular function. | |
| No Intervention: Type 2 diabetic subjects<br>12 men with type 2 diabetes will be included in order to assess postprandial microvascular function. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glucose tolerance as assessed by the area under the curve for glucose (AUCgluc) during a standardized meal test. |  | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incretin secretion during standardized meal test |  | 14 days | 
| Insulin sensitivity |  | 14 days | 
| Microvascular function: fasting and postprandial |  | 14 days | 
| Body composition, body fat distribution and intra organ fat accumulation |  | 28 days | 
| Molecular mechanisms in subcutaneous adipose tissue |  | 14 days | 
| Blood pressure and hemodynamic parameters |  | 28 days | 
| Biomarkers such as lipoproteins, adipocytokines, and markers of systemic inflammation |  | 14 days | 
| Time to recovery after cessation of the two-week prednisolone treatment |  | 28 days | 
| Beta-cell function as determined by hyperglycemic clamp tests and modeling analysis from mixed-meal tests. |  | 14 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
beta-cell function, glucocorticoid-induced diabetes, glucocorticoid, DPP-4 inhibitors, sitagliptin, diabetes mellitus, steroid diabetes, insulin resistance, insulin sensitivity