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

Diabetes Mellitus Clinical Trial

— SPHINX  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00721552
• Other study ID #: DC2008Pred002
• Secondary ID: Eudract 2008-004
• Status: Completed
• Phase: N/A
• First received: July 22, 2008
• Last updated: June 28, 2012
• Start date: October 2008
• Est. completion date: June 2012

Study information

• Verified date: June 2012
• Source: VU University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: Medical Ethics Review Committee (METC)Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 82
• Est. completion date: June 2012
• Est. primary completion date: June 2012
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 35 Years to 65 Years

Eligibility

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

Study Design

Allocation: Randomized, Intervention Model: Factorial Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Beta-cell Function
• Diabetes Mellitus
• Glucocorticoid-induced Diabetes
• Metabolic Syndrome X
• Steroid Diabetes

Intervention

Drug:
• Sitagliptin 100 mg
28 days administration of 100 mg daily
• Prednisolone 30 mg
14 days administration of 30 mg daily
• Sitagliptin-placebo
28 days administration once daily
• Prednisolone-placebo
14 days administration once daily

Locations

Country	Name	City	State
Netherlands	VUmc Diabetes Center	Amsterdam	Noord-Holland

Sponsors (1)

Lead Sponsor	Collaborator
VU University Medical Center

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Glucose tolerance as assessed by the area under the curve for glucose (AUCgluc) during a standardized meal test.		14 days	No
Secondary	Incretin secretion during standardized meal test		14 days	No
Secondary	Insulin sensitivity		14 days	No
Secondary	Microvascular function: fasting and postprandial		14 days	No
Secondary	Body composition, body fat distribution and intra organ fat accumulation		28 days	No
Secondary	Molecular mechanisms in subcutaneous adipose tissue		14 days	No
Secondary	Blood pressure and hemodynamic parameters		28 days	No
Secondary	Biomarkers such as lipoproteins, adipocytokines, and markers of systemic inflammation		14 days	No
Secondary	Time to recovery after cessation of the two-week prednisolone treatment		28 days	No
Secondary	Beta-cell function as determined by hyperglycemic clamp tests and modeling analysis from mixed-meal tests.		14 days	No