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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
M. Diamant, VU University Medical Center
ClinicalTrials.gov Identifier:
NCT00721552
First received: July 22, 2008
Last updated: June 28, 2012
Last verified: June 2012
  Purpose

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.


Condition Intervention
Diabetes Mellitus
Steroid Diabetes
Glucocorticoid-induced Diabetes
Beta-cell Function
Drug: Sitagliptin 100 mg
Drug: Prednisolone 30 mg
Drug: Sitagliptin-placebo
Drug: Prednisolone-placebo

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

Resource links provided by NLM:


Further study details as provided by VU University Medical Center:

Primary Outcome Measures:
  • Glucose tolerance as assessed by the area under the curve for glucose (AUCgluc) during a standardized meal test. [ Time Frame: 14 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Incretin secretion during standardized meal test [ Time Frame: 14 days ] [ Designated as safety issue: No ]
  • Insulin sensitivity [ Time Frame: 14 days ] [ Designated as safety issue: No ]
  • Microvascular function: fasting and postprandial [ Time Frame: 14 days ] [ Designated as safety issue: No ]
  • Body composition, body fat distribution and intra organ fat accumulation [ Time Frame: 28 days ] [ Designated as safety issue: No ]
  • Molecular mechanisms in subcutaneous adipose tissue [ Time Frame: 14 days ] [ Designated as safety issue: No ]
  • Blood pressure and hemodynamic parameters [ Time Frame: 28 days ] [ Designated as safety issue: No ]
  • Biomarkers such as lipoproteins, adipocytokines, and markers of systemic inflammation [ Time Frame: 14 days ] [ Designated as safety issue: No ]
  • Time to recovery after cessation of the two-week prednisolone treatment [ Time Frame: 28 days ] [ Designated as safety issue: No ]
  • Beta-cell function as determined by hyperglycemic clamp tests and modeling analysis from mixed-meal tests. [ Time Frame: 14 days ] [ Designated as safety issue: No ]

Enrollment: 82
Study Start Date: October 2008
Study Completion Date: June 2012
Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: I
prednisolone + sitagliptin
Drug: Sitagliptin 100 mg
28 days administration of 100 mg daily
Other Names:
  • Januvia
  • MK-0431
  • ATC A10BH01
Drug: Prednisolone 30 mg
14 days administration of 30 mg daily
Other Names:
  • prednison
  • ATC H02AB06
Experimental: II
prednisolone + sitagliptin-placebo
Drug: Prednisolone 30 mg
14 days administration of 30 mg daily
Other Names:
  • prednison
  • ATC H02AB06
Drug: Sitagliptin-placebo
28 days administration once daily
Experimental: III
prednisolone-placebo + sitagliptin
Drug: Sitagliptin 100 mg
28 days administration of 100 mg daily
Other Names:
  • Januvia
  • MK-0431
  • ATC A10BH01
Drug: Prednisolone-placebo
14 days administration once daily
Placebo Comparator: IV
prednisolone-placebo + sitagliptin-placebo
Drug: Sitagliptin-placebo
28 days administration once daily
Drug: Prednisolone-placebo
14 days administration once daily
No Intervention: Healthy controls
12 healthy men will be included to assess postprandial microvascular function.
No Intervention: Type 2 diabetic subjects
12 men with type 2 diabetes will be included in order to assess postprandial microvascular function.

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.

  Eligibility

Ages Eligible for Study:   35 Years to 65 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
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
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00721552

Locations
Netherlands
VUmc Diabetes Center
Amsterdam, Noord-Holland, Netherlands, 1081 HV
Sponsors and Collaborators
VU University Medical Center
Investigators
Principal Investigator: Michaela Diamant, Md PhD VUmc Diabetes Center, Amsterdam, The Netherlands
  More Information

No publications provided by VU University Medical Center

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: M. Diamant, Prof. M. Diamant, VU University Medical Center
ClinicalTrials.gov Identifier: NCT00721552     History of Changes
Other Study ID Numbers: DC2008Pred002, Eudract 2008-004985-25
Study First Received: July 22, 2008
Last Updated: June 28, 2012
Health Authority: Netherlands: Medical Ethics Review Committee (METC)
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by VU University Medical Center:
beta-cell function
glucocorticoid-induced diabetes
glucocorticoid
DPP-4 inhibitors
sitagliptin
diabetes mellitus
steroid diabetes
insulin resistance
insulin sensitivity

Additional relevant MeSH terms:
Diabetes Mellitus
Metabolic Syndrome X
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Insulin Resistance
Hyperinsulinism
Glucocorticoids
Prednisolone
Methylprednisolone
Methylprednisolone Hemisuccinate
Prednisolone hemisuccinate
Prednisolone phosphate
Methylprednisolone acetate
Prednisolone acetate
Sitagliptin
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Inflammatory Agents
Therapeutic Uses
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Gastrointestinal Agents
Neuroprotective Agents

ClinicalTrials.gov processed this record on July 22, 2014