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

Primary Purpose

Diabetes Mellitus, Steroid Diabetes, Glucocorticoid-induced Diabetes

Status

Completed

Phase

Not Applicable

Locations

Netherlands

Study Type

Interventional

Intervention

Sitagliptin 100 mg

Prednisolone 30 mg

Sitagliptin-placebo

Prednisolone-placebo

About this trial

This is an interventional prevention trial for Diabetes Mellitus focused on measuring beta-cell function, glucocorticoid-induced diabetes, glucocorticoid, DPP-4 inhibitors, sitagliptin, diabetes mellitus, steroid diabetes, insulin resistance, insulin sensitivity

Eligibility Criteria

35 Years - 65 Years (Adult, Older Adult)MaleAccepts Healthy Volunteers

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

Sites / Locations

VUmc Diabetes Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Placebo Comparator

No Intervention

Arm Label

III

Healthy controls

Type 2 diabetic subjects

Arm Description

prednisolone + sitagliptin

prednisolone + sitagliptin-placebo

prednisolone-placebo + sitagliptin

prednisolone-placebo + sitagliptin-placebo

12 healthy men will be included to assess postprandial microvascular function.

12 men with type 2 diabetes will be included in order to assess postprandial microvascular function.

Outcomes

Primary Outcome Measures

Glucose tolerance as assessed by the area under the curve for glucose (AUCgluc) during a standardized meal test.

Secondary Outcome Measures

Incretin secretion during standardized meal test

Insulin sensitivity

Microvascular function: fasting and postprandial

Body composition, body fat distribution and intra organ fat accumulation

Molecular mechanisms in subcutaneous adipose tissue

Blood pressure and hemodynamic parameters

Biomarkers such as lipoproteins, adipocytokines, and markers of systemic inflammation

Time to recovery after cessation of the two-week prednisolone treatment

Beta-cell function as determined by hyperglycemic clamp tests and modeling analysis from mixed-meal tests.

Full Information

NCT ID

NCT00721552

First Posted

July 22, 2008

Last Updated

June 28, 2012

Sponsor

Amsterdam UMC, location VUmc

1. Study Identification

Unique Protocol Identification Number

NCT00721552

Brief Title

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

Acronym

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

Study Type

Interventional

2. Study Status

Record Verification Date

June 2012

Overall Recruitment Status

Completed

Study Start Date

October 2008 (undefined)

Primary Completion Date

June 2012 (Actual)

Study Completion Date

June 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Amsterdam UMC, location VUmc

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

Keywords

beta-cell function, glucocorticoid-induced diabetes, glucocorticoid, DPP-4 inhibitors, sitagliptin, diabetes mellitus, steroid diabetes, insulin resistance, insulin sensitivity

7. Study Design

Primary Purpose

Prevention

Study Phase

Not Applicable

Interventional Study Model

Factorial Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

82 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm Type

Experimental

Arm Description

prednisolone + sitagliptin

Arm Title

Arm Type

Experimental

Arm Description

prednisolone + sitagliptin-placebo

Arm Title

III

Arm Type

Experimental

Arm Description

prednisolone-placebo + sitagliptin

Arm Title

Arm Type

Placebo Comparator

Arm Description

prednisolone-placebo + sitagliptin-placebo

Arm Title

Healthy controls

Arm Type

No Intervention

Arm Description

12 healthy men will be included to assess postprandial microvascular function.

Arm Title

Type 2 diabetic subjects

Arm Type

No Intervention

Arm Description

12 men with type 2 diabetes will be included in order to assess postprandial microvascular function.

Intervention Type

Drug

Intervention Name(s)

Sitagliptin 100 mg

Other Intervention Name(s)

Januvia, MK-0431, ATC A10BH01

Intervention Description

28 days administration of 100 mg daily

Intervention Type

Drug

Intervention Name(s)

Prednisolone 30 mg

Other Intervention Name(s)

prednison, ATC H02AB06

Intervention Description

14 days administration of 30 mg daily

Intervention Type

Drug

Intervention Name(s)

Sitagliptin-placebo

Intervention Description

28 days administration once daily

Intervention Type

Drug

Intervention Name(s)

Prednisolone-placebo

Intervention Description

14 days administration once daily

Primary Outcome Measure Information:

Title

Glucose tolerance as assessed by the area under the curve for glucose (AUCgluc) during a standardized meal test.

Time Frame

14 days

Secondary Outcome Measure Information:

Title

Incretin secretion during standardized meal test

Time Frame

14 days

Title

Insulin sensitivity

Time Frame

14 days

Title

Microvascular function: fasting and postprandial

Time Frame

14 days

Title

Body composition, body fat distribution and intra organ fat accumulation

Time Frame

28 days

Title

Molecular mechanisms in subcutaneous adipose tissue

Time Frame

14 days

Title

Blood pressure and hemodynamic parameters

Time Frame

28 days

Title

Biomarkers such as lipoproteins, adipocytokines, and markers of systemic inflammation

Time Frame

14 days

Title

Time to recovery after cessation of the two-week prednisolone treatment

Time Frame

28 days

Title

Beta-cell function as determined by hyperglycemic clamp tests and modeling analysis from mixed-meal tests.

Time Frame

14 days

10. Eligibility

Sex

Male

Minimum Age & Unit of Time

35 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Michaela Diamant, Md PhD

Organizational Affiliation

VUmc Diabetes Center, Amsterdam, The Netherlands

Official's Role

Principal Investigator

Facility Information:

Facility Name

VUmc Diabetes Center

City

Amsterdam

State/Province

Noord-Holland

ZIP/Postal Code

1081 HV

Country

Netherlands

12. IPD Sharing Statement

Citations:

PubMed Identifier

24297090

Citation

van Genugten RE, van Raalte DH, Muskiet MH, Heymans MW, Pouwels PJ, Ouwens DM, Mari A, Diamant M. Does dipeptidyl peptidase-4 inhibition prevent the diabetogenic effects of glucocorticoids in men with the metabolic syndrome? A randomized controlled trial. Eur J Endocrinol. 2014 Feb 4;170(3):429-39. doi: 10.1530/EJE-13-0610. Print 2014 Mar.

Results Reference

derived

PubMed Identifier

23178932

Citation

van Genugten RE, Serne EH, Heymans MW, van Raalte DH, Diamant M. Postprandial microvascular function deteriorates in parallel with gradual worsening of insulin sensitivity and glucose tolerance in men with the metabolic syndrome or type 2 diabetes. Diabetologia. 2013 Mar;56(3):583-7. doi: 10.1007/s00125-012-2783-y. Epub 2012 Nov 24.

Results Reference

derived

Learn more about this trial

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

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