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

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

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.

Study Overview

• Status: Completed
• 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

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.

• Study Type: Interventional
• Enrollment (Actual): 82
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1081 HV
      • VUMC Diabetes Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Triple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc
• Investigators: Principal Investigator: Michaela Diamant, Md PhD, VUmc Diabetes Center, Amsterdam, The Netherlands

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: October 1, 2008
• Primary Completion (Actual): June 1, 2012
• Study Completion (Actual): June 1, 2012

Study Registration Dates

• First Submitted: July 22, 2008
• First Submitted That Met QC Criteria: July 22, 2008
• First Posted (Estimate): July 24, 2008

Study Record Updates

• Last Update Posted (Estimate): July 2, 2012
• Last Update Submitted That Met QC Criteria: June 28, 2012
• Last Verified: June 1, 2012

More Information

Terms related to this study

• Keywords: insulin sensitivity; insulin resistance; DPP-4 inhibitors; sitagliptin; diabetes mellitus; glucocorticoid; beta-cell function; glucocorticoid-induced diabetes; steroid diabetes
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Insulin Resistance; Hyperinsulinism; Diabetes Mellitus; Metabolic Syndrome; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protease Inhibitors; Neuroprotective Agents; Protective Agents; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Sitagliptin Phosphate
• Other Study ID Numbers: DC2008Pred002; Eudract 2008-004985-25