Diabetogenicity of Cyclosporine and Tacrolimus
Information source: University of Aarhus
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Complications of Transplanted Organs and Tissue; Diabetes Mellitus Nos New Onset
Intervention: cyclosporine (Drug); tacrolimus (Drug); Capsules and isotonic saline (Other)
Phase: Phase 4
Status: Completed
Sponsored by: University of Aarhus Official(s) and/or principal investigator(s): Lara Aygen Øzbay, MD, Principal Investigator, Affiliation: Aarhus University Hospital Skejby
Summary
Cyclosporine (CsA) and Tacrolimus (Tac) are immunosuppressive agents comprising the
cornerstone of treatment among organ transplant recipients. Unfortunately diabetes is a
known complication after transplantation, yet the underlying mechanisms of this type of
diabetes are still unresolved. A direct comparison of the diabetogenic effects of CsA and
Tac, without interference of corticosteroid treatment, has not yet been investigated using a
hyperinsulinemic euglycemic glucose clamp technique, which is the best method for estimating
insulin sensitivity.
Randomized, investigator-blinded cross-over studies will be carried out, studying 10 healthy
subjects and 10 hemodialysis patients. Each participant will receive treatment with CsA, Tac
and placebo respectively in a random order. The results will be of relevance to the choice
and monitoring of immunosuppressive regimens in kidney transplant recipients as well as the
development of better treatment modalities for diabetes.
Clinical Details
Official title: Diabetogenicity of Cyclosporine and Tacrolimus
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Primary outcome: Insulin Sensitivity
Secondary outcome: insulin secretionserum free fatty acids serum C-peptide blood cyclosporine blood tacrolimus respiratory gas exchange, substrate metabolism Pulsatile Insulin secretion plasma Glucose plasma glucagon
Detailed description:
Background: Post-transplantation diabetes mellitus (PTDM) is a complication of the
calcineurin inhibitors (CI) cyclosporine (CsA) and Tacrolimus (Tac), but much controversy
still exists regarding the mechanism leading to this disorder. Several studies using
intravenous (IVGTT) or oral glucose tolerance tests have shown that CsA and Tac tend to
reduce insulin release, while corticosteroids increase insulin resistance. Decreased
insulin secretion may be the result of beta-cell toxicity, apoptosis or inhibition of
calcineurin signaling cessating insulin gene transcription. Comparing the drug using IVGTT
has shown that long-term glucose metabolism is not significantly different between the two.
Reviewing the literature brings forth that some of these data and the observed higher
incidence of PTDM in Tac-treated recipients are conflicting.
To or knowledge, comparison of the diabetogenic effects of CsA and Tac, without concomitant
corticosteroids, has never been investigated using the gold standard to estimate insulin
sensitivity; a hyperinsulinemic euglycemic glucose clamp (HEGC).
Hypotheses: CsA and Tac are able to induce diabetes, by exerting acute and chronic effects
on pancreas beta-cell performance and insulin sensitivity.
The hypothesized effects will be investigated during following studies:
1. Acute effect in 10 healthy subjects undergoing HEGC
2. Chronic effect in 10 pre-transplant uremic patients undergoing HEGC
Methods: The studies are randomized, double-blinded (Study 1) and investigator blinded
(Study 2) cross-over designs. Each study subject participates in three experimental study
days with an interval of 4-6 weeks. A HEGC is carried out on the study days, where treatment
includes CsA, Tac and placebo respectively in random order. Following an overnight fast the
healthy subject / uremic patient arrives in the research laboratory, where a catheter is
implanted in each arm for blood sampling and infusion purposes.
Pulse induction: Glucose 6 mg/kg/min is infused every 10 minutes followed by a 9 minute
pause. From 30 to 90 min blood is drawn every minute for insulin and every 10th minute for
glucose measurements.
First phase insulin secretion: After 120 minutes glucose 0. 3 g/kg (maximally 25 g) is
infused over 2 min and the catheter is flushed with 50 ml of isotonic saline. Insulin,
glucose and c-peptide are measured with a few minutes intervals.
Insulin infusion/HEGC: 1. 0 mU/kg/min insulin infusion is initiated at the 165th minute and
blood glucose levels are kept at 5. 0 mmol/L, using variable infusion of a 20% glucose
dilution throughout the following 120 minutes. The final 30 min of the clamp is considered
the hyperinsulinaemic steady state period. Aside from glucose, insulin and other
endocrinological parameters, measurements of drug concentration and CaN will also be
performed.
Perspectives: The studies are expected to give valuable insight into the diabetogenic
effects of CI, and to show whether or not CsA and Tac are comparable in their
Diabetogenicity. The results will be of relevance to the choice and monitoring of
immunosuppressive regimens in kidney transplant recipients as well as the development of
better treatment modalities for diabetes.
Eligibility
Minimum age: 18 Years.
Maximum age: 70 Years.
Gender(s): Both.
Criteria:
Inclusion Criteria:
Healthy volunteers (Study 1):
1. Men.
2. Age between 18 years and 50 years. Upper limit can be +2 years if approved by main
investigator.
3. Normal OGTT (0 and 120 min test).
4. Body mass index (BMI) 20 - 30 kg/m2. Allowed variations are 5% from the upper and
lower limit.
5. Normal serum creatinine and ionisized calcium. Allowed variations are 20% from the
upper and lower limit of the normal value for creatinine and 5% for calcium.
6. Normal urine stix
7. Written consent to participate.
Hemodialysis Patients (study 2):
1. Age between 18 years and 70 years. Upper limit can be +2 years if approved by main
investigator.
2. BMI < 30 kg/m2. Allowed variations are 5% over the upper limit.
3. On the waiting-list for a kidney transplant.
4. Haemodialysis candidate.
5. Anti-conceptive treatment (contraceptive pill/intrauterine device/patch/ring/
implant/injectable contraceptive) if the patient is a fertile woman.
6. Written consent to participate. -
Exclusion Criteria:
Healthy volunteers (Study 1):
1. Anaemia with haemoglobin levels < 7 mmol/L
2. Participation in any other clinical trial.
3. Subjects who cannot adhere to test conditions.
4. Anamnesis of clinically significant disease, such as:
- liver disease
- kidney disease,
- neurological disease
- gastrointestinal disease
- haematological disease
- endocrine disease
- lung disease
- cardiac disease
5. Drug or alcohol abuse, which would render the subject unfit according to the main
investigator.
6. Blood donation 1 month prior to the study day
7. Patients with established allergy against CI or other medical products, which might
pose a risk if they participated in this study.
8. Use of prescription drugs within one month prior to the study days, unless they are
clinically insignificant according to the main investigator.
9. Smoking 8 hours prior to the study day
10. Vigorous exercise 30 minutes prior to the study day.
Hemodialysis Patients (study 2):
1. Peritoneal dialysis.
2. Anaemia with haemoglobin levels < 6 mmol/L.
3. Participation in any other clinical trial.
4. Treatment with corticosteroids, CsA or Tac.
5. Patients who cannot adhere to test conditions.
6. Patients with established allergy against CI or other medical product, which might
pose a risk if they participated in this study.
7. Drug or alcohol abuse, which would render the subject unfit according to the main
investigator.
8. Anamnesis of current diabetes and/or intake of anti-diabetic medication.
9. Malignancy.
10. Uncontrolled infection.
11. Uncontrolled hypertension.
12. Smoking 8 hours prior to the study day.
13. Vigorous exercise 30 minutes prior to the study day
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Locations and Contacts
Department of Nephrology, Aarhus University Hospital, Skejby, Aarhus, Jutland 8200, Denmark
Additional Information
Starting date: March 2008
Last updated: November 7, 2011
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