The objective of this study is to assess whether sitagliptin may prevent prednisolone-induced impairment of glucose metabolism and beta-cell function.
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
- Therapeutic and nontherapeutic effects (excl toxicity)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To compare the effect of sitagliptin 100 mg daily versus placebo, given
simultaneously with prednisolone 30 mg daily during 2 weeks, on
glucocorticoid-induced glucometabolic abnormalities (measured as area-under the
curve of postprandial glucose during a standardized mixed-meal test) in males
with the metabolic syndrome.
Secondary outcome
To compare the effect of sitagliptin 100 mg daily versus placebo, given
simultaneously with prednisolone 30 mg daily during 2 weeks, on
glucocorticoid-induced beta-cell dysfunction in males with the metabolic
syndrome.
Various measures of beta-cell function will be used, including:
o First-phase insulin secretion during a hyperglycemic clamp test
o Second-phase insulin secretion during a hyperglycemic clamp test
o Arginine-induced insulin secretion during a hyperglycemic clamp test
o Model-derived parameters of beta-cell function derived from a mixed-meal test
Exploratory objectives:
A: To compare the effects of sitagliptin versus placebo given simultaneously
with prednisolone during 2 weeks in males with the metabolic syndrome with
respect to:
- Insulin sensitivity
- Incretin secretion during standardized meal tests
- The plasma levels of additional biomarkers such as lipoproteins,
adipo(cyto)kines, and markers of systemic inflammation, both in the fasting and
postprandial state
- Body composition and body fat distribution
- mRNA and protein expression of genes involved in glucose and lipid metabolism
in subcutaneous adipose tissue and/or skeletal muscle
- Blood pressure
- Microvascular function
B: To compare the effect of a four-week treatment with sitagliptin, versus
placebo in males with the metabolic syndrome on:
- Time to normalization of glucose metabolism after cessation of the two-week
prednisolone treatment
- Liver fat content
C: To compare the effect of a two-week treatment with prednisolone 30 mg daily,
on the under A summarized parameters, relative to placebo in males with the
metabolic syndrome.
Background summary
Glucocorticoids (GCs) are the most frequently prescribed anti-inflammatory and
immunosuppressive drugs, with proven efficacy in a wide range of (auto-immune)
disorders. Unfortunately, GC therapy is also associated with numerous side
effects, including osteoporosis, gastric ulcers, hypertension and dysmetabolic
changes, which in a large number of patients lead to glucose intolerance and
diabetes. Interestingly, in clinical practice, drugs are routinely prescribed
to prevent GC-induced osteoporosis and gastric ulcers, however, to date no
measures are being undertaken to prevent the development of diabetes. GCs are
well known to reduce insulin sensitivity, both after acute and chronic
exposure. In the last decade however, research on the diabetogenic effects of
GCs has become more focused on the role of impaired insulin secretion and
beta-cell dysfunction. GCs acutely inhibit insulin release in vitro, but also
increased insulin secretion in vivo, most likely to compensate for insulin
resistance. Rodents and humans with pre-existent compromised glucose
metabolism, showed impaired insulin secretion after GC treatment. In a pilot
study in healthy males, GCs significantly interfered with various aspects of
beta-cell function, as assessed by modelling analysis of glucose and insulin
concentrations during mixed-meal tests, a method that has been developed in
recent years. In particular, the potentiation factor which encompasses various
potentiating signals to the beta-cell (e.g. glucose-induced potentiation,
non-glucose stimuli, incretins, neural factors) was markedly impaired. These
data suggest that the harmful effects of GCs on beta-cell function are not as
yet fully detailed and that the complete spectrum of these actions may only
become unveiled when using a more physiological approach, in particular by
addressing the role of the intestinal-islet axis.
Based on these preliminary findings, we hypothesized that, inasmuch as GCs
interfere with various aspects of the relation between nutrient stimuli and
insulin secretion, the novel modality to treat T2DM, i.e. DPP-4 inhibitors such
as sitagliptin, which potentially restore this relation by enhancing incretin
activity, may particularly be effective in reducing GC-induced deleterious
effects on the beta-cell in males with the metabolic syndrome.
Study objective
The objective of this study is to assess whether sitagliptin may prevent
prednisolone-induced impairment of glucose metabolism and beta-cell function.
Study design
The SPHINX study is a randomized, placebo-controlled, double-blind, 2x2
factorial-designed intervention trial.
It concerns a monocenter studie (VUmc, Amsterdam) and a total of 60
participants will be included.
Intervention
Subjects will be randomized to one of four groups, to receive either 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.
Prednisolone/prednisolone-placebo will be administered for 14 days and
sitagliptin/sitagliptin-placebo for 28 days.
Study burden and risks
We are well aware of the possible demand that may be imposed on the
participants. Overall, participants will travel 7 times to the study location.
The duration of these visits ranges between 30 minutes and 7 hours, with a
total of 34,5 hours. A total amount of 500 mL blood will be withdrawn. The
maximum amount of blood to be collected during one visit is 120 mL.
All possible measures will be taken to minimize the discomfort for the
participants. During the clamps and meal tests, patients will assume a
semirecumbent position, to alleviate discomfort, and will be allowed to read or
watch TV/video. Following the tests, all participants will be presented with a
meal and coffee/tea. During the clamps (a restricted regimen of) water intake
is allowed. Subjects with claustrophobia are excluded from MRI-scans. Lidocaine
will be used as a local anaesthetic during the biopsy procedures. Ice packages
will be used to reduce the development of a hematoma. Our current experience
indicates that participants tolerate these muscle and adipose tissue biopsies
very well. Sitagliptin is tolerated very well by it's users. Only mild side
effects such as nasopharyngitis and headache occur in a small percentage of
users. Since prednisolone has been used extensively, its potential, clinically
relevant side-effects are well documented. Aside from the development of
transient impairment of insulin sensitivity and beta-cell dysfunction, we do
not expect to find other adverse effects in our short treatment period with
medium-doses of prednisolone. In a recent study in healthy males, using an
identical intervention as in our study, it was shown that GC-induced insulin
resistance was quickly resolved after cessation of therapy. Glucose levels were
not changed during the study, and the increased levels of C-peptide and
pro-insulin (signs of insulin resistance) had returned to baseline after
one-week of follow-up. Furthermore, no participants had to discontinue the
study due to health problems, and no serious adverse events were reported
(refer to protocol page 16-18).
De Boelaan 1117
1081 HV Amsterdam
NL
De Boelaan 1117
1081 HV Amsterdam
NL
Listed location countries
Age
Inclusion criteria
1. signed informed consent
2. caucasian male
3. normal day-and night rythm
4. metabolic syndrome (according to IDF criteria):
Waist > 93 cm and at least 3 of the following criteria:
- triglycerides > 1.7 mmol/L
- HDL cholesterol < 1.03 mmol/L
- blood pressure > 130/85 mmHg
- disturbed glucose tolerance (definded as: fasting plasma glucose above 5.6 mmol/L, but no diabetes [see exclusion criteria]).
Exclusion criteria
1. allergy for prednisolone
2. any other contra-indication for prednisolone use.
3. use of glucocorticoids in the past 3 months
4. Recent participation in a clinical trial
5. Blood donation in the past 3 months
6. (history of) alcohol or drugs abuse.
7. Not willing or able to sign the informed consent or not being able to understand the study information
8. serious (pulmonary, liver, kidney) diseases
9. history of cardiovascular disease (such as MI or CVA)
10. psychiatric disorder
11. depression
12. any condition that interferes with the HPA axis
13. malignancy
14. diabetes mellitus (defined as FPG * 7.0 mmol/l and/or 2hPG * 11.1 mmol/l)
15. other condition or usage of medication that may interfere with study endpoints of hypothesis. Eligibility will be assessed in each individual case by the research physician and internist.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2008-004985-25-NL |
| ClinicalTrials.gov | NCT00721552 |
| CCMO | NL25430.029.08 |