The aim of the study is to investigate effects of dapagliflozin on potential mechanisms explaining improved insulin sensitivity in skeletal muscles.
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
- Glucose metabolism disorders (incl diabetes mellitus)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To investigate if dapagliflozin improves skeletal muscle insulin sensitivity
expressed as cGDR between placebo and active treatment after 5-week double
blind treatment. Insulin sensitivity will be determined using a 2-step EHC
procedure.
Secondary outcome
This study has the following exploratory objectives:
To investigate if dapagliflozin changes Endogenous Glucose Production (EGP) in
comparison with placebo after 5 weeks of double blind treatment
To investigate if dapagliflozin improves metabolic flexibility as compared to
placebo, determined by the change in respiratory exchange ratio (RER) from
fasted state to insulin stimulated state during EHC after 5-week double blind
treatment
To investigate if dapagliflozin changes RER and energy expenditure as well as
plasma metabolites such as beta-hydroxybutyrate and glucose as compared to
placebo, before and after meals in the metabolic chamber after 5-week double
blind treatment
To investigate if dapagliflozin improves maximal capacity to form
acetylcarnitine following exercise and CRAT activity in muscle biopsy, as
compared to placebo after 5-week double blind treatment
To investigate if dapagliflozin improves in vivo mitochondrial function as
measured by phosphocreatinine recovery following exercise, as compared to
placebo after 5-week double blind treatment
To investigate if dapagliflozin improves ex vivo mitochondrial function in
permeabilized muscle fibers using high resolution respirometry, as compared to
placebo after 5-week double blind treatment
To investigate if dapagliflozin changes body composition, skeletal muscle and
liver fat content, as compared to placebo after 5-week double blind treatment.
To investigate if dapagliflozin changes blood biomarkers such as glucagon,
insulin and FGF21 in comparison with placebo after 5 weeks of double blind
treatment
To investigate if dapagliflozin changes expression of mRNA and/or proteins
involved in metabolic regulation in muscle tissue in comparison with placebo
after 5-weeks of double blind treatment.
Background summary
Type 2 diabetes mellitus (T2DM) results from combined derangements of insulin
sensitivity and beta-cell function. The main tissues contributing to reduced
whole body insulin resistance (IR) are the liver, skeletal muscles and adipose
tissues. One of the earliest changes in first degree relatives to T2DM patients
is reduced skeletal muscle insulin sensitivity. The degree of IR in skeletal
muscle is typically investigated using an euglycemic hyperinsulinemic clamp
(EHC) technique and given as glucose disposal rate (GDR). The cause of the IR
associated with T2DM has not yet been fully understood.
A decreased mitochondrial function has been associated with skeletal muscle IR
in several studies. However, it has been unclear if reduced mitochondrial
function is a cause or a consequence of IR. A possible causal relationship
between mitochondrial function and skeletal muscle insulin sensitivity is the
ability of the mitochondria to export excess acetyl-CoA as acetylcarnitine by
the action of carnitine acetyltransferase (CRAT). A strong association between
levels of acetylcarnitine in skeletal muscles and insulin sensitivity has been
shown in subjects with various levels of insulin resistance, indicating that
decreased mitochondrial formation of acetylcarnitine could explain skeletal
muscle insulin resistance.
T2DM and IR are associated with metabolic inflexibility as first described by
Kelly et al. Metabolic inflexibility is likely to be caused by nutrient
overload resulting in substrate competition at the level of the mitochondria.
Dapagliflozin is a sodium glucose co-transporter-2 (SGLT2) inhibitor indicated
for the treatment of T2DM. The SGLT2 inhibition results in a loss of glucose
and its associated energy (about 50-70 g/day) via urine. This mechanism results
in a reduction in Hemoglobin A1c (HbA1c) and body weight. In a 2-year study, it
was shown that dapagliflozin reduces HbA1c by 0.3%, weight by 4.5 kg and fat
mass by 2.8 kg. It has also been shown that the reduction in body weight is
faster over the first few weeks, followed by a more gradual decline that
plateaus between 24 and 50 weeks of therapy).
An effect on insulin sensitivity, measured as a 17.5% increase in cGDR, has
been demonstrated after 12 weeks of treatment with 5 mg dapagliflozin. This
finding was repeated in a study with a treatment period of about 2 weeks where
cGDR increased by 16% in the dapagliflozin group but remained unchanged in the
placebo treated group (p<0.05 vs baseline and placebo). This study also showed
that endogenous glucose production (EGP) increased as a result of dapagliflozin
treatment. In summary, 3 studies have investigated the effect of 2-12 weeks of
treatment with SGLT2 inhibitors on insulin sensitivity and found 16 24% net
improvements in cGDR. Treatment with SGLT2 inhibitors increases glucose
excretion via the urine, which results in energy losses. Increased
glucagon/insulin ratio explains increased hepatic glucose production, while
indirect mechanisms explaining improved skeletal muscle insulin sensitivity are
not known.
Study objective
The aim of the study is to investigate effects of dapagliflozin on potential
mechanisms explaining improved insulin sensitivity in skeletal muscles.
Study design
This is a randomized, double-blind, cross-over, placebo controlled,
single-center phase 4 study
Intervention
This study has a cross-over design with two periods:
Period 1: Patients will receive either dapagliflozin 10 mg or matching placebo
for a maximum of 40 days based on randomization sequence.
Period 2: Patients that received 10 mg dapagliflozin in the first treatment
period will receive matching placebo in the second treatment period and
patients who received placebo in the first treatment will receive 10 mg
dapagliflozin in the second treatment period, for a maximum of 40 days.
Study burden and risks
The use of Dapagliflozin can have side effects, which are described in the
IB.
The study will last a maximum of 134 days in total. The patient will have 9
visits during this period. The burden and risks of the tests performed are
described below.
Muscle biopsy (2 times): patients can experience a dull pain when the biopsy
is taken, despite sedation. A small scar remains where the biopsy was taken.
After the biopsy, patients are not allowed to perform intense exercise and
should not remove the bandage for 24 hours. In extreme circumstances patients
may have to take paracetamol.
DEXA (2 times): exposure to a very small dose of radiation (0.001 mSv).
MRs (MRI) (6 times): the patiens will enter the MRI scanner 6 times, during
which 8 MRS scans are made. There is a chance that the MRS may reveal an
unexpected medical condition, of which the patient and the treating physician
will be informed.
VO2 max and knee-extension test (6 times all together): can cause muscle ache
and discomfort
Euglycemic hyperinsulinemic clamp (2 times): in extreme circumstances symptoms
of hypoglycemia can occur. Furthermore, placing a catheter can be painful and
can cause a bruise and discomfort.
Venapunction (3 times): this procedure can cause temporary pain and a bruise.
In exceptional cases, nerve damage can occur.
Overnight stay in the respiration chamber (2 times): the patients will stay in
the respiration chamber for 36 hours per visit, where they have access to a
toilet, bed, computer and television set.
All together, approximately 625 mL of blood will be taken during the course of
the study.
The benefits of participating in the study for the patient is that
dapagliflozin could reduce blood sugar levels. Furthermore, dapagliflozin can
reduce body weight, HbA1c and can increase insulin sensitivity. Patients will
receive compensation for participating in the study. Patients will receive 1000
euros for completing all study tests. If patients make expenses regarding
parking costs, travel expenses and/or hotel stays (hotel stays are optional for
visits 4 and 7) they will be compensated.
Louis Pasteurlaan 5
Zoetermeer 2719 EE
NL
Louis Pasteurlaan 5
Zoetermeer 2719 EE
NL
Listed location countries
Age
Inclusion criteria
1. Patients are able to provide signed and dated written informed consent prior to any study specific procedures.
2. Women are post-menopausal (defined as at least 1 year post cessation of menses) and aged >= 45 and <= 70 years. Males are aged >= 40 years and <= 70 years. Patients should have suitable veins for cannulation or repeated venipuncture.
3. Patients are diagnosed with T2DM for at least the last 6 months, based on American Diabetes Association 2016 standards
4. Patients are on no anti-diabetic drug treatment or on stable metformin treatment for at least the last 3 months: maximum 3000 mg metformin daily dose.
5. HbA1c levels >=6.0% (=42 mmol/mol) and <=9.0% (75 mmol/mol).
6. Have a body mass index (BMI) <= 38 kg/m2.
Exclusion criteria
1. Involvement in the planning and conduct of the study (applies to both AstraZeneca staff and staff at third party vendor or at the investigational sites).
2. Previous enrolment in the present study or participation in another clinical study with an investigational product during the last 3 months or as judged by the Investigator.
3. History of or presence of any clinically significant disease or disorder including a recent (< 3 months) cardiovascular event which, in the opinion of the Investigator, may either put the patient at risk because of participation in the study or influence the results or the patient*s ability to participate in the study.
4. Clinical diagnosis of Type 1 diabetes, maturity onset diabetes of the young, secondary diabetes or diabetes insipidus.
5. Unstable/rapidly progressing renal disease or estimated Glomerular Filtration Rate < 60 mL/min (Cockcroft-Gault formula).
Males:
Creatinine clearance (mL/min) = Weight (kg) X (140-Age) X 1.23
Serum creatinine (µmol/l)
Females:
Creatinine clearance (mL/min) = Weight (kg) X (140-Age) X 1.04
Serum creatinine (µmol/l)
6. Clinically significant out of range values of serum levels of either alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase (ALP) in the Investigator*s opinion.
7. Contraindications to dapagliflozin according to the local label.
8. Use of antidiabetic drugs other than metformin within 3 months prior to screening.
9. Weight gain or loss > 5 kg in the last 3 months, ongoing weight-loss diet (hypocaloric diet) or use of weight loss agents.
10. History of drug abuse or alcohol abuse in the past 12 months. Alcohol abuse is defined as > 14 drinks per week for women and > 21 drinks per week for men (1 drink = 35 cl beer, 14 cl wine or 4 cl hard liquor) or as judged by the Investigator.
11. Any clinically significant abnormalities in clinical chemistry, hematology or urinalysis or other condition the Investigator believes would interfere with the patient*s ability to provide informed consent, comply with study instructions, or which might confound the interpretation of the study results or put the patient at undue risk.
12. Plasma donation within one month of screening or any blood donation/ blood loss > 500 mL within 3 months prior to screening or during the study.
13. Anemia defined as Hemoglobin (Hb) < 115 g/L (7.1 mM) in women and < 120 g/L (7.5 mM) in men.
14. Use of anti-coagulant treatment such as heparin, warfarin, platelet inhibitors, thrombin and factor X inhibitors.
15. Use of medication such as oral glucocorticoids, anti-estrogens or other medications that are known to markedly influence insulin sensitivity.
16. Use of loop diuretics.
17. Regular smoking and other regular nicotine use.
18. Any contra-indication to magnetic resonance imaging scanning. These contra indications include patients with following devices:
- Central nervous system aneurysm clip
- Implanted neural stimulator
- Implanted cardiac pacemaker of defibrillator
- Cochlear implant
- Metal containing corpora aliena in the eye or brain.
19. Patients, who do not want to be informed about unexpected medical findings, or do not wish that their physician be informed about coincidental findings, cannot participate in the study.
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 | EUCTR2016-003991-27-NL |
| ClinicalTrials.gov | NCT03338855 |
| CCMO | NL63333.068.17 |