The primary objective is to examine the effects of dapagliflozin on nocturnal substrate oxidation in overweight or obese subjects with disrupted glucose homeostasis but without T2D.
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 nightly substrate oxidation as
measured by respiratory quotient (VCO2/VO2) between placebo and active
treatment after 2 week double blind treatment. Nightly substrate oxidation will
be determined during the sleep-period.
Secondary outcome
This study has the following secundary objectives:
To investigate if Dapagliflozin changes hepatic glycogen content in the morning
and evening as compared to placebo after 2 week double blind treatment.
To investigate if Dapagliflozin changes muscle mitochondrial function as
compared to placebo after 2 week double blind treatment.
Background summary
Metabolic health is characterized by a good metabolic flexibility: the capacity
to switch from fat oxidation in the overnight fasted state to glucose oxidation
in the postprandial state when insulin levels are high. Patient with Type 2
Diabetes Mellitus (T2D), but also individuals with so-called pre-diabetes *
healthy, but have a disrupted glucose homeostasis - have an impaired metabolic
flexibility. Including higher rates of glucose oxidation in the fasted state,
and reduced insulin-induced glucose oxidation rates. A continuous state of
*over-nutrition* either due to high food intake and/or excessive substrate
storage and turnover - including substrate storage in peripheral tissues such
as muscle and liver - will contribute to this lack of substrate switch over the
day. In fact, among the best strategies to prevent and/or treat T2D are
exercise and calorie restrictions: both interventions result in a temporary
energy deficit, even when 24h energy balance may not be affected by
compensatory food intake. The beneficial health effects of calorie restriction
and exercise do not seem to depend on weight loss.
Inhibition of sodium-glucose cotransporter 2 (SGLT2) by a pharmacological
intervention results in excessive glucose drainage via the urine. SGLT2
inhibitors have been shown to have beneficial effects on glucose homeostasis
and metabolic health in general in T2D patients. We here suggest that the
glucosuria resulting from SGLT2 inhibition results in an energy deficit that
may trigger exercise-like improvements in metabolic health. More specific, we
hypothesize that especially urinary glucose loss during the night will result
in a larger energy deficit during this period, resulting in a more pronounced
fasting state. We propose that this may lead to a more pronounced decrease in
insulin and increase in glucagon during the night and a pronounced switch to
fatty acids oxidation. This restoration of a normal day-night pattern in
substrate metabolism will also trigger energy and substrate turnover in
peripheral tissues, resulting in larger intracellular glycogen depletion,
leading to improvements in mitochondrial function and restoration of metabolic
flexibility.
Study objective
The primary objective is to examine the effects of dapagliflozin on nocturnal
substrate oxidation in overweight or obese subjects with disrupted glucose
homeostasis but without T2D.
Study design
The study is a double-blind, randomized, phase IV, mechanistic,
placebo-controlled, cross-over, single-center study
Intervention
This study has a cross-over design with two periods:
Period 1: Participants will receive either 10mg dapagliflozin or the matching
placebo for a maximum of 14 days based on randomization sequence.
Period 2: Participants that received 10mg dapagliflozin in the first treatment
period will receive the matching placebo in the second treatment period and
patients who received the placebo in the first treatment period will receive 10
mg dapagliflozin in the second treatment period, for a maximum of 14 days.
Study burden and risks
The use of Dapagliflozin can have side effects, which are described in the IB.
The patient will have 5 visits, which will take about 103 hours in total. The
burden and risks of the tests performed are described below.
Muscle biopsy (4 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, subjects are not allowed to perform intense exercise and should not
remove the bandage for 24 hours. In extreme circumstances subjects may have to
take paracetamol.
DEXA (1 time): exposure to a very small dose of radiation (<0.01mSv)
MRS (MRI) (4 times): the subjects will enter the MRI scanner 4 times, during
which 4 MRS scans are made. There is a chance that MRI/MRS reveals an
unexpected medical condition, of which the subject and treating physician will
be informed.
Venapunction (2 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 subjects will stay in
the respiration chamber for 36 hours per visit, where they have access to a
toilet, bed, computer and television set.
There are no direct benefits for the subject. Subjects will receive
compensation for participating in the study. Subjects will receive 853 euros
for completing all study test, and expenses regarding travel expenses and
parking costs will be compensated.
Universiteitssingel 50
Maastricht 6229 ER
NL
Universiteitssingel 50
Maastricht 6229 ER
NL
Listed location countries
Age
Inclusion criteria
1. Provision of signed and dated informed consent prior to any study specific
procedures.
2. Males aged * 40 and * 75 years and post-menopausal women (defined as at
least 1 year post cessation of menses) aged * 50 and * 75 years
3. Body mass index (BMI) * 27 and * 38 kg/m2.
4. Sedentary lifestyle (not more than 2 hours of vigorous exercise per week).
5. Stable dietary habits.
6. Disrupted glucose homeostasis based on one or a combination of the following
criteria:
- Impaired Glucose Tolerance (IGT): plasma glucose values * 7.8 mmol/l and *
11.1 mmol/l 120 minutes after consumption of the glucose drink during the 2h,
3-point OGTT.
- Impaired Fasting Glucose (IFG): fasting plasma glucose * 6.1 mmol/l and * 6.9
mmol/l.
- Insulin Resistance: glucose clearance rate * 360 ml/kg/min, as calculated by
Oral Glucose Insulin Sensitivity 120 (OGIS120) model based on the 2h, 3-point
OGTT.
- HbA1c * 5.7% and * 6.4%.
Exclusion criteria
1. Clinical diagnosis of Type 1 or 2 Diabetes Mellitus.
2. Active cardiovascular disease
3. Weight gain or loss > 5 kg in the last 3 months, ongoing weight-loss diet
(hypocaloric diet) or use of weight loss agents.
4. Regular smoking and other regular nicotine use.
5. Anaemia.
6. Uncontrolled hypertension.
7. Clinically significant abnormalities in clinical chemistry or hematology
8. Unstable or rapidly progressing renal disease or estimated Glomeral
Filtration Rate (eGFR) <60 mL/min (Cockcroft-Gault formula).
9. Use of anti-coagulant treatment
10. Use of medication such as oral glucocorticoids, anti-estrogens or other
medications that are known to markedly influence insulin sensitivity.
11. Use of loop diuretics.
12. Intake of dietary supplements except multi-vitamins and minerals.
13. Alcohol consumption of > 14 drinks per week for women and > 21 drinks per
week for men.
14. Known hypersensitivity to dapagliflozin or any of the excipients of the
product.
15. For women only - currently pregnant (confirmed with positive pregnancy
test) or breast-feeding.
16. Any contraindication for MRI scanning.
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 | EUCTR2018-003283-31-NL |
| ClinicalTrials.gov | NCT03721874 |
| CCMO | NL67170.068.18 |