Clinical trial NCT03721874: Effects of 2 Weeks Treatment With Dapagliflozin in Subjects With an Impaired Glucose Homeostasis on Nocturnal Substrate Oxidation
Official title: MaasFlex: Double-Blind, Randomized, Phase IV, Mechanistic, Placebo-Controlled, Cross-Over, Single-Center Study to Evaluate the Effects of 2 Weeks Dapagliflozin Treatment on Nocturnal Substrate Oxidation, Glucose Metabolism and Muscle Mitochondrial Function in Individuals With Impaired Glucose Homeostasis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Prediabetic State
Substrate Oxidation
Keywords: Dapagliflozin
Disrupted glucose homeostasis
Nocturnal substrate oxidation
Glucose metabolism
Lead sponsor: Maastricht University
Sponsor class: OTHER
Collaborators: name: AstraZeneca
First posted: 2018-10-26
Enrollment: 16
Sex: ALL
Minimum age (years): 40
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Double-Blind, Randomized, Phase IV, Mechanistic, Placebo-Controlled, Cross-Over, Single-Center Study
Primary purpose: BASIC_SCIENCE

Brief summary: The purpose of this study is to investigate the effect of 2 weeks dapagliflozin treatment in individuals with a disrupted glucose homeostasis on the switch between carbohydrate and lipid oxidation during the night

Detailed description: To investigate if dapagliflozin improves nocturnal substrate oxidation expressed as respiration quotient (RQ) during the sleeping period in comparison with placebo after 2-weeks double blind treatment in subjects with a disrupted glucose homeostasis.

Eligibility criteria: 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 3 hours of programmed exercise per week).
5. Stable dietary habits.
6. Impaired 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: participants who experienced a heart attack in the last year, or participants who are currently under regular control of a physician for a heart condition.
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 out of range values of serum levels of either alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) in the Investigator's opinion.
8. Unstable or rapidly progressing renal disease or estimated Glomerular Filtration Rate (eGFR) \<60 mL/min (Cockcroft-Gault formula).
9. Use of anti-coagulant treatment and other concomitant medication will be evaluated on a case to case basis with a general physician.
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 (1 drink = 35 cl beer, 14 cl wine or 4 cl hard liquor).
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. Participation in another biomedical study within 1 month before the screening visit.
17. Any contraindication for MRI scanning.
18. Participants 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.

Primary outcomes:
measure: Change in nightly substrate oxidation measured as respiration quotient (RQ) during the sleeping period
timeFrame: From screening to day 14
Secondary outcomes:
measure: Change in morning and late afternoon hepatic glycogen content
timeFrame: 1 hour
measure: Change in 24h substrate oxidation as determined by indirect calorimetry in a whole-body respiratory chamber and based on urinary nitrogen excretion
timeFrame: 24 hours
measure: Change in 24h plasma markers
timeFrame: 24 hours
measure: Change in muscle mitochondrial function
timeFrame: 60 minutes
measure: Change in intrahepatic lipid content and composition
timeFrame: 45 minutes
measure: Change in intramyocellular lipid content and composition - including acylcarnitine levels
timeFrame: 45 minutes
measure: Change in muscle glycogen content
timeFrame: 45 minutes
measure: Change in systolic and diastolic blood pressure
timeFrame: 45 minutes
Other outcomes:
Locations:
city: Maastricht
country: Netherlands
facility: Maastricht University and Medical Centre
state: Limburg
Study officials:
affiliation: principle investigator
name: Patrick Schrauwen, Prof. dr.
role: PRINCIPAL_INVESTIGATOR
References: