Clinical trial NCT03338855: Effects of 5 Weeks Treatment With Dapagliflozin in Type 2 Diabetes Patients on How the Hormone Insulin Acts on Sugar Uptake in Muscles.
Official title: DAPAMAAST: A Double-blind, Randomized, Phase IV, Mechanistic, Placebo-controlled, Cross-over, Single-center Study to Evaluate the Effects of 5 Weeks Dapagliflozin Treatment on Insulin Sensitivity in Skeletal Muscle in Type 2 Diabetes Mellitus Patients.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Diabetes Mellitus, Type 2
Skeletal Muscle Insulin Sensitivity
Keywords: T2DM, insulin resistance, skeletal muscle, mitochondria, dapagliflozin
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2017-11-09
Enrollment: 26
Sex: ALL
Minimum age (years): 40
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: The purpose of this study is to investigate the effects of 5 weeks treatment with dapagliflozin in type 2 diabetes patients on how the hormone insulin acts on sugar uptake in muscles.

Detailed description: To investigate if dapagliflozin improves skeletal muscle insulin sensitivity expressed as corrected glucose disposal rate (cGDR) in comparison with placebo after 5-week double blind treatment. Insulin sensitivity will be determined using a 2-step euglycemic hyperinsulinemic clamp (EHC) procedure

Eligibility criteria: Inclusion Critieria:

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.
4. Patients are on no other anti-diabetic drug treatment, or on stable maximum 3000 mg daily dose metformin treatment and/or on stable dose of a DPPIV inhibitor treatment for at least the last 3 months5. HbA1c levels ≥6.0% (=42 mmol/mol) and ≤9.0% (75 mmol/mol).
5. Have a body mass index (BMI) ≤ 35 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).
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.
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.

Primary outcomes:
measure: Corrected Glucose Disposal Rate (cGDR) Measured as Change in Rate of Disposal (Delta RD) Basal vs High Insulin After 5 Weeks of Treatment
timeFrame: At end (Week 5) of Treatment Periods 1 and 2
Secondary outcomes:
Other outcomes:
measure: Change in Endogenous Glucose Production (EGP) After 5 Weeks of Treatment
timeFrame: At end (Week 5) of Treatment Periods 1 and 2
measure: Change in Respiratory Exchange Ratio (RER) From Fasted State to Insulin Stimulated State After 5 Weeks of Treatment
timeFrame: At end (Week 5) of Treatment Periods 1 and 2
measure: 24-Hour RER After 5 Weeks of Treatment
timeFrame: At end (Week 5) of Treatment Periods 1 and 2
measure: 24-Hour Energy Expenditure After 5 Weeks of Treatment
timeFrame: At end (Week 5) of Treatment Periods 1 and 2
measure: Body Composition (Fat Mass and Lean Mass) After 5 Weeks of Treatment
timeFrame: At end (Week 5) of Treatment Periods 1 and 2
measure: Body Composition (Total Mass) After 5 Weeks of Treatment
timeFrame: At end (Week 5) of Treatment Periods 1 and 2
measure: Fibroblast Growth Factor 21 (FGF21) Area Under the Curve (AUC) in Plasma After 5 Weeks of Treatment
timeFrame: At end (Week 5) of Treatment Periods 1 and 2
Locations:
city: Maastricht
country: Netherlands
facility: Research Site
Study officials:
References:
citation: Op den Kamp YJM, Gemmink A, de Ligt M, Dautzenberg B, Kornips E, Jorgensen JA, Schaart G, Esterline R, Pava DA, Hoeks J, Schrauwen-Hinderling VB, Kersten S, Havekes B, Koves TR, Muoio DM, Hesselink MKC, Oscarsson J, Phielix E, Schrauwen P. Effects of SGLT2 inhibitor dapagliflozin in patients with type 2 diabetes on skeletal muscle cellular metabolism. Mol Metab. 2022 Dec;66:101620. doi: 10.1016/j.molmet.2022.101620. Epub 2022 Oct 21.
citation: Op den Kamp YJM, de Ligt M, Dautzenberg B, Kornips E, Esterline R, Hesselink MKC, Hoeks J, Schrauwen-Hinderling VB, Havekes B, Oscarsson J, Phielix E, Schrauwen P. Effects of the SGLT2 Inhibitor Dapagliflozin on Energy Metabolism in Patients With Type 2 Diabetes: A Randomized, Double-Blind Crossover Trial. Diabetes Care. 2021 Jun;44(6):1334-1343. doi: 10.2337/dc20-2887. Epub 2021 Apr 15.