Effects of 5 Weeks Treatment With Dapagliflozin in Type 2 Diabetes Patients on How the Hormone Insulin Acts on Sugar Uptake in Muscles. (DAPAMAAST)

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.

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2; Skeletal Muscle Insulin Sensitivity
• Intervention / Treatment: Drug: Dapagliflozin

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

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Maastricht, Netherlands, 6229 ER
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Dapagliflozin; Patients will receive dapagliflozin 10 mg in tablet for a maximum of 40 days based on randomization sequence in Period 1. Patients that received 10 mg dapagliflozin in the first treatment period will receive matching placebo in the second treatment period for a maximum of 40 days.	Drug: Dapagliflozin; The study consist of 5 weeks treatment period 1, 6-8 weeks wash-out period and 5 weeks treatment period 2. The patient will be administered dapagliflozin 10 mg during Period 1 or Period 2.
PLACEBO_COMPARATOR: Placebo matching to dapagliflozin; Patients will receive matching placebo in tablet for a maximum of 40 days based on randomization sequence. Patients who received placebo in the first treatment will receive 10 mg dapagliflozin in the second treatment period, for a maximum of 40 days	Drug: Dapagliflozin; The study consist of 5 weeks treatment period 1, 6-8 weeks wash-out period and 5 weeks treatment period 2. The patient will be administered dapagliflozin 10 mg during Period 1 or Period 2.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Corrected Glucose Disposal Rate (cGDR) Measured as Change in Rate of Disposal (Delta RD) Basal vs High Insulin After 5 Weeks of Treatment	Skeletal muscle insulin sensitivity was measured as cGDR (referred to as delta RD [basal vs high insulin]) using a 2-step 5.5 hour euglycemic hyperinsulinemic clamp (EHC) procedure in combination with infusion of D-glucose (6,6-D2) glucose. Delta RD (basal vs high insulin) was corrected for urinary glucose excretion and measured at the end of Treatment Periods 1 and 2.	At end (Week 5) of Treatment Periods 1 and 2

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Endogenous Glucose Production (EGP) After 5 Weeks of Treatment	A 2-step 5.5 hour EHC in combination with infusion of 6,6-D2 glucose was used to determine rates of EGP at the end of Treatment Periods 1 and 2. Results of the change in EGP are presented as delta EGP (basal vs low insulin and basal vs high insulin).	At end (Week 5) of Treatment Periods 1 and 2
Change in Respiratory Exchange Ratio (RER) From Fasted State to Insulin Stimulated State After 5 Weeks of Treatment	During the indirect calorimetry of the EHC test, respiratory gas exchange was measured using open air circuit respirometry with an automated ventilated hood system. Metabolic flexibility was determined by the change in RER from fasted state to insulin stimulated state at the end of Treatment Periods 1 and 2 and results are presented as delta RER (basal vs high insulin).	At end (Week 5) of Treatment Periods 1 and 2
24-Hour RER After 5 Weeks of Treatment	RER was measured before and after meals over a 24-hour period.	At end (Week 5) of Treatment Periods 1 and 2
24-Hour Energy Expenditure After 5 Weeks of Treatment	Whole body energy expenditure was measured over a 24-hour period.	At end (Week 5) of Treatment Periods 1 and 2
Body Composition (Fat Mass and Lean Mass) After 5 Weeks of Treatment	On Day 6, 7 or 8 of the end of treatment visit in both treatment periods, a Dual-energy X-ray absorptiometry (DEXA) scan was used to determine body composition.	At end (Week 5) of Treatment Periods 1 and 2
Body Composition (Total Mass) After 5 Weeks of Treatment	On Day 6, 7 or 8 of the end of treatment visit in both treatment periods a DEXA scan was used to determine body composition.	At end (Week 5) of Treatment Periods 1 and 2
Fibroblast Growth Factor 21 (FGF21) Area Under the Curve (AUC) in Plasma After 5 Weeks of Treatment	From the end of Day 1 until the morning of Day 3 of the end of each treatment visit, the patients stayed in the metabolic chamber (36 hours). During this stay FGF21 was measured in plasma before and after meals and before bed-time to determine the AUC (last 24 hours).	At end (Week 5) of Treatment Periods 1 and 2

Collaborators and Investigators

• Sponsor: AstraZeneca

Publications and helpful links

General Publications

• 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.
• 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. Erratum In: Diabetes Care. 2022 May 1;45(5):1297.

Helpful Links

• Redacted CSP
• Redacted SAP

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 5, 2018
• Primary Completion (ACTUAL): November 4, 2019
• Study Completion (ACTUAL): November 4, 2019

Study Registration Dates

• First Submitted: November 7, 2017
• First Submitted That Met QC Criteria: November 7, 2017
• First Posted (ACTUAL): November 9, 2017

Study Record Updates

• Last Update Posted (ACTUAL): January 15, 2021
• Last Update Submitted That Met QC Criteria: January 10, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: T2DM, insulin resistance, skeletal muscle, mitochondria, dapagliflozin
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Endocrine System Diseases; Hyperinsulinism; Hypersensitivity; Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin Resistance; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: D1690C00047; 2016-003991-27 (EUDRACT_NUMBER)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No