Diabetes Mellitus, Type 2, Skeletal Muscle Insulin Sensitivity
Conditions
Keywords
T2DM, insulin resistance, skeletal muscle, mitochondria, dapagliflozin
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
Interventions
DRUGDapagliflozin
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.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 70 Years
Healthy volunteers
No
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Corrected Glucose Disposal Rate (cGDR) Measured as Change in Rate of Disposal (Delta RD) Basal vs High Insulin After 5 Weeks of Treatment | At end (Week 5) of Treatment Periods 1 and 2 | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Respiratory Exchange Ratio (RER) From Fasted State to Insulin Stimulated State After 5 Weeks of Treatment | At end (Week 5) of Treatment Periods 1 and 2 | 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). |
| 24-Hour RER After 5 Weeks of Treatment | At end (Week 5) of Treatment Periods 1 and 2 | RER was measured before and after meals over a 24-hour period. |
| 24-Hour Energy Expenditure After 5 Weeks of Treatment | At end (Week 5) of Treatment Periods 1 and 2 | Whole body energy expenditure was measured over a 24-hour period. |
| Change in Endogenous Glucose Production (EGP) After 5 Weeks of Treatment | At end (Week 5) of Treatment Periods 1 and 2 | 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). |
| Body Composition (Total Mass) After 5 Weeks of Treatment | At end (Week 5) of Treatment Periods 1 and 2 | 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. |
| Fibroblast Growth Factor 21 (FGF21) Area Under the Curve (AUC) in Plasma After 5 Weeks of Treatment | At end (Week 5) of Treatment Periods 1 and 2 | 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). |
| Body Composition (Fat Mass and Lean Mass) After 5 Weeks of Treatment | At end (Week 5) of Treatment Periods 1 and 2 | 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. |
Countries
Netherlands
Participant flow
Recruitment details
This was a double-blind, randomized, placebo-controlled, cross-over Phase IV mechanistic study which was conducted in 1 study center in the Netherlands between 05 March 2018 and 04 November 2019.
Pre-assignment details
Eligible patients with Type 2 diabetes mellitus were randomized to a specific double-blind treatment sequence (either dapagliflozin then placebo or placebo then dapagliflozin). Each of the 2 treatment periods had a maximum duration of 40 days, separated by a wash-out period of 6 to 8 weeks.
Participants by arm
| Arm | Count |
|---|---|
| Dapagliflozin 10 mg Then Placebo Patients received an oral dose of 10 mg dapagliflozin, once daily for 5 weeks. After a wash-out period of 6 to 8 weeks, matched placebo tablets were taken orally, once daily for 5 weeks. | 12 |
| Placebo Then Dapagliflozin 10 mg Patients received placebo tablets (matched to dapagliflozin) taken orally, once daily for 5 weeks. After a wash-out period of 6 to 8 weeks, patients received an oral dose of 10 mg dapagliflozin, once daily for 5 weeks. | 14 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawn as birth control pill stopped | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo Then Dapagliflozin 10 mg | Total | Dapagliflozin 10 mg Then Placebo |
|---|---|---|---|
| Age, Continuous | 64.4 years STANDARD_DEVIATION 4.7 | 63.8 years STANDARD_DEVIATION 4.7 | 63.0 years STANDARD_DEVIATION 4.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 26 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 14 Participants | 26 Participants | 12 Participants |
| Sex: Female, Male Female | 1 Participants | 6 Participants | 5 Participants |
| Sex: Female, Male Male | 13 Participants | 20 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 25 |
| other Total, other adverse events | 0 / 26 | 0 / 25 |
| serious Total, serious adverse events | 0 / 26 | 0 / 25 |
Outcome results
Primary
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.
Time frame: At end (Week 5) of Treatment Periods 1 and 2
Population: The evaluable analysis set (clamp) was a subset of the randomized analysis set, consisting of patients who received at least 1 dose of any investigational product. Any patients with important procedure specific protocol deviations regarding the clamp method were excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin 10 mg | Corrected Glucose Disposal Rate (cGDR) Measured as Change in Rate of Disposal (Delta RD) Basal vs High Insulin After 5 Weeks of Treatment | 8.523 micromole/kilogram body weight/minute |
| Placebo | Corrected Glucose Disposal Rate (cGDR) Measured as Change in Rate of Disposal (Delta RD) Basal vs High Insulin After 5 Weeks of Treatment | 9.592 micromole/kilogram body weight/minute |
Comparison: Comparison of delta RD (basal vs high insulin) between dapagliflozin and placebo after 5 weeks of treatment was performed using a random effects analysis of variance model.p-value: 0.304795% CI: [-3.183, 1.047]Linear Mixed Effects Model
Other Pre-specified
24-Hour Energy Expenditure After 5 Weeks of Treatment
Whole body energy expenditure was measured over a 24-hour period.
Time frame: At end (Week 5) of Treatment Periods 1 and 2
Population: The evaluable analysis set (chamber) was a subset of the randomized analysis set, consisting of patients who received at least 1 dose of any investigational product. Any patients with important procedure specific protocol deviations regarding the chamber method were excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin 10 mg | 24-Hour Energy Expenditure After 5 Weeks of Treatment | 9.519 megajoules/day |
| Placebo | 24-Hour Energy Expenditure After 5 Weeks of Treatment | 9.628 megajoules/day |
Comparison: Comparison of energy expenditure between dapagliflozin and placebo after 5 weeks of treatment was performed using a random effects analysis of variance model.p-value: 0.109595% CI: [-0.245, 0.027]Linear Mixed Effects Model
Other Pre-specified
24-Hour RER After 5 Weeks of Treatment
RER was measured before and after meals over a 24-hour period.
Time frame: At end (Week 5) of Treatment Periods 1 and 2
Population: The evaluable analysis set (chamber) was a subset of the randomized analysis set, consisting of patients who received at least 1 dose of any investigational product. Any patients with important procedure specific protocol deviations regarding the chamber method were excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin 10 mg | 24-Hour RER After 5 Weeks of Treatment | 0.812 ratio |
| Placebo | 24-Hour RER After 5 Weeks of Treatment | 0.835 ratio |
Comparison: Comparison of 24-hour RER between dapagliflozin and placebo after 5 weeks of treatment was performed using a random effects analysis of variance model.p-value: 0.000195% CI: [-0.033, -0.013]Linear Mixed Effects Model
Other Pre-specified
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.
Time frame: At end (Week 5) of Treatment Periods 1 and 2
Population: The evaluable analysis set (DEXA) was a subset of the randomized analysis set, consisting of patients who received at least 1 dose of any investigational product. Any patients with procedure specific protocol deviations regarding the DEXA method were excluded.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Dapagliflozin 10 mg | Body Composition (Fat Mass and Lean Mass) After 5 Weeks of Treatment | Fat Mass | 25318.3 grams |
| Dapagliflozin 10 mg | Body Composition (Fat Mass and Lean Mass) After 5 Weeks of Treatment | Lean Mass | 59929.0 grams |
| Placebo | Body Composition (Fat Mass and Lean Mass) After 5 Weeks of Treatment | Fat Mass | 25564.9 grams |
| Placebo | Body Composition (Fat Mass and Lean Mass) After 5 Weeks of Treatment | Lean Mass | 60595.4 grams |
Comparison: Comparison of fat mass between dapagliflozin and placebo after 5 weeks of treatment was performed using a random effects analysis of variance model.p-value: 0.600595% CI: [-1209.5, 716.2]Linear Mixed Effects Model
Comparison: Comparison of lean mass between dapagliflozin and placebo after 5 weeks of treatment was performed using a random effects analysis of variance model.p-value: 0.037695% CI: [-1291, -41.9]Linear Mixed Effects Model
Other Pre-specified
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.
Time frame: At end (Week 5) of Treatment Periods 1 and 2
Population: The evaluable analysis set (DEXA) was a subset of the randomized analysis set, consisting of patients who received at least 1 dose of any investigational product. Any patients with important procedure specific protocol deviations regarding the DEXA method were excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin 10 mg | Body Composition (Total Mass) After 5 Weeks of Treatment | 85.248 kilograms |
| Placebo | Body Composition (Total Mass) After 5 Weeks of Treatment | 86.504 kilograms |
Comparison: Comparison of total mass between dapagliflozin and placebo after 5 weeks of treatment was performed using a random effects analysis of variance model.p-value: 0.000395% CI: [-1.854, -0.657]Linear Mixed Effects Model
Other Pre-specified
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).
Time frame: At end (Week 5) of Treatment Periods 1 and 2
Population: The evaluable analysis set (clamp) was a subset of the randomized analysis set, consisting of patients who received at least 1 dose of any investigational product. Any patients with important procedure specific protocol deviations regarding the clamp method were excluded.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Dapagliflozin 10 mg | Change in Endogenous Glucose Production (EGP) After 5 Weeks of Treatment | Delta EGP (basal vs low insulin) | -4.656 micromole/kilogram body weight/minute |
| Dapagliflozin 10 mg | Change in Endogenous Glucose Production (EGP) After 5 Weeks of Treatment | Delta EGP (basal vs high insulin) | -10.803 micromole/kilogram body weight/minute |
| Placebo | Change in Endogenous Glucose Production (EGP) After 5 Weeks of Treatment | Delta EGP (basal vs low insulin) | -2.591 micromole/kilogram body weight/minute |
| Placebo | Change in Endogenous Glucose Production (EGP) After 5 Weeks of Treatment | Delta EGP (basal vs high insulin) | -8.512 micromole/kilogram body weight/minute |
Comparison: Comparison of delta EGP (basal vs low insulin) between dapagliflozin and placebo after 5 weeks of treatment was performed using a random effects analysis of variance model.p-value: 0.003695% CI: [-2.784, -0.625]Linear Mixed Effects Model
Comparison: Comparison of delta EGP (basal vs high insulin) between dapagliflozin and placebo after 5 weeks of treatment was performed using a random effects analysis of variance model.p-value: <0.000195% CI: [-3.146, -1.438]Linear Mixed Effects Model
Other Pre-specified
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).
Time frame: At end (Week 5) of Treatment Periods 1 and 2
Population: The evaluable analysis set (indirect calorimetry) was a subset of the randomized analysis set, consisting of patients who received at least 1 dose of any investigational product. Any patients with important procedure specific protocol deviations regarding the indirect calorimetry method were excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin 10 mg | Change in Respiratory Exchange Ratio (RER) From Fasted State to Insulin Stimulated State After 5 Weeks of Treatment | 0.101 ratio |
| Placebo | Change in Respiratory Exchange Ratio (RER) From Fasted State to Insulin Stimulated State After 5 Weeks of Treatment | 0.089 ratio |
Comparison: Comparison of delta RER (basal vs high insulin) between dapagliflozin and placebo after 5 weeks of treatment was performed using a random effects analysis of variance model.p-value: 0.184295% CI: [-0.006, 0.03]Linear Mixed Effects Model
Other Pre-specified
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).
Time frame: At end (Week 5) of Treatment Periods 1 and 2
Population: The evaluable analysis set (chamber) was a subset of the randomized analysis set, consisting of patients who received at least 1 dose of any investigational product. Any patients with important procedure specific protocol deviations regarding the chamber method were excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin 10 mg | Fibroblast Growth Factor 21 (FGF21) Area Under the Curve (AUC) in Plasma After 5 Weeks of Treatment | 3310.415 nanograms/liter/hour |
| Placebo | Fibroblast Growth Factor 21 (FGF21) Area Under the Curve (AUC) in Plasma After 5 Weeks of Treatment | 3554.716 nanograms/liter/hour |
Comparison: Comparison of FGF21 AUC between dapagliflozin and placebo after 5 weeks of treatment was performed using a random effects analysis of variance model.p-value: 0.155595% CI: [-590.002, 101.401]Linear Mixed Effects Model