Physical Activity
Conditions
Brief summary
Exercise is frequently prescribed as a favorable lifestyle intervention to prevent/reverse type 2 diabetes. It is also prescribed in addition to concurrent pharmacological treatment, such as metformin. Recent data (animal and human) suggest that metformin may attenuate the favorable benefits of exercise training. In light of the physiological mechanism of Dapagliflozin (sodium-glucose co-transporter 2 (SGLT2) inhibition), one might speculate that rather than inhibit, it will augment the favorable adaptations to exercise training.
Detailed description
This is a randomized, placebo-controlled, double blind, repeated measures study. 30 sedentary adults will be recruited for participation and randomly assigned to one of two 12-week treatments: 1) supervised endurance exercise training 4 days per week plus daily oral administration of Dapagliflozin; 2) supervised endurance exercise training 4 days per week plus daily oral administration of placebo. Prior to and following completion of the treatment the following dependent variables will be quantified: a) maximal aerobic capacity; b) substrate utilization during standardized low-moderate intensity exercise; c) skeletal muscle aerobic enzyme activity; d) body composition; and, e) oral glucose tolerance, fasting glucose and insulin resistance. The dose of Dapagliflozin will begin as 5 mg/day for the first 14-days. In the absence of complications, side effects, or unfavorable reactions, the dose will then increase to 10 mg/day for the remainder of the study.
Interventions
DRUGDapagliflozin
Dapagliflozin tablets, 5 mg, one per day for the first 14 days, increase to two per day for 70 days.
DRUGPlacebo
Matching placebo for Dapagliflozin 5 mg, one per day for the first 14 days, increase to two per day for 70 days.
Sponsors
AstraZeneca
Christopher Bell
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
1. Provision of informed consent prior to any study specific procedures. 2. No known Type 2 Diabetes. 3. Body mass index 25-45 kg/m\^2 4. Sedentary (maximum of 2/week regularly scheduled activity sessions of \< 20 minutes during the previous 2 years). 5. Completion of a screening visit consisting of medical history, physical examination, and 12-lead electrocardiogram and blood pressure assessment at rest and during incremental exercise to volitional exhaustion (Note: Subjects with abnormal screening values may be eligible if the results are not clinically significant, as judged by the investigator or medical monitor). 6. Agree to abide by the study schedule and to return for the required assessments. 7. Be willing and able to repeatedly perform exercise. 8. Women of childbearing potential must have negative pregnancy test and be using acceptable contraception.
Exclusion criteria
Subjects should not enter the study if any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline of Maximal Oxygen Uptake at Week 12 | Baseline,12 weeks | Indirect calorimetry |
| Change From Baseline of Respiratory Exchange Ratio at Week 12 | Baseline, 12 weeks | The respiratory exchange ratio (RER) is the ratio between the amount of carbon dioxide (CO2) produced in metabolism and oxygen (O2) used during standardized exercise. |
| Change From Baseline of Maximal Aerobic Enzyme Activities in Skeletal Muscle at Week 12 | Baseline, 12 weeks | Maximal citrate synthase activity in skeletal muscle sample |
| Change From Baseline of Insulin Sensitivity at Week 12 | Baseline, 12 weeks | Insulin Sensitivity was estimated by measuring circulating glucose and insulin concentrations after a 12-hour fast and after ingestion of 75 g of glucose. Glucose was measured 5, 10, 15, 20, 30, 45, 60, 75, 90, 105 and 120 minutes after glucose ingestion. Insulin was measured 15, 30, 45, 60, 90 and 120 minutes after glucose ingestion. Insulin sensitivity was estimated using the Matsuda Index, represented by the formula: Matsuda index = 10,000/SQRT \[fasting glucose\*fasting insulin\* (mean glucose from time 5, 10, 15, 20, 30, 45, 60, 75, 90, 105 and 120 minutes) \* (mean insulin from time 15, 30, 45, 60, 90 and 120 minutes)\], with higher numbers indicating better insulin sensitivity. |
| Change From Baseline of Fat Free Mass at Week 12 | Baseline, 12 weeks | Via dual energy X-ray absorptiometry |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dapagliflozin The dose of Dapagliflozin will begin as one 5 mg tablet per day for the first 14-days. In the absence of complications, side effects, or unfavorable reactions, the dose will then increase to two 5 mg tablets per day for the remainder of the study.
Dapagliflozin: Dapagliflozin tablets, 5 mg, one per day for the first 14 days, increase to two per day for 70 days. | 15 |
| Placebo Matching placebo for Dapagliflozin 5 mg will begin as one tablet per day for the first 14-days. In the absence of complications, side effects, or unfavorable reactions, the dose will then increase to two tablets for the remainder of the study.
Placebo: Matching placebo for Dapagliflozin 5 mg, one per day for the first 14 days, increase to two per day for 70 days. | 15 |
| Total | 30 |
Baseline characteristics
| Characteristic | Dapagliflozin | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants | 15 Participants | 30 Participants |
| Body Mass | 87.8 Kilograms STANDARD_DEVIATION 17.3 | 91.8 Kilograms STANDARD_DEVIATION 16.9 | 89.80 Kilograms STANDARD_DEVIATION 16.9 |
| Body Mass Index | 31.3 kilograms per meters squared STANDARD_DEVIATION 5.4 | 31.2 kilograms per meters squared STANDARD_DEVIATION 4.3 | 31.3 kilograms per meters squared STANDARD_DEVIATION 4.77 |
| Diastolic Blood Pressure | 83 millimeters of mercury STANDARD_DEVIATION 10 | 82 millimeters of mercury STANDARD_DEVIATION 11 | 83 millimeters of mercury STANDARD_DEVIATION 10.5 |
| Fasting Glucose | 78.8 milligrams per deciliter STANDARD_DEVIATION 7.3 | 75.8 milligrams per deciliter STANDARD_DEVIATION 5.1 | 77.3 milligrams per deciliter STANDARD_DEVIATION 5.9 |
| Fasting Insulin | 7.6 MilliUnits per Liter STANDARD_DEVIATION 4 | 8.9 MilliUnits per Liter STANDARD_DEVIATION 6.7 | 8.3 MilliUnits per Liter STANDARD_DEVIATION 5.4 |
| Height | 1.67 meters STANDARD_DEVIATION 0.08 | 1.71 meters STANDARD_DEVIATION 0.1 | 1.69 meters STANDARD_DEVIATION 8.92 |
| Peak Oxygen Uptake | 26.9 milliliter per kilogram per minute STANDARD_DEVIATION 5.3 | 30.1 milliliter per kilogram per minute STANDARD_DEVIATION 6.1 | 27.49 milliliter per kilogram per minute STANDARD_DEVIATION 5.7 |
| 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 | 15 Participants | 15 Participants | 30 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 11 Participants | 8 Participants | 19 Participants |
| Sex: Female, Male Male | 4 Participants | 7 Participants | 11 Participants |
| Systolic Blood Pressure | 130 millimeter of mercury STANDARD_DEVIATION 14 | 129 millimeter of mercury STANDARD_DEVIATION 13 | 129.5 millimeter of mercury STANDARD_DEVIATION 13 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 19 |
| other Total, other adverse events | 17 / 18 | 18 / 19 |
| serious Total, serious adverse events | 0 / 18 | 0 / 19 |
Outcome results
Primary
Change From Baseline of Fat Free Mass at Week 12
Via dual energy X-ray absorptiometry
Time frame: Baseline, 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dapagliflozin | Change From Baseline of Fat Free Mass at Week 12 | Pre-Exercise Training | 52 Kilograms | Standard Deviation 9.9 |
| Dapagliflozin | Change From Baseline of Fat Free Mass at Week 12 | Post-Exercise Training | 52.2 Kilograms | Standard Deviation 9.9 |
| Placebo | Change From Baseline of Fat Free Mass at Week 12 | Pre-Exercise Training | 57.8 Kilograms | Standard Deviation 12.2 |
| Placebo | Change From Baseline of Fat Free Mass at Week 12 | Post-Exercise Training | 58.3 Kilograms | Standard Deviation 12.1 |
Primary
Change From Baseline of Insulin Sensitivity at Week 12
Insulin Sensitivity was estimated by measuring circulating glucose and insulin concentrations after a 12-hour fast and after ingestion of 75 g of glucose. Glucose was measured 5, 10, 15, 20, 30, 45, 60, 75, 90, 105 and 120 minutes after glucose ingestion. Insulin was measured 15, 30, 45, 60, 90 and 120 minutes after glucose ingestion. Insulin sensitivity was estimated using the Matsuda Index, represented by the formula: Matsuda index = 10,000/SQRT \[fasting glucose\*fasting insulin\* (mean glucose from time 5, 10, 15, 20, 30, 45, 60, 75, 90, 105 and 120 minutes) \* (mean insulin from time 15, 30, 45, 60, 90 and 120 minutes)\], with higher numbers indicating better insulin sensitivity.
Time frame: Baseline, 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dapagliflozin | Change From Baseline of Insulin Sensitivity at Week 12 | Pre-Training | 8.7 MATSUDA Index | Standard Deviation 4.8 |
| Dapagliflozin | Change From Baseline of Insulin Sensitivity at Week 12 | Post-Training | 9.5 MATSUDA Index | Standard Deviation 4.8 |
| Placebo | Change From Baseline of Insulin Sensitivity at Week 12 | Pre-Training | 8.3 MATSUDA Index | Standard Deviation 4.9 |
| Placebo | Change From Baseline of Insulin Sensitivity at Week 12 | Post-Training | 12.9 MATSUDA Index | Standard Deviation 8.9 |
Primary
Change From Baseline of Maximal Aerobic Enzyme Activities in Skeletal Muscle at Week 12
Maximal citrate synthase activity in skeletal muscle sample
Time frame: Baseline, 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dapagliflozin | Change From Baseline of Maximal Aerobic Enzyme Activities in Skeletal Muscle at Week 12 | Pre-Exercise Training | 6.3 micromol/min/miligram protein | Standard Deviation 3.7 |
| Dapagliflozin | Change From Baseline of Maximal Aerobic Enzyme Activities in Skeletal Muscle at Week 12 | Post Exercise Training | 8.1 micromol/min/miligram protein | Standard Deviation 4.5 |
| Placebo | Change From Baseline of Maximal Aerobic Enzyme Activities in Skeletal Muscle at Week 12 | Pre-Exercise Training | 5.8 micromol/min/miligram protein | Standard Deviation 3.6 |
| Placebo | Change From Baseline of Maximal Aerobic Enzyme Activities in Skeletal Muscle at Week 12 | Post Exercise Training | 8.0 micromol/min/miligram protein | Standard Deviation 4 |
Primary
Change From Baseline of Maximal Oxygen Uptake at Week 12
Indirect calorimetry
Time frame: Baseline,12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dapagliflozin | Change From Baseline of Maximal Oxygen Uptake at Week 12 | Pre-Exercise Training | 26.9 Milliliters/Kilogram/Minute | Standard Deviation 5.3 |
| Dapagliflozin | Change From Baseline of Maximal Oxygen Uptake at Week 12 | Post-Exercise Training | 30.6 Milliliters/Kilogram/Minute | Standard Deviation 6.1 |
| Placebo | Change From Baseline of Maximal Oxygen Uptake at Week 12 | Pre-Exercise Training | 30.1 Milliliters/Kilogram/Minute | Standard Deviation 6.1 |
| Placebo | Change From Baseline of Maximal Oxygen Uptake at Week 12 | Post-Exercise Training | 32.4 Milliliters/Kilogram/Minute | Standard Deviation 7.5 |
Primary
Change From Baseline of Respiratory Exchange Ratio at Week 12
The respiratory exchange ratio (RER) is the ratio between the amount of carbon dioxide (CO2) produced in metabolism and oxygen (O2) used during standardized exercise.
Time frame: Baseline, 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dapagliflozin | Change From Baseline of Respiratory Exchange Ratio at Week 12 | Pre-Exercise Training | 1.91 Respiratory Exchange Ratio | Standard Deviation 0.05 |
| Dapagliflozin | Change From Baseline of Respiratory Exchange Ratio at Week 12 | Post-Exercise Training | 1.19 Respiratory Exchange Ratio | Standard Deviation 0.05 |
| Placebo | Change From Baseline of Respiratory Exchange Ratio at Week 12 | Pre-Exercise Training | 1.16 Respiratory Exchange Ratio | Standard Deviation 0.12 |
| Placebo | Change From Baseline of Respiratory Exchange Ratio at Week 12 | Post-Exercise Training | 1.13 Respiratory Exchange Ratio | Standard Deviation 0.06 |