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.
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.
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
Subjects should not enter the study if any of the following exclusion criteria are
1. Evidence of clinically significant cardiovascular, respiratory, renal, hepatic,
pulmonary, gastrointestinal, hematological, neurological, psychiatric, or other
disease that may interfere with the objectives of the study or the safety of the
subject, as judged by the investigator in agreement with the sponsor or medical
monitor, have been hospitalized in the past 2 years as a result of these conditions,
or are receiving pharmacological treatment for these conditions.
2. Use of prescription drugs (see exceptions listed below) or herbal preparations in the
4 weeks before study commencement.
Permitted Prescription Drugs
- Birth Control
- Less than 7 days, short course antibiotics. Note: Rifampin is not permitted.
- Other medicines, for gastroesophageal reflux disease (GERD), depression, seasonal
allergies and over-the-counter analgesics, may be allowed, but will be approved
on a case-by-case basis.
3. Is currently enrolled in another clinical study for another investigational drug or
has taken any other investigational drug within 30 days before the screening visit.
4. Habitual and/or recent use (within 2 years) of tobacco.
5. Being considered unsuitable for participation in this trial for any reason, as judged
by the investigator or medical monitor.
6. History of serious hypersensitivity reaction to Dapagliflozin.
7. Severe renal impairment, end-stage renal disease, or dialysis.
8. Pregnant or breastfeeding patients.
9. Severe hepatic insufficiency and/or significant abnormal liver function defined as
aspartate aminotransferase (AST) >3x upper limit of normal and/or alanine
aminotransferase (ALT) >3x upper limit of normal.
10. Total bilirubin >2.0 mg/dL (34.2 umol/L).
11. Positive serologic evidence of current infectious liver disease including Hepatitis B
viral antibody Immunoglobulin M, Hepatitis B surface antigen and Hepatitis C virus
12. Estimated Glomerular Filtration Rate <60 mL/min/1.73 m^2 (calculated by
13. History of bladder cancer.
14. Recent cardiovascular events in a patient, including any of the following: acute
coronary syndrome within 2 months prior to enrollment; hospitalization for unstable
angina or acute myocardial infarction within 2 months prior to enrolment; acute stroke
or trans-ischemic attack within two months prior to enrollment; less than two months
post coronary artery re-vascularization; congestive heart failure defined as New York
Heart Association class IV, unstable or acute congestive heart failure. Note: eligible
patients with congestive heart failure,especially those who are on diuretic therapy,
should have careful monitoring of their volume status throughout the study.
15. Blood pressure at enrollment: Systolic blood pressure ≥165 mmHg and/or diastolic blood
pressure ≥100 mmHg.
16. Blood pressure at randomization: Systolic blood pressure ≥165 mmHg and/or diastolic
blood pressure ≥100 mmHg
17. Patients who, in the judgment of the medical monitor, may be at risk for dehydration.