Weight Loss
Conditions
Brief summary
Th mechanism of action of dapagliflozin is via sodium-glucose co-transporter 2 (SGLT2) inhibition. Sodium-glucose co-transporter 2 inhibition is associated with moderate weight (fat) loss, in addition to other health benefits, including decreased blood pressure, decreased inflammation, and decreased oxidative stress. It is unclear as to whether these health benefits are due to SGLT2 inhibition per se, or as a secondary effect of weight loss.
Detailed description
This is a randomized, prospective, placebo-controlled, double-blind, repeated measures study. 92 overweight/obese adults (body mas index \> 27.5 kg/m\^2) will be recruited for participation and randomly assigned to one of four 12 week treatments: 1) daily oral administration of dapagliflozin with ad-libitum dietary intake; 2) daily oral administration of dapagliflozin with supplemented dietary intake to achieve weight maintenance; 3) daily oral administration of a placebo plus dietary restriction such that weight loss is matched to participants in treatment 1; or, 4) daily oral administration of a placebo with ad-libitum dietary intake.
Interventions
DRUGDapagliflozin
DRUGPlacebo
BEHAVIORALWeight maintenance
BEHAVIORALAd libitum dietary intake
BEHAVIORALDietary restriction
Sponsors
AstraZeneca
Christopher Bell
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
1. Provision of informed consent prior to any study specific procedures. 2. Aged 18-65 years. 3. No known Type 2 Diabetes 4. Body mass index greater than or equal to 27.5 kg/m\^2 5. Sedentary (maximum of 2/week regularly scheduled activity sessions of \< 20 minutes during the previous 2 years) 6. 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) 7. Agree to abide by the study schedule and dietary restrictions and to return for the required assessments 8. Women of childbearing potential must have negative pregnancy test and be using acceptable contraception
Exclusion criteria
1. Evidence of clinically significant cardiovascular, respiratory, renal, hepatic, pulmonary, gastrointestinal, haematological, 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, maybe 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 antibody 12. Estimated Glomerular Filtration Rate \<60 mL/min/1.73 m\^2 (calculated by Cockcroft-Gault formula). 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 enrollment; acute stroke or trans-ischemic attack within two months prior to enrollment; less than two months post coronary artery revascularization; 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 enrolment: 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Insulin Sensitivity at Week 12 | Baseline,12 weeks | Via oral glucose tolerance test. |
| Change From Baseline in Blood Pressure at Week 12 | Baseline, 12 weeks | — |
| Change From Baseline in Perception of Satiety at Week 12 | Baseline, 12 weeks | Perceptions of satiety will be determined using a visual analog scale called a Hunger Rating Scales. The minimum value is 1 (not at all full) and the maximum value is 100 (extremely full). One value between 1 and 100 is reported by the participant dependent on their perception. No sub scores are used. The perceived values are reported as the group average at baseline and 12 weeks. There is not a better or worse outcome, but rather a measure of perceived satiety. If Dapagliflozin were effective at increasing fullness, respondents would exhibit 12-week scores for the question in comparison to their baseline scores. |
| Change From Baseline in Perception of Hunger at Week 12 | Baseline, 12 weeks | Perceptions of Hunger will be determined using a visual analog scale called a Hunger Rating Scales. The minimum value is 1 (not at all hungry) and the maximum value is 100 (very hungry). One value between 1 and 100 is reported by the participant dependent on their perception. No sub scores are used. The perceived values are reported as the group average at baseline and 12 weeks. There is not a better or worse outcome, but rather a measure of perceived hunger. If Dapagliflozin were effective at decreasing hunger, respondents would exhibit 12-week scores for the question in comparison to their baseline scores. |
| Change From Baseline in Marker of Inflammation (High Sensitive C-reactive Protein) at Week 12 | Baseline, 12 weeks | Will be analyzed using a commercially available biochemical assay. |
| Change From Baseline in Marker of Inflammation (Tumor Necrosis Factor Alpha) at Week 12 | Baseline, 12 weeks | Will be analyzed using a commercially available biochemical assay. |
| Change From Baseline in Marker of Inflammation (Interleukin 6) at Week 12 | Baseline, 12 weeks | Will be analyzed using a commercially available biochemical assay. |
| Change From Baseline in Hunger Hormone Ghrelin at Week 12 | Baseline, 12 weeks | Will be analyzed using a commercially available biochemical assay. |
| Change From Baseline in Hunger Hormone Peptide Tyrosine Tyrosine at Week 12 | Baseline, 12 weeks | Will be analyzed using a commercially available biochemical assay. |
| Change From Baseline in Maker of Oxidative Stress (Oxidized Low Density Lipoprotein) at Week 12 | Baseline, 12 weeks | Will be analyzed using a commercially available biochemical assay. |
| Change From Baseline in Maker of Oxidative Stress (Low Density Thiobarbituric Acid Reactive Substances) at Week 12 | Baseline, 12 weeks | Will be analyzed using a commercially available biochemical assay. |
| Change From Baseline in Satiety Hormone Leptin at Week 12 | Baseline, 12 weeks | Will be analyzed using a commercially available biochemical assay. |
| Change From Baseline in Satiety Hormone Insulin at Week 12 | Baseline, 12 weeks | Will be analyzed using a commercially available biochemical assay. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dapagliflozin: ad Libitum Dietary Intake Daily oral administration of dapagliflozin with ad libitum dietary intake. 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
Ad libitum dietary intake | 3 |
| Dapagliflozin: Weight Maintenance Daily oral administration of dapagliflozin with supplemented dietary intake to achieve weight maintenance. 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
Weight maintenance | 1 |
| Placebo: ad Libitum Dietary Intake Daily oral administration of a placebo with ad-libitum dietary intake. 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
Ad libitum dietary intake | 3 |
| Placebo: Dietary Restriction Daily oral administration of a placebo plus dietary restriction such that weight loss is matched to participants in Arm 1. 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
Dietary restriction | 2 |
| Total | 9 |
Baseline characteristics
| Characteristic | Total | Dapagliflozin: Weight Maintenance | Placebo: ad Libitum Dietary Intake | Placebo: Dietary Restriction | Dapagliflozin: ad Libitum Dietary Intake |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 1 Participants | 3 Participants | 2 Participants | 3 Participants |
| Race and Ethnicity Not Collected | 0 Participants | — | — | — | — |
| Region of Enrollment United States | 9 participants | 1 participants | 3 participants | 2 participants | 3 participants |
| Sex: Female, Male Female | 9 Participants | 1 Participants | 3 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 1 | 0 / 3 | 0 / 2 |
| other Total, other adverse events | 3 / 3 | 1 / 1 | 1 / 3 | 1 / 2 |
| serious Total, serious adverse events | 0 / 3 | 0 / 1 | 0 / 3 | 0 / 2 |
Outcome results
Primary
Change From Baseline in Blood Pressure at Week 12
Time frame: Baseline, 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dapagliflozin: ad Libitum Dietary Intake | Change From Baseline in Blood Pressure at Week 12 | Diastolic Blood Pressure Change | -1 mmHg | Standard Deviation 0.2 |
| Dapagliflozin: ad Libitum Dietary Intake | Change From Baseline in Blood Pressure at Week 12 | Systolic Blood Pressure Change | 2 mmHg | Standard Deviation 1 |
| Dapagliflozin: Weight Maintenance | Change From Baseline in Blood Pressure at Week 12 | Systolic Blood Pressure Change | 5 mmHg | Standard Deviation 0 |
| Dapagliflozin: Weight Maintenance | Change From Baseline in Blood Pressure at Week 12 | Diastolic Blood Pressure Change | -1 mmHg | Standard Deviation 0 |
| Placebo: ad Libitum Dietary Intake | Change From Baseline in Blood Pressure at Week 12 | Diastolic Blood Pressure Change | 11 mmHg | Standard Deviation 4 |
| Placebo: ad Libitum Dietary Intake | Change From Baseline in Blood Pressure at Week 12 | Systolic Blood Pressure Change | 11 mmHg | Standard Deviation 8 |
| Placebo: Dietary Restriction | Change From Baseline in Blood Pressure at Week 12 | Diastolic Blood Pressure Change | 1 mmHg | Standard Deviation 2 |
| Placebo: Dietary Restriction | Change From Baseline in Blood Pressure at Week 12 | Systolic Blood Pressure Change | 0 mmHg | Standard Deviation 3 |
Primary
Change From Baseline in Hunger Hormone Ghrelin at Week 12
Will be analyzed using a commercially available biochemical assay.
Time frame: Baseline, 12 weeks
Population: Data were not collected.
Primary
Change From Baseline in Hunger Hormone Peptide Tyrosine Tyrosine at Week 12
Will be analyzed using a commercially available biochemical assay.
Time frame: Baseline, 12 weeks
Population: Data were not collected.
Primary
Change From Baseline in Insulin Sensitivity at Week 12
Via oral glucose tolerance test.
Time frame: Baseline,12 weeks
Population: Data were not collected.
Primary
Change From Baseline in Maker of Oxidative Stress (Low Density Thiobarbituric Acid Reactive Substances) at Week 12
Will be analyzed using a commercially available biochemical assay.
Time frame: Baseline, 12 weeks
Population: Data were not collected.
Primary
Change From Baseline in Maker of Oxidative Stress (Oxidized Low Density Lipoprotein) at Week 12
Will be analyzed using a commercially available biochemical assay.
Time frame: Baseline, 12 weeks
Population: Data were not collected.
Primary
Change From Baseline in Marker of Inflammation (High Sensitive C-reactive Protein) at Week 12
Will be analyzed using a commercially available biochemical assay.
Time frame: Baseline, 12 weeks
Population: Data were not collected.
Primary
Change From Baseline in Marker of Inflammation (Interleukin 6) at Week 12
Will be analyzed using a commercially available biochemical assay.
Time frame: Baseline, 12 weeks
Population: Data collection was not performed
Primary
Change From Baseline in Marker of Inflammation (Tumor Necrosis Factor Alpha) at Week 12
Will be analyzed using a commercially available biochemical assay.
Time frame: Baseline, 12 weeks
Population: Data collection was not performed
Primary
Change From Baseline in Perception of Hunger at Week 12
Perceptions of Hunger will be determined using a visual analog scale called a Hunger Rating Scales. The minimum value is 1 (not at all hungry) and the maximum value is 100 (very hungry). One value between 1 and 100 is reported by the participant dependent on their perception. No sub scores are used. The perceived values are reported as the group average at baseline and 12 weeks. There is not a better or worse outcome, but rather a measure of perceived hunger. If Dapagliflozin were effective at decreasing hunger, respondents would exhibit 12-week scores for the question in comparison to their baseline scores.
Time frame: Baseline, 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dapagliflozin: ad Libitum Dietary Intake | Change From Baseline in Perception of Hunger at Week 12 | 12 weeks | 28 score on a scale | Standard Deviation 38 |
| Dapagliflozin: ad Libitum Dietary Intake | Change From Baseline in Perception of Hunger at Week 12 | Baseline | 20 score on a scale | Standard Deviation 22 |
| Dapagliflozin: Weight Maintenance | Change From Baseline in Perception of Hunger at Week 12 | Baseline | 24 score on a scale | Standard Deviation 0 |
| Dapagliflozin: Weight Maintenance | Change From Baseline in Perception of Hunger at Week 12 | 12 weeks | 77 score on a scale | Standard Deviation 0 |
| Placebo: ad Libitum Dietary Intake | Change From Baseline in Perception of Hunger at Week 12 | Baseline | 23.5 score on a scale | Standard Deviation 1 |
| Placebo: ad Libitum Dietary Intake | Change From Baseline in Perception of Hunger at Week 12 | 12 weeks | 65 score on a scale | Standard Deviation 0 |
| Placebo: Dietary Restriction | Change From Baseline in Perception of Hunger at Week 12 | 12 weeks | 31 score on a scale | Standard Deviation 15 |
| Placebo: Dietary Restriction | Change From Baseline in Perception of Hunger at Week 12 | Baseline | 32 score on a scale | Standard Deviation 27 |
Primary
Change From Baseline in Perception of Satiety at Week 12
Perceptions of satiety will be determined using a visual analog scale called a Hunger Rating Scales. The minimum value is 1 (not at all full) and the maximum value is 100 (extremely full). One value between 1 and 100 is reported by the participant dependent on their perception. No sub scores are used. The perceived values are reported as the group average at baseline and 12 weeks. There is not a better or worse outcome, but rather a measure of perceived satiety. If Dapagliflozin were effective at increasing fullness, respondents would exhibit 12-week scores for the question in comparison to their baseline scores.
Time frame: Baseline, 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dapagliflozin: ad Libitum Dietary Intake | Change From Baseline in Perception of Satiety at Week 12 | Baseline | 50 score on a scale | Standard Deviation 14 |
| Dapagliflozin: ad Libitum Dietary Intake | Change From Baseline in Perception of Satiety at Week 12 | 12 weeks | 56 score on a scale | Standard Deviation 29 |
| Dapagliflozin: Weight Maintenance | Change From Baseline in Perception of Satiety at Week 12 | Baseline | 61 score on a scale | Standard Deviation 0 |
| Dapagliflozin: Weight Maintenance | Change From Baseline in Perception of Satiety at Week 12 | 12 weeks | 33 score on a scale | Standard Deviation 0 |
| Placebo: ad Libitum Dietary Intake | Change From Baseline in Perception of Satiety at Week 12 | 12 weeks | 38 score on a scale | Standard Deviation 0 |
| Placebo: ad Libitum Dietary Intake | Change From Baseline in Perception of Satiety at Week 12 | Baseline | 35 score on a scale | Standard Deviation 34 |
| Placebo: Dietary Restriction | Change From Baseline in Perception of Satiety at Week 12 | 12 weeks | 42 score on a scale | Standard Deviation 10 |
| Placebo: Dietary Restriction | Change From Baseline in Perception of Satiety at Week 12 | Baseline | 39 score on a scale | Standard Deviation 14 |
Primary
Change From Baseline in Satiety Hormone Insulin at Week 12
Will be analyzed using a commercially available biochemical assay.
Time frame: Baseline, 12 weeks
Population: Data were not collected.
Primary
Change From Baseline in Satiety Hormone Leptin at Week 12
Will be analyzed using a commercially available biochemical assay.
Time frame: Baseline, 12 weeks
Population: Data were not collected.