Does Dapagliflozin Provide Additional Health Benefits To Dietary Counseling For Weight Loss?

Study Overview
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Brief Summary
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Dapagliflozin is a medicine to treat diabetes. Its mechanism of action is via sodium-glucose co-transporter 2 (SGLT2) inhibition. In adults with diabetes, use of sodium-glucose co-transporter 2 inhibitors 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. We wish to compare the health benefits of dietary counseling for weight loss with and without concomitant use of an SGLT2 inhibitor.

Detailed Description
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This is a randomized, prospective, placebo-controlled, double blind, repeated measures study. 50 overweight/obese adults (body mas index > 27.5 kg/m2) will be recruited for participation and randomly assigned to one of two 12 week treatments: (1) daily oral administration of Dapagliflozin with dietary counseling to promote weight loss; or, (2) daily oral administration of a placebo with dietary counseling to promote weight loss.

Official Title
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Does Dapagliflozin Provide Additional Health Benefits To Dietary Counseling For Weight Loss?

Conditions
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Weight Loss

Intervention / Treatment
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* Drug: Dapagliflozin Tablet
* Drug: Placebo Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of informed consent prior to any study specific procedures. Aged 18-65 years. No known Type 2 Diabetes Body mass index greater than or equal to 27.5 kg/m^2 Limited exercise participation (maximum of 3/week regularly scheduled activity sessions of < 30 minutes during the previous month). 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) Agree to abide by the study schedule and dietary restrictions and to return for the required assessments Women of childbearing potential must have negative pregnancy test and be using acceptable contraception Exclusion Criteria: 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. Use of prescription drugs (see exceptions listed below) or herbal preparations in the 2 weeks before study commencement. Prior use of medication or herbal preparations in the 4 weeks before study commencement that are intended for weight-loss and/or sold/marketed as weight-loss products or may alter metabolism. Permitted Prescription Drugs: Birth Control, Less than a 7 day short course of antibiotics. Note: Rifampicin is not permitted. Other medicines, such as those for gastroesophageal reflux disease, depression, and Over The Counter analgesics and allergy medications,may be allowed, but will be approved on a case-by-case basis. 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. Habitual and/or recent use (within 2 years) of tobacco. Being considered unsuitable for participation in this trial for any reason, as judged by the investigator or medical monitor. History of serious hypersensitivity reaction to Dapagliflozin. Severe renal impairment, end-stage renal disease, or dialysis. Pregnant or breastfeeding individual. 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. Total bilirubin >2.0 mg/dL (34.2 umol/L). Positive serologic evidence of current infectious liver disease including Hepatitis B viral antibody immunoglobulin M, Hepatitis B surface antigen and Hepatitis C virus antibody. Estimated Glomerular Filtration Rate <60 mL/min/1.73 m^2 (calculated by Cockcroft-Gault formula). History of bladder cancer. Recent cardiovascular events in a patient, including any of the following: acute coronary syndrome within 2 months prior to enrolment; 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 enrolment; 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. Blood pressure at enrolment: Systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg. Blood pressure at randomization: Systolic blood pressure ≥165 mmHg and/or diastolic blood pressure ≥100 mmHg Individuals who, in the judgment of the medical monitor, may be at risk for dehydration. Individuals with a history of fragility fracture, or bone mineral density values reflective of risk for fracture (DEXA Z-score <or= to -2 in pre-menopausal women, and men <50, and T-score <or= to -1) will not be permitted to participate.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dapagliflozin with dietary counseling<br>Daily oral administration of dapagliflozin tablet with dietary counseling to promote weight loss. | Drug: Dapagliflozin Tablet<br>* Daily oral administration of dapagliflozin with dietary counseling to promote weight loss. Dapagliflozin 5 mg tablet 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.<br>* Other names: Farxiga;|
| Placebo Comparator: Placebo with dietary counseling<br>Daily oral administration of placebo tablet with dietary counseling to promote weight loss. | Drug: Placebo Tablet<br>* Daily administration of placebo tablet with dietary counseling to promote weight loss. Matching placebo for dapagliflozin 5 mg tablet 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Insulin Sensitivity at Week 12 Via Oral Glucose Tolerance Test | Insulin sensitivity was estimated by measuring circulating insulin concentrations after a 12 hour fast and after ingesting 75 g of glucose. Insulin was measured 0, 30, 60, 90 and 120 minutes after glucose ingestion. Time point 0 minutes is reported below. | Baseline, 12 weeks | 
| Change From Baseline in Blood Pressure at Week 12 | Blood pressure was measured with an automatic machine at baseline. Numbers are reported as systolic/diastolic | Baseline, 12 weeks | 
| Change From Baseline in Perception of Satiety at Week 12 | Participants answered a satiety questionnaire before liquid meal primer, immediately post liquid meal primer, 60 minutes post liquid primer, immediately post breakfast buffet, 60 minutes, 120 minutes and 180 minutes post breakfast buffet. Responses how full do you feel right now? for 60 minutes post liquid meal primer ingestion are reported below. This was determined by using a visual analog scale. The left side of the analog scale represents a null answer (e.g. How full do you feel right now)? Answer 0: Not full at all. The right side of the line represented the strongest answer in the opposite direction (e.g. How full to you feel right now)? Answer 100: Extremely full. The length of the line is 100 mm, thus the scale ranges for all answers were 0-100. All values are reported as values between 0 and 100. If the answers to the fullness questions increased, this represented a decreased desire to eat. | Baseline, 12 weeks | 
| Change From Baseline in Perception of Hunger at Week 12 | Participants answered a hunger questionnaire before liquid meal primer, immediately post liquid meal primer, 60 minutes post liquid primer, immediately post breakfast buffet, 60 minutes, 120 minutes and 180 minutes post breakfast buffet. Responses to how hungry do you feel right now? for 60 minutes post liquid meal primer ingestion are reported below. This was determined by using a visual analog scale. The left side of the analog scale represents a null answer (e.g. How hungry do you feel right now? Answer 0: Not hungry at all. The right side of the line represented the strongest answer in the opposite direction (e.g. How full to you feel right now)? Answer 100: Extremely hungry. The length of the line is 100 mm, thus the scale ranges for all answers were 0-100. All values are reported as values between 0 and 100. If the answers to the fullness questions increased, this represented an increased desire to eat. | Baseline, 12 weeks | 
| Change From Baseline in Marker of Inflammation (High Sensitive C-reactive Protein) at Week 12 | Will be analyzed using a commercially available biochemical assay. | Data not collected | 
| Change From Baseline in Marker of Inflammation (Tumor Necrosis Factor Alpha) at Week 12 | Will be analyzed using a commercially available biochemical assay. | Data not collected | 
| Change From Baseline in Marker of Inflammation (Interleukin 6) at Week 12 | Will be analyzed using a commercially available biochemical assay. | data not collected | 
| Change From Baseline in Hunger Hormone Ghrelin at Week 12 | Will be analyzed using a commercially available biochemical assay. | data not collected | 
| Change From Baseline in Hunger Hormone Peptide Tyrosine Tyrosine at Week 12 | Will be analyzed using a commercially available biochemical assay. | data not collected | 
| Change From Baseline in Maker of Oxidative Stress (Oxidized Low Density Lipoprotein) at Week 12 | Will be analyzed using a commercially available biochemical assay. | Data not collected | 
| 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. | Data not collected | 
| Change From Baseline in Satiety Hormone Leptin at Week 12 | Will be analyzed using a commercially available biochemical assay. | Data not collected | 
| Change From Baseline in Satiety Hormone Insulin at Week 12 | Will be analyzed using a commercially available biochemical assay. | Data not collected |