Does Dapagliflozin Promote Favorable Health Benefits That Are Independent Of Weight Loss?

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.

Study Overview

• Status: Terminated
• Conditions: Weight Loss
• Intervention / Treatment: Drug: Placebo; Drug: Dapagliflozin; Behavioral: Ad libitum dietary intake; Behavioral: Weight maintenance; Behavioral: Dietary restriction

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.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Fort Collins, Colorado, United States, 80523-1582
      • Colorado State University, Dept. of Health and Exercise Science

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Dapagliflozin; Other Names: Farxiga; Behavioral: Ad libitum dietary intake
Experimental: 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.	Drug: Dapagliflozin; Other Names: Farxiga; Behavioral: Weight maintenance
Placebo Comparator: 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.	Drug: Placebo; Behavioral: Ad libitum dietary intake
Placebo Comparator: 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.	Drug: Placebo; Behavioral: Dietary restriction

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Insulin Sensitivity at Week 12	Via oral glucose tolerance test.	Baseline,12 weeks
Change From Baseline in Blood Pressure at Week 12		Baseline, 12 weeks
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.	Baseline, 12 weeks
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.	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.	Baseline, 12 weeks
Change From Baseline in Marker of Inflammation (Tumor Necrosis Factor Alpha) at Week 12	Will be analyzed using a commercially available biochemical assay.	Baseline, 12 weeks
Change From Baseline in Marker of Inflammation (Interleukin 6) at Week 12	Will be analyzed using a commercially available biochemical assay.	Baseline, 12 weeks
Change From Baseline in Hunger Hormone Ghrelin at Week 12	Will be analyzed using a commercially available biochemical assay.	Baseline, 12 weeks
Change From Baseline in Hunger Hormone Peptide Tyrosine Tyrosine at Week 12	Will be analyzed using a commercially available biochemical assay.	Baseline, 12 weeks
Change From Baseline in Maker of Oxidative Stress (Oxidized Low Density Lipoprotein) at Week 12	Will be analyzed using a commercially available biochemical assay.	Baseline, 12 weeks
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.	Baseline, 12 weeks
Change From Baseline in Satiety Hormone Leptin at Week 12	Will be analyzed using a commercially available biochemical assay.	Baseline, 12 weeks
Change From Baseline in Satiety Hormone Insulin at Week 12	Will be analyzed using a commercially available biochemical assay.	Baseline, 12 weeks

Collaborators and Investigators

• Sponsor: Christopher Bell
• Collaborators: AstraZeneca

Study record dates

Study Major Dates

• Study Start: August 1, 2015
• Primary Completion (Actual): May 1, 2017
• Study Completion (Actual): May 1, 2017

Study Registration Dates

• First Submitted: July 27, 2015
• First Submitted That Met QC Criteria: August 7, 2015
• First Posted (Estimate): August 13, 2015

Study Record Updates

• Last Update Posted (Actual): January 3, 2019
• Last Update Submitted That Met QC Criteria: December 11, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Body Weight Changes; Weight Loss; Body Weight; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: 14-5531H