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

Christopher Bell

Status and phase: Terminated; Phase 2

Conditions: Weight Loss

Treatments: Drug: Dapagliflozin; Behavioral: Weight maintenance; Drug: Placebo; Behavioral: Ad libitum dietary intake; Behavioral: Dietary restriction

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT02520518

14-5531H

Details and patient eligibility

About

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.

Full 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.

Enrollment: 9 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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9 participants in 4 patient groups, including a placebo group

Dapagliflozin: ad libitum dietary intake

Experimental group

Description:

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.

Treatment:

Behavioral: Ad libitum dietary intake

Drug: Dapagliflozin

Dapagliflozin: weight maintenance

Experimental group

Description:

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.

Treatment:

Behavioral: Weight maintenance

Drug: Dapagliflozin

Placebo: ad libitum dietary intake

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo

Behavioral: Ad libitum dietary intake

Placebo: dietary restriction

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo

Behavioral: Dietary restriction