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Effectiveness of Dapagliflozin for Weight Loss

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ClinicalTrials.gov Identifier: NCT03968224
Recruitment Status : Recruiting
First Posted : May 30, 2019
Last Update Posted : September 2, 2020
Sponsor:
Information provided by (Responsible Party):
Aldo Ferreira Hermosillo, Centro Medico Nacional Siglo XXI IMSS

Brief Summary:

Mexico has one of the highest prevalence of obesity, reported on 32.4 percent of people over 20 years old, with a prevalence of obesity class III of 1.8 percent on males and 4.1 percent on females.

According to previous data in our Obesity Clinic the mean age of these patients is 41 years, 46 percent have pre-diabetes or type 2 diabetes mellitus (T2D); 66 percent has hypertension and 33 percent has dyslipidemia. The management of alterations in the glucose metabolism in this unit is made by dietary treatment and with the use of metformin at doses of 1,700 mg/day and/or basal insulin.

Dapagliflozin is a selective SGLT2 inhibitor than has shown a sustained effect on the reduction of glycated hemoglobin at 0.4 to 0.8 percent (initial 7.8 to 8.0 percent). Additionally, due to the induction of glycosuria up to 20 to 85 g/day, it has been calculated that its use induces a caloric deficit at 80 to 340 kcal/day. This has been tested in patients with T2D in which induces a weight loss of 2 to 3 kg and in combination with metformin even a weight loss up to 5.07 kg (-6.21 to 3.93 kg) without regain (at least for 2 years). Furthermore, dapagliflozin decrease systolic blood pressure, increases HDL cholesterol concentrations and decreases triglyceride concentration. The drug product action is independent of the insulin production at pancreas, consequently, it exists a possibility of using the drug product on patients with prediabetes or even on other types of diabetes. Regarding the adverse effects related to its use, it has been described an increase in the risk of genitourinary infections with a low risk for inducing hypoglycemia.

A previous study that included 182 patients with T2D inadequately controlled with metformin assessed the effect of dapagliflozin 10 mg in total weight loss after 24 weeks compared to placebo. It was found a decrease in weight of 2.08 kg (2.8 to 1.31 kg), decrease in waist circumference of 1.52 cm (2.74 to 0.31), decrease in total fat mass assessed with densitometry of 1.48 kg (2.22 to 0.74), decrease of visceral fat mass of 258.4 cm^3 (448.1 to 68.6) and subcutaneous fat of 184.9 cm^3 (359.7 to 10.1). Most of these studies on weight and metabolic control have been performed in patients with obesity class II or I. The aim of this study is to assess if dapagliflozin in combination with metformin is at least 10 percent more effective for weight reduction in comparison with metformin in patients with prediabetes or T2D and obesity grade III.


Condition or disease Intervention/treatment Phase
PreDiabetes Obesity, Morbid Diabetes Mellitus, Type 2 Drug: Dapagliflozin/Metformin Drug: Metformin Phase 2 Phase 3

Detailed Description:

Methods:

A convenience sampling will be done for patients diagnosed with diabetes or prediabetes according to the American Diabetes Association (ADA) criteria, who assist to the Obesity Clinic and meet the selection criteria. Data from patients that during the study protocol are called to undergo bariatric surgery procedure will be used until the time of surgery (intention-to-treat analysis). The prevalence of comorbidities at baseline and the type and dose of drugs used for treatment will be recorded. Patients will be randomized by a random numbers system generated with a computational software and will be assigned to a group: metformin (1,700 mg/day) or metformin (1,700 mg/day) and dapagliflozin 10 mg. All patients will receive dietary treatment and follow-up during the study by the Nutrition Service. Once assigned to the corresponding group, patients will receive an identification code that will be retained throughout the study. One of the researchers not directly involved in patient care, will assign tablets needed for daily intake for a month and then the number of tablets required for 3 months in a sealed envelope. A run-in period will be used to assess tolerance to treatments. This period will be for a month. At this time patients may notice an increase of uresis and will be instructed to increase fluid intake. Anthropometric and biochemical variables will be recorded baseline and at 1, 3, 6 and 12 months. The determination of glucagon, ghrelin, adiponectin, resistin, interleukin 6 (IL-6) and interleukin 10 (IL-10) will be held on initial appointment and before surgery (depending on the response of each patient). For the determination of these cytokines and peptides, an ELISA kit (Enzyme Linked Immunosorbent Assay) will be used. Adherence to treatment will be evaluated and will consist in consumption of 90 percent of pills granted. The patient will be required to return the drug blister. The registration of adverse events will take place from the start of treatment and throughout the study. Each event will be evaluated by researchers and classified according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 list. CTCAE considers that an adverse event grade 4 or 5 indicates discontinuation of treatment; grade 3 must be submitted to review by the medical team, and grades 1 or 2 require registration and intervention but not discontinuation of treatment. Adverse events will be recorded in the report sheet. An intention-to-treat analysis will be used if patients require treatment with insulin or sulfonylureas (grade 3 adverse event). They will provide information until the time of its inception. Patients who do not achieve weight loss at one year follow-up, will be discarded to their primary care hospital for continue with dietary recommendations.

Sample Size:

A convenience sample will be performed of patients with obesity class III and prediabetes or diabetes according ADA criteria at Obesity Clinic who meet selection criteria. The sample size was calculated using a mean difference formula with data from Zhang et al. who evaluated weight loss in patients using metformin/dapagliflozin and compared with placebo. Sample size required is 90 patients: 45 patients in metformin group and 45 patients in dapagliflozin/metformin group. Considering a loss of 20 percent of population during study, the final sample size required is 108 patients: 54 patients in metformin and 54 patients in dapagliflozin group.

Statistical analysis Quantitative variables will be presented as means and standard deviation or median with interquartile ranges according to data distribution. Qualitative variables will be presented as frequencies or percentages. For assessing data distribution, a Shapiro-Wilk test will be performed. Association between quantitative variables will be assessed through Repeated measures ANOVA and qualitative variables with McNemar test. Statistical significance will be evaluated with p < 0.05. Statistical analysis will be performed using statistical packages: Statistical Package for the Social Sciences (SPSS) version 17.0.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized single-blind controlled clinical trial
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: Effectiveness of the Treatment With Dapagliflozin and Metformin Compared to Metformin Monotherapy for Weight Loss on Diabetic and Prediabetic Patients With Obesity Class III
Actual Study Start Date : July 7, 2018
Estimated Primary Completion Date : July 1, 2021
Estimated Study Completion Date : July 1, 2021


Arm Intervention/treatment
Experimental: Metformin/Dapagliflozin
Metformin 1,700 mg/day and Dapagliflozin 10 mg/day for a year.
Drug: Dapagliflozin/Metformin
Two tablets of Metformin 850 mg every 12 hours will be provided in combination with Dapagliflozin 10 mg per day. Each participant will receive diet and exercise intervention according to their BMI and current physical condition.
Other Name: Group 1

Active Comparator: Metformin
Metformin 1,700 mg/day
Drug: Metformin
Two tablets of Metformin 850 mg every 12 hours will be provided. Each participant will receive diet and exercise intervention according to their BMI and current physical condition.
Other Name: Group 2




Primary Outcome Measures :
  1. Change in Weight [ Time Frame: 12 months ]
    Change of 10 percent of initial weight


Secondary Outcome Measures :
  1. Change in Blood Pressure [ Time Frame: 12 months ]
    Change of 10 percent of initial blood pressure (systolic and diastolic)

  2. Change in Waist Circumference [ Time Frame: 12 months ]
    Change of 10 percent of initial waist circumference

  3. Change in Triglycerides level [ Time Frame: 12 months ]
    Change of 10 percent of initial triglycerides levels


Other Outcome Measures:
  1. Change in Cytokines Level [ Time Frame: 12 months ]
    Change in interleukin-6, interleukin-10, adiponectin, and resistin, comparing initial versus final levels



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • BMI greater than or equal to 40 kg/m^2
  • Diagnosis of diabetes or prediabetes according to the criteria of the ADA
  • Patients who sign informed consent letter

Exclusion Criteria:

  • Use of insulin or sulfonylureas
  • Chronic renal failure with glomerular filtration rate <60 ml/min/1.73 m^2
  • Use of loop diuretics with no possibility to suspend
  • Active genitourinary tract infections determined by symptomatology or urinalysis
  • Use of drugs for weight control
  • Patients with untreated or uncontrolled hypothyroidism

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03968224


Contacts
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Contact: Aldo Ferreira-Hermosillo, MSc +52156276900 ext 21551 aldo.nagisa@gmail.com

Locations
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Mexico
Hospital de Especialidades Centro Médico Nacional Siglo XXI Recruiting
Mexico City, Mexico, 06720
Contact: Aldo Ferreira-Hermosillo, MSc         
Sub-Investigator: Victoria Mendoza-Zubieta, MSc         
Sub-Investigator: Claudia Ramírez-Rentería, MSc         
Sub-Investigator: Mario A Molina-Ayala, MD         
Sub-Investigator: Etual Espinosa-Cárdenas, MSc         
Sub-Investigator: Alejandra Albarrán-Sánchez, MD         
Principal Investigator: Moisés Mercado, PhD         
Sub-Investigator: Aldo Ferreira-Hermosillo, MSc         
Sponsors and Collaborators
Centro Medico Nacional Siglo XXI IMSS
Investigators
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Principal Investigator: Moises Mercado, PhD
Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Aldo Ferreira Hermosillo, Research Associate, Centro Medico Nacional Siglo XXI IMSS
ClinicalTrials.gov Identifier: NCT03968224    
Other Study ID Numbers: R-2016-785-094
First Posted: May 30, 2019    Key Record Dates
Last Update Posted: September 2, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Data will be shared upon reasonable request to principal investigator

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Aldo Ferreira Hermosillo, Centro Medico Nacional Siglo XXI IMSS:
Metformin
Sodium-Glucose Transporter 2 Inhibitors
PreDiabetes
Obesity, Morbid
Diabetes Mellitus, Type 2
Additional relevant MeSH terms:
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Diabetes Mellitus
Obesity
Diabetes Mellitus, Type 2
Prediabetic State
Glucose Intolerance
Obesity, Morbid
Weight Loss
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Overnutrition
Nutrition Disorders
Overweight
Body Weight
Body Weight Changes
Hyperglycemia
Metformin
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
Hypoglycemic Agents
Physiological Effects of Drugs
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action