DAPA-ANDO: The Effect of Dapagliflozin on Weight Loss in Obese Adults Without Diabetes

Sponsor

Oman Ministry of Health (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT06000462

Collaborator

(none)

150

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

The goal of this clinical trial is to examine the effectiveness of a drug named dapagliflozin (tested drug) on weight loss in young adults aged between 18 and 40 years with obesity who are not diagnosed with diabetes.

The main questions it aims to answer are:

How much weight in average can people loose with the use of tested drug compared to 2 other 2 comparator drugs: metformin and placebo (non-medicated pill)?
What is the effect of using tested drug on other measures used to assess blood pressure, cholesterol and sugar levels, and mental health?
How frequent are the side effects from using the tested drug compared to the comparator drugs? Participants will go through a 6-month program of physical activity and diet and measure their weight progress. Those who do not achieve the target weight reduction will be randomly assigned to any of the three drug groups, either testes drug group, comparator 1 (metformin), or comparator 2 (placebo).

Condition or Disease	Intervention/Treatment	Phase
Obesity Dapagliflozin Adverse Reaction Weight Loss Effect of Drug	Drug: Dapagliflozin 10mg Tab	Phase 2/Phase 3

Detailed Description

Background Obesity is a disease, generally defined as a body mass index (BMI) ≥ 30 kg/m2, 1 is a global issue that continues to grow at an alarming rate, imposing serious threat to individuals, public health, and the economy. The he prevalence of overweight and obesity has tripled since 1975, with 1.6 billion overweight adults and 650 million obese adults, according to World Health Organization report.2 In Oman, non-communicable diseases (NCDs) represent a major burden on healthcare system at which 185.75 deaths per 100,000 population were attributed to NCDs.3 Obesity is an independent risk factor for most NCDs, adding to disease morbidity and mortality. According to a national survey conducted in 2017, the prevalence of obesity and overweight were 30.7% and 66.1%, respectively, with higher prevalence in females compared to males.4 The Look AHEAD trial revealed that losing 5% to 10% of body weight through diet and exercise alone has been associated with reduced risk of cardiovascular disease in obese and overweight adult patients.5 Whilst healthy lifestyle is the mainstay for obesity management, there is a growing interest over pharmaceuticals that support weight loss and prevent metabolic complications.

The US Food and Drug Administration (FDA) approved five drug therapies to treat obesity, namely orlistat, phentermine/topiramate, lorcaserin, naltrexone/bupropion, liraglutide, and recently saxenda,6 while the European Medicines Agency (EMA) supported three drug therapies, orlistat, bupropion/naltrexone and liraglutide.7 Several anti-diabetic drugs have been authorized for weight loss even for patients without diabetes. (reference) Sodium glucose cotransporter 2 inhibitors (SGLT2i) including empagliflozin, dapagliflozin and canagliflozin are classes of hypoglycemic agents that have been studied in both human and animal models to measure their glycemic and metabolic effect. These drugs reduce plasma glucose levels by inhibiting the sodium glucose cotransporter 2, located in the proximal tubule of the kidney, leading to increased urinary glucose excretion and a reduction in plasma glucose levels in patients with type 2 diabetes mellitus (T2DM).8-11 This mechanism of action was found to lower the risk of hypoglycemia, with additional benefits of weight loss, reductions in blood pressure, cardiovascular (CVD), and chronic kidney disease risk (CKD). 8, 12, 13 The drugs are prominent in most recent guidelines for the management on T2DM and are particularly recommended when, in addition to glucose lowering, there is a compelling need to reduce body weight.14

Behavior weight management Weight reduction via behavior change and maintaining healthy lifestyle is the first line and cost-effective treatment for obesity. According to the US Preventive Services Task Force, all adults aged 18 years or above should be screened for obesity and intensive behavior intervention to be given for weight loss,15 with at least one session per month for at least three months.16 Body mass index (BMI) is a key indicator for weight assessment; however waist circumference may be an acceptable alternative in people with central obesity because BMI may not account for the cardiovascular risk of central adiposity.17 Behavior modifications can lead to clinically important weight loss of 5%, improved glucose tolerance, and reduction in other cardiovascular risk factors.15 It has been found that low calorie diet regardless of macronutrient ingredients, had a successful weight loss effect,18,19 hence this indicates the importance of compliance to low calorie diet, as the most important factor for weight loss.

In addition, increasing physical activity is an important component of any weight loss plan. The recommendations vary according to health organization. The National Institute for Health and Care Excellence (NICE) recommends 45 to 60 minutes per day of moderate-intensity exercise to prevent obesity and 60 to 90 minutes per day to avoid regaining weight.20 The U.S. Department of Health and Human Services recommends 150 to 300 minutes of moderate-intensity activity or 75 to 150 minutes of vigorous activity per week.21 Several RCTs have shown the effectiveness of combining behavioral weight-management programs (Exercise with diet) to achieve a beneficial weight loss.22,23 A 2006 Cochrane review showed modest weight loss with exercise alone (95% confidence intervals -1.1 to -8.8 lb [-0.5 to -4.0 kg]), but the effect was significantly larger when exercise was combined to dietary modification (-7.5 to -39.0 lb [-3.4 to -17.7 kg]).23

Dapagliflozin Dapagliflozin is a highly selective SGLT2i that blocks the reabsorption of 80%

90% of the glucose filtered by the glomerulus. It is an oral medication with three different dose strengths; 2.5 mg, 5mg, 10 mg once daily, in addition to the combination formula with metformin; dapagliflozin/ metformin, with strength of 2.5mg/1000mg, 5mg/500mg, 5mg/1000mg, 10mg/500mg, and 10mg/1000mg. Several RCTs have shown its effectiveness on glycaemic control, weight loss, and blood pressure in patients with T2DM, in addition to the cardiovascular and renal protection.24 A randomized placebo control trial (RCT) that enrolled 534 patients with T2DM on preceding metformin treatment investigated the effectiveness of dapagliflozin 2·5 mg, 5 mg, and 10 mg per day dose versus placebo, over 24 weeks. There was a dose dependent reduction in HbA1c in patients treated with dapagliflozin, with a reduction of 0·84% in patients assigned to a maximum dose of 10 mg per day compared with a reduction of 0·3% in the placebo group, at the end of study period. Mean HbA1c had decreased by -0·30% (95% CI -0·44 to -0·16) in the placebo group, compared with -0·67% (-0·81 to -0·53, p=0·0002) in the dapagliflozin 2·5 mg group, -0·70% (-0·85 to -0·56, p<0·0001) in the dapagliflozin 5 mg group, and -0·84% (-0·98 to -0·70, p<0·0001) in the dapagliflozin 10 mg group.25 The trial also showed no apparent changes in fasting lipid profiles, apart from greater mean increases in HDL cholesterol (1·8-4·4% vs 0·4%) and decreases in triglycerides (-2·4% to -6·2% vs 2·1%) compared with placebo.25 Treatment with dapagliflozin was not superior to placebo in reducing the risk of major adverse cardiovascular events but lowered the risk of hospitalization due to heart failure or death from CVD (hazard ratio: 0.83; 95% CI, 0.73 to 0.95; P=0.005).26 In patients with established chronic renal disease with an estimated glomerular filtration rate (eGFR) of 25 to 75 ml per minute per 1.73 m2 of body-surface area and/ or urinary albumin-to-creatinine ratio of 200 to 5000) who received dapagliflozin 10 mg a day, showed a significantly lower risk for sustained decline in the estimated eGFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes than with placebo. The hazard ratio for renal dysfunction or death from renal causes was 0.56 (95% CI, 0.45 to 0.68; P<0.001) in dapagliflozin compared with placebo and a hazard ratio 0.71 (95% CI, 0.55 to 0.92; P=0.009) for death from cardiovascular causes or hospitalization for heart failure.27 In patients with mild to moderate chronic kidney disease of diabetes, no alterations in mean renal function measures, including serum creatinine concentration, were reported.28 The most common side effects of dapagliflozin were urinary and genital infection, 29 besides headache, backpain, and diarrhea.30 An analysis of published data from 12 RCTs, included 3152 patients who received dapagliflozin 2.5 mg, 5 mg, or 10 mg as monotherapy or add-on treatment, and 1393 placebo-treated patients, showed that the diagnosis of infection were reported in 3.6%, 5.7%, 4.3%, and 3.7%, respectively. However, most infections were treated and responded to antimicrobial therapy. Discontinuations due to urinary tract infection were rare: 8 (0.3%) dapagliflozin-treated patients and 1 (0.1%) placebo-treated patient.30 Most studies were in patients with diabetes who are at risk of asymptomatic bacteriuria and pyelonephritis in combination with dysfunction of the urinary tract compared with people without diabetes, the fact that further studies with longer observation period are required to confirm that infection is related to the drug and not diabetes status.31 In fact, it has been found that the frequency of serious adverse effects including urinary and genital fungal infection from dapagliflozin were comparable to placebo in patients with T2DM.30

Dapagliflozin and obesity management Obesity and T2DM are intrinsically linked with multiple shared pathology, besides being associated with increased risk of multiple comorbidities.32 The weight loss observed with SGLT2i is thought to be due to fluid loss, reduction in lean body mass, and thereafter loss of calories via increased urinary glucose excretion. Dapagliflozin was found to improve adipocyte function by lowering inflammatory markers, C-reactive protein and increasing adiponectin besides lowering glycated hemoglobin and body weight, however evidence was inconclusive due to small sample size.33 Animal based trials are still ongoing to provide evidence of actual mechanism of weight loss with SGLT2i. Modest body of evidence have shown the effectiveness of dapagliflozin in causing clinically significant reductions in body weight.34 A double-blind placebo-controlled study of 182 patients with T2DM treated with dapagliflozin 10mg a day versus placebo (added on metformin) over 102 weeks showed reductions in HbA1c by -0.3%, weight by -4.54 kg, waist circumference by -5.0 cm and fat mass by -2.80 kg without increases in rate of hypoglycemia, in former drug compared with later placebo. In addition to that, no significant changes from baseline in bone density or markers of bone turnover, compared with placebo. The frequency of patients with at least one adverse event (mainly urinary and genital infections) were comparable; 71.4% in the dapagliflozin and 69.2% in placebo group by week 102. 35 Another RCT compared the metabolic effect of dapagliflozin versus placebo on high density lipoprotein (HDL-C) over 16 weeks of treatment, showed reduced HbA1c by 0.9% and body weight by 3.1 kg, mainly attributable to reduction of body water and lean mass, without evidence of improving HDL-cholesterol.36 Treatment with dapagliflozin 5 mg/day over 24 weeks showed a decrease in total body weight of 2.9kg (3.9%). Furthermore, there was a decrease in serum alanine aminotransferase and γ-glutamyl transpeptidase levels and a significant decrease in controlled attenuation parameter (CAP)- a measure of liver stiffness and fibrosis from 314 ± 61 to 290 ± 73 decibel dibutyryl (dB)/m (P = 0.0424), concluding that dapagliflozin might improve liver steatosis in patients with type 2 diabetes and NAFLD. However, the possibility that a reduction in body weight or visceral adipose tissue by dapagliflozin may be associated with a decrease of liver steatosis or fibrosis, cannot be excluded.37 A small, prospective study of 26 patients with T2DM who received dapagliflozin 5mg/day over 12 weeks showed a 23.8% loss of lean body mass but modest weight loss of 2.5 Kg.36 A randomized double blind placebo control trial showed that empagliflozin monotherapy at doses of 10 mg and 25 mg for ≥76 weeks was well tolerated and led to sustained reductions in glycated hemoglobin (HbA1c) and weight compared with placebo.37 The glucose-dependent mechanisms of action of SGLT2-i comes with low risk of hypoglycemia, particularly when not used with sulphonylureas or insulin.38 Several studies have been undertaken to evaluate and measure the effectiveness of SGLT-2i in managing obesity in diabetic and non-diabetic patients, however evidence is inconclusive and necessitates further high-quality trials to assess the long-term outcomes of this drug that is administered orally, once daily dose, with expected low risk of severe adverse events.

The Directorate of Primary care in Muscat Governorate established the obesity clinic in primary care health centers in 2016. A total of 1934 patients with overweight and 3,628 with obesity received weight management care, between 2016 and 2019. The obesity clinic service was lagging due to lack of inclusive resources including pharmacotherapy, psychotherapy, and referral pathway for bariatric surgery.

Thus, we decided to take the opportunity and assess the effectiveness of pharmacotherapy combined to mentored, tailored healthy lifestyle program in obesity management. This trial will evaluate the efficacy and safety of dapagliflozin with a mentored, tailored healthy lifestyle program in wight loss in young adults with obesity, who are not yet diagnosed with diabetes, in polyclinics.

Problem statement Obesity and overweight are steadily rising in Oman, increasing the risk for morbidity and mortality due to the devastating complications from chronic disease. Approximately, 40% of the obese and overweight population are among the young adults, which makes obesity prevention and control a serious public health issue. The literature has shown positive effect of SGLT2i on weight loss in obese patients, not diagnosed with diabetes, however, evidence is inconclusive and higher quality trials are required to support this claim. Given the shared intrinsic pathological link between obesity and T2DM, and considering the feasibility of SGLT2i, it is worthy to investigate the effectiveness of SGLT2i (dapagliflozin) for weight management in obese young adults, not diagnosed with T2DM.

The Directorate of Primary Health Care of Muscat Governorate established an obesity clinic in 2017, where services were provided by endocrinologists for patients with obesity identified in primary care health centers. However, the service was lagging due to lack of inclusive resources including pharmacotherapy and structured lifestyle program. Weight reduction service was then integrated in primary care where counselling alone is the main means of treatment provided to patients.

Thus, we decided to take the opportunity and assess the effectiveness of oral pharmacotherapy combined to mentored, tailored healthy lifestyle program in obesity management. This trial will evaluate the efficacy and safety of dapagliflozin on wight loss in young adults with obesity, who are not yet diagnosed with diabetes.

Methods:

Study design:

All subjects will be prescribed a structured monitored and tailored program from the beginning of the 24-week run-in period before randomization to drug therapy.

Patients who do not respond to the structured lifestyle program (not losing 10% of weight or BMI still above 30 to 35) will be randomized to any of the three arms: placebo, metformin, or dapagliflozin.

After randomization, we plan for 48-week double-blind, randomized, parallel-group, placebo-controlled, trial. The trial will involve young adults with obesity (non-diabetic) aged between 18 and 40 years. In the first 32 weeks, subjects will be randomized 1:1:1 to receive either dapagliflozin 10 mg or metformin or placebo. The randomization will be stratified according to age and metabolic parameters. At least 30% of subjects will be from areas with comparable lifestyle and nutrition in Muscat governorate. After 32 weeks drugs will be discontinued and patients will be followed for another 16 weeks after end of drug therapy "off-study-drug follow-up period" to assess effect maintenance and any evidence of rebound, as well as to monitor post-treatment safety - this phase is aligned with regulatory recommendations. Overall, patients will be followed for a total of 48 weeks after randomization to study arms.

Trial setting:

The trial will be conducted in obesity clinics in primary health centers in Muscat. These two centers are enlisted within healthcare facilities that operate under the umbrella of Directorate General of Health Services (DGHS) of Muscat governorate. Specialized medical care is provided by these centers for patients referred from primary health care who require specialized advance management according to a standard protocol. Participants will attend the obesity clinics where medical care will be provided by family physicians and endocrinologists.

Trial interventions:

Run- in period:

Behavioral weight management program:

Physical activity:

At baseline visit, the participants will be given a physical activity prescription written by the family physician/ endocrinologist in obesity clinic to guide type and frequency of exercises. Participants will be enrolled in a structured program for physical activity in a fitness gym that is well-known of high fitness, health, and safety standards throughout the study period - 24 (run-in) and 48 (post randomization) weeks. A contract will be signed with a gym that has several branches in Muscat Governorate to ensure easy access, besides the standards. A list of participant names will be given to a prespecified branch according to patients' location preference. Each gym should nominate fitness instructors to monitor the way workouts are done by the participants. A logbook approach will be used to ensure adherence by patients and instructors, in which patients must submit to the care provider every time they visit the clinic on their appointment. The logbook will include information regarding date, time, type of exercise, duration of exercises, progress. In case any participant missed more than one class, the instructor is expected to call for a reminder and reschedule for the missing session. Type of exercises will include muscle strengthening and aerobic exercises using machines. The participant is expected to complete 75 to 150 minutes for muscle strengthening and 150 - 300 minutes for cardio-based exercises per week, to achieve the World Health Organization recommendation for physical activity, hence, at least 4 sessions of 30 minutes in each per week, might be a target.

Nutrition counselling clinical nutritionist will be involved in providing proper dietary and behavior modification counselling to all study participants and maintain schedule follow ups later. Patients will be seen at baseline, 24 weeks, 48 weeks from baseline. The nutritionists have been trained on motivational interview skills as part of their professional development, hence motivation and encouragement care will be provided during the dietary counselling sessions. The dietary plans will mainly focus on calorie reduction rather than specific dietary composition of macronutrients to make it simple, without overwhelming patients and ensure good adherence. A deficit of at least 500 kcal per day can be achieved with intake of 1,200 to 1,500 kcal for women and 1,500 to 1,800 kcal for men. Although different diets with similar caloric intake can result in comparable weight loss, a higher-quality diet of nutrient-dense foods (e.g., vegetables, fruits, whole grains) that are rich in fiber, vitamins, and minerals will produce greater results. Dieticians will follow the general guidance from Dietary Guidelines for Americans 2015 - 2020 that reinforces the need for healthier food and beverage choices by consuming nutrient-dense foods from all food groups and limiting intake of added sugars, saturated fats, and sodium. In addition, intermittent fasting schedule will be incorporated into the dietary regime.

Behavior modification counselling Motivational interview will be the main technique used to encourage behavior change and adherence to healthy lifestyle including physical activity and low-calorie diet. The technique includes 1. Asking permission to discuss behavior change, 2. Showing empathy throughout discussion, 3. Using scale of motivation and confidence, 4. Enquiring about the chosen scores, 5. Exploring barriers to change, 6. Exploring pros and cons of behavior change. 7. Listening to change talk "where the patient takes the ownership to generate ideas and ways" and reinforce it. The psychologists will provide comprehensive counselling at baseline and 12 weeks from baseline, besides the scheduled counselling that will be given by dieticians throughout the scheduled follow ups.

Pharmacotherapy

Recruitment of patients:

Recruitment will take place over a 6-month period in the primary care health centers by the trial investigators. Patients fulfilling the inclusion criteria will be provided with a participant information sheet about the study by the project officers and patients showing interest will be given a consent sheet to confirm participation and adherence to study conditions in written. Participants will be involved in 24 weeks (6 months) run in period to provide them with a comparable behavior modification and healthy lifestyle program in their health centers before randomization to ensure homogeneity and patient safety as drug of interest is used off-label. Appointments will be given to all participants to attend the obesity clinic for baseline measures and to receive care in polyclinics. Recruitment will be monitored on a monthly basis and efforts to reduce loss to follow-up will be made. Participants not attending their appointment will be called to consider rescheduling their appointments.

Key randomization criteria:

BMI corresponding to 30-35 kg/m2 for adults by international cut-off points (for diagnosis of obesity).
Compliance with run-in procedures and visit schedule (during the period between screening and randomization) as judged by the investigator.

Randomization and allocation concealment After recruitment of eligible participants, computerized number generator will be used to generate random identification of study arms and patients, stratified according to age, gender, and metabolic parameters. The allocation would be 1:1:1to each arm of the study group. An independent healthcare professional "most probably a nurse" who is not part of the study investigators team will lead the allocation concealment of the randomized groups who will also be concealed from the study arms. The arms will be coded A, B, C and only independent nurses will be aware of these codes that are saved and registered electronically.

Ensure patient safety:

Any study participant is noticed to have side effects that warrants the clinician to know with certainty, the medication he/she has been receiving, the Pharmacist who has the key to the code can be asked to reveal the medication given to that patient and the treating physician can manage the patient with this knowledge. If several patients show side effects and the code shows them to be in the same treatment arm, a decision can then be made to discontinue that arm or stop the study (as per the severity or risk of continuing the study) all these safety features can be built into the study.

Sample size:

To demonstrate a between groups difference of 5kg in body weight over 3 months from baseline, that would be detected at a power of 80%, with significance level of 5%, and a standardized difference of 0.700 gm (i.e., 0.394 of a standard deviation can be detected), the minimum required sample size is 300 (75 in each arm). With an attrition rate of 20% and a recruitment rate of 70% the required sample size is 500 (125 in each arm). However, due to the patient safety issue related to using a drug off-label, a sample size of 150 will be used in this study.

Statistical analysis The difference between the baseline and post intervention values of BMI in each of the study groups and the comparison between post intervention values between each of the study groups will be calculated. It will generally be presented by two-sided confidence intervals (CIs) with a confidence level of 95%. Superiority will be claimed if the two-sided p-value is less than 5% and the treatment estimate favors dapagliflozin arms. If the upper limit is below 0, superiority of dapagliflozin against placebo can be concluded.

• Analysis of outcomes The full analysis set (FAS) will be used in the analysis of the efficacy endpoints. For the safety endpoints, the safety analysis set (SAS) will be used.

FAS: includes all randomized subjects who have received at least one dose of trial product and have any post-randomization data. The statistical evaluation of the FAS will follow the intention-to-treat (ITT) principle and subjects will contribute to the evaluation "as randomized".

SAS: includes all subjects exposed to at least one dose of trial product. Subjects in the SAS will contribute to the evaluation "as treated".

Before data are locked for statistical analysis, a blinded review of all data will take place. Any decision to exclude a subject or single observation from the statistical analysis is the joint responsibility of principal investigator and co investigators. Exclusion of data from analyses will be used restrictively and normally no data should be excluded from the FAS. The subjects or observations to be excluded, and the reasons for their exclusion must be documented and signed by those responsible before database lock. The subjects and observations excluded from analysis sets, and the reason for this, will be described in the clinical trial report

Handling of missing values Missing data in the main analysis will be handled by the following multiple imputation (MI) method. A pattern mixture model approach is applied where withdrawn subjects or treatment discontinued subjects without a follow-up visit are assumed to respond as if treated with placebo for the entire trial. Multiple copies (100 copies) of the full dataset will be generated by imputing missing values based on estimated parameters for the placebo group.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

150 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Triple-blind, parallel groups, randomized, placebo control trialTriple-blind, parallel groups, randomized, placebo control trial

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Masking Description:

To blind the investigators and participants,150 packs of medication labelled from 1 to 150 numbered randomly from 1-150 (but this depends on number of patients who did not respond to run in period intervention), 50 each containing either 10 mg dapagliflozin or 1000mg metformin or the placebo. The label on the pack only has the serial number but the pharmacist (who is not part of this study) has the code of what each bottle contains and that is kept safely and confidentially (Hard copy and multiple soft copies in safe custody). Participants are numbered serially according to recruitment, and each gets the correspondingly numbered bottle (which has been previously randomly assigned by the pharmacist).

Primary Purpose:

Treatment

Official Title:

The Effect of Sodium Glucose Co-transporter 2 Inhibitor (Dapagliflozin) on Weight Loss in Non-diabetic Adults With Obesity: Triple-blinded, Randomized, Placebo-controlled Trial.

Anticipated Study Start Date :

Dec 1, 2023

Anticipated Primary Completion Date :

Dec 1, 2025

Anticipated Study Completion Date :

Dec 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dapagliflozin arm 10 mg strength will be used in this study. The drug is usually taken orally once a day, preferably in the morning. The participants will be using the medication for 32 weeks only, then continue follow up for another 16 weeks (off drug therapy) with behavior weight management program only. The patients will be informed from the beginning of the study with the general side effects of medication (patient information sheet) that should be reported if experienced.	Drug: Dapagliflozin 10mg Tab Mentioned in detailed description. Other Names: metformin 1000 mg Tab Placebo
Active Comparator: Metformin arm 1000 mg strength will be used once daily dose. Medication will be provided randomly to the patient according to the corresponding number. The patients are informed to declare any experienced side effects that has been stated in the patient information sheet without informing the name of drugs.	Drug: Dapagliflozin 10mg Tab Mentioned in detailed description. Other Names: metformin 1000 mg Tab Placebo
Placebo Comparator: Placebo arm receive a harmless substance or treatment that has no therapeutic effect, once daily.	Drug: Dapagliflozin 10mg Tab Mentioned in detailed description. Other Names: metformin 1000 mg Tab Placebo

Arm

Intervention/Treatment

Experimental: Dapagliflozin arm

10 mg strength will be used in this study. The drug is usually taken orally once a day, preferably in the morning. The participants will be using the medication for 32 weeks only, then continue follow up for another 16 weeks (off drug therapy) with behavior weight management program only. The patients will be informed from the beginning of the study with the general side effects of medication (patient information sheet) that should be reported if experienced.

Drug: Dapagliflozin 10mg Tab

Mentioned in detailed description.

Other Names:

metformin 1000 mg Tab

Placebo

Active Comparator: Metformin arm

1000 mg strength will be used once daily dose. Medication will be provided randomly to the patient according to the corresponding number. The patients are informed to declare any experienced side effects that has been stated in the patient information sheet without informing the name of drugs.

Drug: Dapagliflozin 10mg Tab

Mentioned in detailed description.

Other Names:

metformin 1000 mg Tab

Placebo

Placebo Comparator: Placebo arm

receive a harmless substance or treatment that has no therapeutic effect, once daily.

Drug: Dapagliflozin 10mg Tab

Mentioned in detailed description.

Other Names:

metformin 1000 mg Tab

Placebo

Outcome Measures

Primary Outcome Measures

Difference in inter-arms percent of subjects achieving ≥5% reduction in baseline weight [32 weeks post randomization]
we will measure the percentage change of weight in terms of achieving 5 or more and compare it with other arms
Inter-arms differences in mean BMI, waist circumference, waist hip ratio, body weight (kilogram, kg), Body fat (%), and Muscle mass (%) [32 weeks post randomization]
we will measure the intra-group mean difference from baseline and then compares the intergroup mean difference.

Secondary Outcome Measures

Inter-arms group mean difference in metabolic parameters, depression, anxiety [32 weeks post randomization]
we will measure the intra-group mean difference from baseline and then compare the intergroup mean difference.
Frequency of adverse event from dapagliflozin [32 weeks post randomization]
We will monitor patients for the development of any signs or symptoms suggestive of side effect and calculate the prevalence. The prevalence rate will be compared between the study arms

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 40 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

BMI 30-35 mg/kg2 for adults by international cut-off points (for diagnosis of obesity)
Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial.
Stable body weight during the previous 90 days before screening (<5 kg self-reported weight change)
History of failing to lose sufficient weight with lifestyle modification as judged by the investigator and documented in subject's medical record.
Willingness to participate in mentored physical activity and dietary program for 72 weeks. (24 months)

Exclusion Criteria:

Type 1 or type 2 diabetes mellitus (T1DM)
Subjects with secondary causes of obesity (i.e., hypothalamic, genetic, or endocrine causes)
Treatment with medications within 90 days before screening that, that are used in obesity treatment including pramlintide, orlistat, zonisamide, topiramate, lorcaserin, phentermine, bupropion, naltrexone, glucagon-like peptide-1 (GLP-1) receptor agonists, or metformin (used as treatment for obesity)
On anti-diabetic treatment
Patients with impaired kidney function including persistent eGFR <= 45 and albuminuria
Patients with peripheral vascular disease
Patients with recurrent urinary tract infection or fungal infections within 12 months before screening
History of major depressive disorder within 2 years before screening
History of cardiopulmonary diseases that prevents from physical activity
Pregnancy