Dapagliflozin and Metformin,Alone and in Combination, in Overweight/Obese Prior GDM Women

Study Overview
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Brief Summary
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Women with a history of gestational diabetes (GDM) are at substantially increased risk of type 2 diabetes mellitus (T2DM). Compared with the general population, these women are more likely to be overweight or obese. Moreover, weight gain after GDM is significantly associated with T2DM, independent of baseline body weight. Weight gain, particularly increased central adiposity after delivery, is strongly associated with deterioration of β-cell compensation for insulin resistance. Taken together, our findings and other studies support increased abdominal fat as the strongest factor associated with declining B-cell compensation for insulin resistance in prior GDM women at high risk for T2DM. Dapagliflozin is a novel highly selective SGLT2 inhibitor that improves glycemic control by reducing renal glucose reabsorption leading to urinary glucose excretion. Its efficacy and safety has been studied in multiple randomized controlled trials including an add-on to metformin compared with a placebo. To the extent that glucotoxicity contributes to the demise in β-cell function in subjects with impaired glucose, SGLT2 inhibitors also may prove useful in the treatment of prediabetes. An additional secondary benefit of SGLT2 inhibition is the elimination of calories in the form of glucose. The loss of glucose with attendant caloric loss contributes to weight loss; in addition, improvements in β cell function have been seen. Weight loss seen with SGLT2 inhibitors is similar to that seen with glucagon-like peptide 1 analogs, and may be more acceptable because they are oral agents. A consistent finding in all dapagliflozin studies has been a reduction in blood pressure. The investigators hypothesize that combination dapagliflozin -metformin treatment over a 24-week period will have a greater positive impact on body weight, anthropometric measurements and glycemic and cardiometabolic parameters than dapagliflozin or metformin monotherapy in overweight/obese at-risk women with a history of GDM.

Detailed Description
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Following written consent, all study patients will undergo the following clinical, metabolic and laboratory evaluations before and during treatment. To ensure that patients remain unidentified, all study subjects will be assigned an individual study identifier which includes the study acronym, patient initials, and unique number. All blood samples will be obtained and results identified and reported using this unique study identifier. A full physical examination will be performed and vital signs (blood pressure, respiration and temperature) determined. Trained personnel using standardized protocols at the baseline and follow-up examination will obtain anthropometric measurements and blood specimens. Absolute body weight, height, waist and hip circumference, body fat distribution (waist/hip {WHR}) and waist/height ratio ({WHtR}) and blood pressure (BP) will be determined. Body weight will be measured to the nearest 0.1 kg using a calibrated digital scale with participants in light clothing and no shoes. Height will be measured to the nearest centimeter. The total body adiposity (total fatness), defined as the accumulation of body fat without regard to regional distribution, will be expressed as BMI and calculated as weight (kg)/ height (m) 2. The circumference measurements will be taken in the upright position using a 15-mm width flexible metric tape held close to the body but not tight enough to indent the skin. Waist circumference (WC) will be measured at the narrowest level midway between the lowest ribs and the iliac crest and hip circumference measured at the widest level over the buttocks while the subjects are standing and breathing normally. The WHR and WHtR will be calculated for measure of body fat distribution. All patients will randomly be assigned to one of 3 medication treatment groups-- dapagliflozin-metformin (DAP-MET; 5 mg DAP/ MET 1000 mg BID), metformin XR (MET 1000 mg BID) or dapagliflozin (DAP 10 mg QD); all subjects will be allocated to one of these 3 groups based on computer-generated random numbers using a block randomization method. Oral glucose tolerance tests (OGTTs) with glucose (G) and insulin (I) measured at 0, 30, 60, and 120 after glucose load to assess diabetes, fasting (FBG) and mean blood glucose (MBG) concentrations, insulin resistance and pancreatic ß-cell function will be performed prior to randomization and at 20-24 weeks after full doses of study medications are reached. Mean blood glucose (MBG) concentrations will be calculated by summing glucose values obtained at 0,30,60 and 120 minutes during the OGTT and dividing by 4. At the initial lab evaluation, creatinine and calculated eGFR, TSH, and ß-hCG will be determined for study inclusion. Baseline blood samples will also be analyzed for lipid profiles and liver enzymes. All patients will receive the same counseling concerning the benefits of lifestyle modification through diet and exercise. The patients will be also encouraged to increase daily exercise (such as walking, using stairs), although this will not be formally assessed. The participants will receive further encouragement to adhere to the regime during follow-up phone calls. Side effects of the treatment and reason for any withdrawals from the study will be recorded.

Official Title
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A Randomized Study Evaluating Dapagliflozin and Metformin, Alone and in Combination, in Overweight Women With a Recent History of Gestational Diabetes Mellitus: Effects on Anthropometric Measurements and Cardiometabolic Abnormalities

Conditions
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Diabetes Prevention in Women After GDM Who Are at High-risk

Intervention / Treatment
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* Drug: DAPA/MET XR
* Drug: DAPA
* Drug: MET XR


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: • Overweight/obese (BMI >25) females 18 years to 45 years of age, who experienced gestational diabetes (GDM) during recent (within 12 months) pregnancy postpartum metabolic abnormalities determined by a 75 g oral glucose tolerance test (Inclusive of prior GDM women with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or both (IFG/IGT) postpartum) Completed lactation Using adequate contraception during study period unless sterilized Written consent for participation in the study Exclusion Criteria: Cholestasis during the past pregnancy Any hepatic diseases in the past (viral hepatitis, toxic hepatic damage, jaundice of unknown etiology), gallstones, abnormal liver function tests or renal impairment (elevated serum creatinine levels or abnormal creatinine clearance Presence of significant systemic disease, heart problems including congestive heart failure, history of pancreatitis, or diabetes mellitus (Type 1 or 2) Renal impairment (e.g., serum creatinine levels ≥1.4 mg/dL for women, or eGFR <60) Significantly elevated triglyceride levels (fasting triglyceride > 400 mg %) Untreated or poorly controlled hypertension (sitting blood pressure >160/95mm Hg) Prior history of a malignant disease requiring chemotherapy Known hypersensitivity or contraindications to use of insulin sensitizers such as metformin or thiazolidinediones History of hypersensitivity reaction to dapagliflozin or other SGLT2 inhibitors (e.g. anaphylaxis, angioedema, exfoliative skin conditions) Current use of metformin, thiazolidinediones, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT2 inhibitors or weight loss medications (prescription or OTC) Uncontrolled thyroid disease (documented normal TSH) or hyperprolactinemia Liver enzymes (serum alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST] ) levels exceeding more than twice normal lab values Use of drugs known to exacerbate glucose tolerance History of diabetes or prior use of medications to treat diabetes except GDM Currently lactating Eating disorders (anorexia, bulimia) or gastrointestinal disorders Suspected pregnancy (documented negative serum pregnancy test within 72 hours before first dose of study drug), desiring pregnancy in next 6 months, breastfeeding, or known pregnancy in last 2 months Active or prior history of substance abuse (smoke or tobacco use within past 3 years) or significant intake of alcohol or history of alcoholism Patient not willing to use adequate contraception during study period and up to 4 weeks after last dose of study drug (unless sterilized). Debilitating psychiatric disorder such as psychosis or neurological condition that might confound outcome variables Inability or refusal to comply with protocol Not currently participating or having participated in an experimental drug study in previous three months

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DAPA/MET Extended Release (XR)<br>Dapagliflozin plus metformin XR- 5 mg/1000 mg with meal for 4 weeks DAPA/MET XR- 5mg/1000 mg BID final dose for 20 weeks | Drug: DAPA/MET XR<br>* final dose- 5 mg dapagliflozin/1000 mg glucophage XR BID for 20-24 weeks<br>* Other names: Xigduo 5mg/1000 mg;|
| Active Comparator: Dapaglifloxin<br>Dapagliflozin- 10 mg once daily before first meal for 24 weeks | Drug: DAPA<br>* 10 mg dapagliflozin QD for 20-24 weeks<br>* Other names: Farxiga 10 mg;|
| Active Comparator: Metformin XR<br>Metformin XR with 500 mg once a day for 2 weeks, followed by 500 mg twice a day for 2 weeks, followed by 500 mg in the morning (AM), 1000 mg in the evening ( PM) for 2 weeks, with 1000 mg twice a day as the final dose for 20 weeks | Drug: MET XR<br>* 1000 mg Metformin XR BID for 20-24 weeks<br>* Other names: Glucophage XR 500 mg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Body Weight | Change in absolute body weight with combination therapy compared to monotherapy from baseline to week 24 | Change from baseline (time 0) to study end (24 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Percent Body Weight | Change in percent body weight with combination therapy compared to monotherapy from baseline to week 24 | Change from baseline (time 0) to study end (24 weeks) | 
| Body Mass Index (BMI) | BMI (measure of overall adiposity) in combination therapy compared to monotherapy after 24 weeks of treatment | 24 weeks of treatment | 
| Waist Circumference (WC) | Waist size (measure of truncal adiposity)with combination therapy compared to monotherapy after 24 weeks of treatment | 24 weeks of treatment | 
| Waist- to -Hip Ratio (WHR; Measure of Central Adiposity) | Waist-to-hip ratio with combination therapy compared to monotherapy after 24 weeks of treatment | 24 weeks of treatment | 
| Waist-to-height Ratio (WHtR) | Waist divided by height a( measure of central adiposity) with combination therapy compared to monotherapy after 24 weeks of therapy | 24 weeks of treatment | 
| Diastolic Blood Pressure (DBP) | Diastolic blood pressure with combination therapy compared to monotherapy after 24 weeks of treatment | 24 weeks of treatment) | 
| Systolic Blood Pressure (SBP) | Systolic blood pressure with combination therapy compared to monotherapy after 24 weeks of therapy | 24 weeks of treatment | 
| Liver Enzymes | ALT/AST ratio with combination therapy compared to monotherapy after 24 weeks of treatment | 24 weeks of treatment | 
| Total Cholesterol Levels (CHOL) | Cholesterol levels with combination therapy compared to monotherapy after 24 weeks of treatment | 24 weeks of treatment | 
| Triglyceride (TRG) Levels | Triglyceride levels with combination therapy compared to monotherapy after 24 weeks of treatment | 24 weeks of treatment | 
| Fasting Blood Glucose (FBG) | Fasting blood glucose levels with combination therapy compared to monotherapy after 24 weeks of treatment | 24 weeks of treatment | 
| Mean Blood Glucose (MBG) During an OGTT | Mean blood glucose after glucose load with combination therapy compared to monotherapy after 24 weeks of treatment | 24 weeks of treatment | 
| Fasting Insulin Sensitivity (HOMA-IR) | HOMA index of insulin resistance calculated from fasting insulin and glucose with combination therapy compared to monotherapy after 24 weeks of treatment | 24 weeks of treatment | 
| Matsuda Sensitivity Index (SI OGTT) | Surrogate measure of insulin sensitivity derived from OGTT with combination therapy compared to monotherapy after 24 weeks of treatment | 24 weeks of treatment | 
| First Phase Insulin Secretion (IGI/HOMA-IR) | Corrected early insulin response to glucose challenge [(insulinogenic index (IGI)/ divided by fasting insulin resistance index (HOMA-IR)] with combination therapy compared to monotherapy after 24 weeks of treatment | 24 weeks of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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T2DM, prediabetes, GDM