Dapagliflozin and Metformin,Alone and in Combination, in Overweight/Obese Prior GDM Women
Condition: Diabetes Prevention in Women After GDM Who Are at High-risk
MeSH terms: Overweight
Study type: Interventional
Phase: Phase 3

Summary: 
      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: 
      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.
    

Intervention name(s): DAPA/MET XR; DAPA; MET XR
Intervention type(s): Drug; Drug; Drug
Intervention description(s): final dose- 5 mg dapagliflozin/1000 mg glucophage XR BID for 20-24 weeks; 10 mg dapagliflozin QD for 20-24 weeks; 1000 mg Metformin XR BID for 20-24 weeks
Other intervention name(s): Xigduo 5mg/1000 mg; Farxiga 10 mg; Glucophage XR 500 mg
Intervention MeSH terms: Metformin; Dapagliflozin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Investigator)
Primary purpose: Treatment
Keywords: GDM; T2DM; prediabetes