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
Intervention: DAPA/MET XR; DAPA; MET XR
Intervention description: 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
Intervention MeSH terms: Metformin; Dapagliflozin
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Investigator)
Enrollment: 69.0
Sex: Female
Minimum age: 18 Years
Maximum age: 45 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: GDM; T2DM; prediabetes

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.
    

Eligibility criteria:

        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