Combined Liraglutide and Metformin Therapy in Women With Previous Gestational Diabetes Mellitus (GDM)
Condition: Gestational Diabetes Mellitus; Type 2 Diabetes Mellitus; Metabolic Syndrome; Impaired Glucose Tolerance; Disorder of Glucose Regulation
MeSH terms: Diabetes, Gestational; Diabetes Mellitus; Diabetes Mellitus, Type 2; Metabolic Syndrome; Glucose Intolerance
Study type: Interventional
Phase: Phase 3

Summary: 
      A diagnosis of gestational diabetes mellitus (GDM)has significant implications for the future
      health of the mother. GDM is often the culmination of years of unrecognized and unmodified
      diabetes risk factors that lead to overt and occult clinical manifestations during pregnancy.
      Systematic reviews of older studies conclude that 35-60% women with gestational diabetes will
      develop type 2 diabetes (DM2) at rates much greater than control groups who did not have
      glucose intolerance during pregnancy. Liraglutide may potentially delay disease progression
      in GDM considering the beta -(ß-)cell function improvement in DM2 and ß-cell mass shown to
      increase in animal models. This study will examine if the addition of liraglutide to
      metformin therapy is more effective than metformin alone in improving insulin sensitivity and
      normalizing insulin secretion in at-risk overweight/obese women with prior GDM.
    

Detailed description: 
      Gestational diabetes is often the culmination of years of unrecognized and unmodified
      diabetes risk factors that lead to overt and occult clinical manifestations during pregnancy.
      . Despite the high and increasing rate of type 2 diabetes in Louisiana, the medical community
      does not have reliable estimates of the number of woman living in southern Louisiana who
      develop diabetes subsequent to GDM. Systematic reviews of older studies conclude that 35-60%
      women with gestational diabetes will develop type 2 diabetes at rates much greater than
      control groups who did not have glucose intolerance during pregnancy. The higher rates were
      in studies of particular ethnic groups in the U.S. Recently, follow-up programs elsewhere
      also have identified increasing rates of type 2 diabetes by 5-10 years after GDM: 9-43% type
      2 diabetes in Europe and 11-21% in Asia. The frequency of type 2 diabetes is influenced by
      BMI, weight gain after pregnancy, family history of diabetes, fasting and postchallenge
      glucose levels during and after pregnancy, postpartum insulin resistance and inadequate
      β-cell secretion, and the need for pharmacological treatment during pregnancy. However, the
      risk factors are unable to predict all cases of subsequent type 2 diabetes: the biggest risk
      factor is a GDM pregnancy. Presently, in the literature, there are described new, more
      efficient methods of diabetes prevention in groups with a high risk of this disorder, which
      involve both, lifestyle modification and pharmacological therapies. Lifestyle intervention
      was found to reduce the incidence of type 2 diabetes by 58% and metformin by 31% as compared
      with placebo. The use of rosiglitazone in subjects with prediabetes resulted in a 60%
      reduction of the diabetes incidence rate. Studies are needed for optimal postpartum and
      long-term health of women who have had GDM. Considerable recent evidence suggests that
      incretin-based therapies may be useful for the treatment of DM2 because continuous
      administration of glucagon-like peptide 1 (GLP-1) produces substantial improvements in
      glucose control and ß-cell function in subjects with type 2 diabetes. Infusion of GLP-1
      improves first and second-phase insulin secretion suggesting that early GLP-1 therapy may
      preserve ß-cell function in subjects with IGT or mild DM2. Whereas native GLP-1 has a very
      short half-life, the GLP-1 analogue liraglutide has a prolonged action (t1/2=13 h) suitable
      for once-daily injection. Liraglutide may potentially delay disease progression in GDM
      considering the ß-cell function improvement in DM2 and ß-cell mass shown to increase in
      animal models. This study will examine if the addition of liraglutide to metformin therapy is
      more effective than metformin alone in improving metabolic parameters in at-risk
      overweight/obese women with prior GDM
    

Intervention name(s): Metformin XR plus placebo; Metformin XR plus liraglutide
Intervention type(s): Drug; Drug
Intervention description(s): Metformin plus Placebo Metformin 500 mg qd 2 weeks 500 mg bid 2 weeks 500 mg am, 1000 mg pm- 2 weeks 1000 mg bid -98 weeks (end study) Placebo-start 1 injection SC QD step up to a max dose as tolerated; Metformin XR-500 qd for 2 weeks, 500 mg bid 2 weeks; 500 mg am, 1000 mg pm- 2 weeks - 1000 bid final dose Liraglutide- start 0.6 mg SC QD step up to 1.2 mg to a max dose of 1.8 mg SC QD as tolerated during the 4-wk non-forced dose-escalation period ( maximum allowed dose of 1.8 mg SC QD)
Other intervention name(s): Metformin XR is generic; Victoza
Intervention MeSH terms: Metformin; Liraglutide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Prevention
Keywords: gestational diabetes mellitus; type 2 diabetes mellitus; metabolic dysfunction; impaired fasting glucose; impaired glucose tolerance; incretin mimetic