Combined Liraglutide and Metformin Therapy in Women With Previous Gestational Diabetes Mellitus (GDM)

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by BC Women's Hospital & Health Centre
Sponsor:
Collaborator:
Novo Nordisk A/S
Information provided by (Responsible Party):
Karen Elkind-Hirsch, BC Women's Hospital & Health Centre
ClinicalTrials.gov Identifier:
NCT01234649
First received: November 3, 2010
Last updated: July 14, 2014
Last verified: July 2014

November 3, 2010
July 14, 2014
August 2011
August 2015   (final data collection date for primary outcome measure)
An index of insulin secretion in relation to insulin resistance (IS-SI) will be calculated [ Time Frame: Change in index from baseline at 32-36 weeks,at 56 -60 weeks, and at study end (80-84 weeks) ] [ Designated as safety issue: No ]
β-cell compensatory capacity will be evaluated by the insulin sensitivity-secretion index (IS-SI) defined as the product of composite insulin sensitivity index and first-phase insulin release index (insulinogenic index).
• An index of insulin secretion in relation to insulin resistance (IS-SI) will be calculated [ Time Frame: Baseline,32-36,56-60,80-84 weeks ] [ Designated as safety issue: No ]
β-cell compensatory capacity will be evaluated by the insulin sensitivity-secretion index (IS-SI) defined as the product of composite insulin sensitivity index and first-phase insulin release index (insulinogenic index).
Complete list of historical versions of study NCT01234649 on ClinicalTrials.gov Archive Site
  • Insulin resistance -baseline {HOMA-IR} and composite insulin sensitivity index [ISIOGTT], and pancreatic ß-cell function (corrected insulin response [CIRglupeak] and insulinogenic index [IGI])/HOMA-IR [ Time Frame: Change in indexes from baseline at 32-36 weeks,at 56 -60 weeks, and at study end (80-84 weeks) ] [ Designated as safety issue: No ]
    Indexes of insulin sensitivity and secretion using the serum glucose and insulin concentrations obtained in the fasting state and during the 2hr OGTT with INS will be computed by several measures previously validated in women
  • Cardiometabolic risk measures [ Time Frame: Change in measures (lipids, liver enzymes, blood pressure) from baseline at 32-36 weeks,at 56 -60 weeks, and at study end (80-84 weeks) ] [ Designated as safety issue: No ]
    lipids, liver enzymes, blood pressure
  • Anthropometric measurements [ Time Frame: Change in measures of total and central adiposity from baseline at 32-36 weeks,at 56 -60 weeks, and at study end (80-84 weeks) ] [ Designated as safety issue: No ]
    body mass index (BMI), absolute body weight, waist circumference, waist: hip ratio
  • Development of dysglycemia [ Time Frame: Changes in glucose tolerance will be evaluated at baseline, at 32-36 weeks, at 56-60 weeks and at study end (80-84 weeks) ] [ Designated as safety issue: No ]
    Change in glycemic status from baseline. at 32-36 weeks, 56-60 weeks and at study end(80-84 weeks). Dysglycemia will be defined as impaired fasting glucose (IFG), impaired glucose tolerance (IGT), combined IFG/IGT and diabetic according to the American Diabetes Association. Patients diagnosed with diabetes will be withdrawn and referred to a specialized physician.
  • Insulin resistance -baseline {HOMA-IR} and composite insulin sensitivity index [ISIOGTT], and pancreatic ß-cell function (corrected insulin response [CIRglupeak] and insulinogenic index [IGI])/HOMA-IR [ Time Frame: Baseline,32-36,56-60,80-84 weeks ] [ Designated as safety issue: No ]
    Indexes of insulin sensitivity and secretion using the serum glucose and insulin concentrations obtained in the fasting state and during the 2hr OGTT with INS will be computed by several measures previously validated in women
  • Cardiometabolic risk measures [ Time Frame: Baseline,32-36,56-60,80-84 weeks ] [ Designated as safety issue: No ]
    lipids, liver enzymes, blood pressure
  • Anthropometric measurements [ Time Frame: Baseline,32-36,56-60 and 80-84 weeks ] [ Designated as safety issue: No ]
    BMI, absolute body weight, waist circumference, waist: hip ratio
  • • Development of diabetes, impaired glucose tolerance or impaired fasting glucose based on positive OGTT [ Time Frame: 32-36,56-60 and 80-84 weeks ] [ Designated as safety issue: No ]
    Glucose tolerance will be defined as normal, impaired glucose tolerance (IGT) or diabetic according to the criteria of the American Diabetes Association. Patients diagnosed with diabetes will be withdrawn from the study and referred to a specialized physician.
Not Provided
Not Provided
 
Combined Liraglutide and Metformin Therapy in Women With Previous Gestational Diabetes Mellitus (GDM)
Effects of Intervention With the Glucagon-like Peptide 1 (GLP-1) Analog Liraglutide Plus Metformin Versus Metformin Monotherapy in Overweight/Obese Women With Metabolic Defects and Recent History of Gestational Diabetes Mellitus (GDM)

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.

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

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Prevention
  • Gestational Diabetes Mellitus
  • Type 2 Diabetes Mellitus
  • Metabolic Syndrome
  • Impaired Glucose Tolerance
  • Disorder of Glucose Regulation
  • Drug: Metformin XR plus placebo
    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
    Other Name: Metformin XR is generic
  • Drug: Metformin XR plus liraglutide
    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 Name: Victoza
  • Experimental: Metformin XR plus liraglutide
    Metformin XR plus Liraglutide Metformin extended release (XR) 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) Liraglutide - start .6 mg SC QD step up to 1.2 mg to a max dose of 1.8 mg SC QD as tolerated
    Intervention: Drug: Metformin XR plus liraglutide
  • Active Comparator: Metformin XR plus placebo
    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
    Intervention: Drug: Metformin XR plus placebo
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
150
December 2015
August 2015   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Adult female 18 years to 45 years of age who experienced GDM within 52 weeks of index pregnancy
  • Actual BMI >25 kg/ m2
  • Written consent for participation in the study
  • Patient completed lactation
  • Dysglycemia (impaired fasting glucose [IFG}, impaired glucose tolerance [IGT} or IFG/IGT) and/or ß-cell dysfunction postpartum requiring pharmacological intervention (except type 1 or 2 diabetes)

Exclusion Criteria:

Personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2

  • History of pancreatitis
  • Significant cardiovascular, cerebrovascular, renal, or hepatobiliary diseases in the past (viral hepatitis, toxic hepatic damage, jaundice of unknown etiology)
  • Serum liver enzymes (AST and/or ALT levels) exceeding more than twice normal laboratory values
  • Uncontrolled hypertension (systolic blood pressure>150 mm Hg and/or diastolic blood pressure >90 mm Hg)
  • Fasting serum triglycerides ≥800 mg/dl at screening. Lipid-lowering medications must have been maintained at the same dose for 3 months prior to enrollment
  • Hematological profiles considered to be clinically significant
  • Cholestasis during the past pregnancy
  • Presence of contradictions for GLP-1 receptor agonist or metformin administration such as allergy or hypersensitivity
  • Current use of metformin, thiazolidinediones, dipeptidyl peptidase-4 inhibitors or GLP-1 receptor agonist medications.
  • Use of drugs known to exacerbate glucose tolerance.
  • Use of prescription or over-the-counter weight-loss drugs
  • Diabetes postpartum or history of diabetes or prior use of medications to treat diabetes except gestational diabetes
  • Creatinine clearance less than 60 ml/min
  • History or currently undergoing chemotherapy or radiotherapy for cancer
  • Pregnancy planned during the coming two years
  • Currently breastfeeding
  • Exclusion criteria include any condition, which in the opinion of the investigator would place the subject at increased risk or otherwise make the subject unsuitable for participation in the study
Female
18 Years to 45 Years
Yes
Contact: Karen E Elkind-Hirsch, Ph.D. 225-231-5278 karen.elkind-hirsch@womans.org
Contact: Martha Paterson, M.D. 225-924-8947 marth.paterson@womans.org
United States
 
NCT01234649
RP10-012
Yes
Karen Elkind-Hirsch, BC Women's Hospital & Health Centre
BC Women's Hospital & Health Centre
Novo Nordisk A/S
Principal Investigator: Karen E Elkind-Hirsch, Ph.D. Woman's Hospital
Study Director: Martha Paterson, M.D. Woman's Hospital
BC Women's Hospital & Health Centre
July 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP