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
  Purpose

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.


Condition Intervention Phase
Gestational Diabetes Mellitus
Type 2 Diabetes Mellitus
Metabolic Syndrome
Impaired Glucose Tolerance
Disorder of Glucose Regulation
Drug: Metformin XR plus placebo
Drug: Metformin XR plus liraglutide
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Prevention
Official Title: 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)

Resource links provided by NLM:


Further study details as provided by BC Women's Hospital & Health Centre:

Primary Outcome Measures:
  • 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).


Secondary Outcome Measures:
  • 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.


Estimated Enrollment: 150
Study Start Date: August 2011
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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
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
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
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

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

  Eligibility

Ages Eligible for Study:   18 Years to 45 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01234649

Contacts
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

Locations
United States, Louisiana
Woman's Hospital Recruiting
Baton Rouge, Louisiana, United States, 70815
Principal Investigator: Karen Elkind-Hirsch, Ph.D.         
Sub-Investigator: Martha Paterson, M.D.         
Sponsors and Collaborators
BC Women's Hospital & Health Centre
Novo Nordisk A/S
Investigators
Principal Investigator: Karen E Elkind-Hirsch, Ph.D. Woman's Hospital
Study Director: Martha Paterson, M.D. Woman's Hospital
  More Information

No publications provided

Responsible Party: Karen Elkind-Hirsch, Scientific Director of Research, BC Women's Hospital & Health Centre
ClinicalTrials.gov Identifier: NCT01234649     History of Changes
Other Study ID Numbers: RP10-012
Study First Received: November 3, 2010
Last Updated: July 14, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by BC Women's Hospital & Health Centre:
gestational diabetes mellitus
type 2 diabetes mellitus
metabolic dysfunction
impaired fasting glucose
impaired glucose tolerance
incretin mimetic

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Metabolic Syndrome X
Diabetes, Gestational
Glucose Intolerance
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Insulin Resistance
Hyperinsulinism
Pregnancy Complications
Hyperglycemia
Liraglutide
Metformin
Glucagon-Like Peptide 1
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists

ClinicalTrials.gov processed this record on September 30, 2014