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

NCT ID: NCT01234649

Last Updated: 2019-07-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 153 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-08-11
• Study Completion Date: 2019-06-14

Brief 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

Conditions

Gestational Diabetes Mellitus; Type 2 Diabetes Mellitus; Metabolic Syndrome; Impaired Glucose Tolerance; Disorder of Glucose Regulation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: TRIPLE

Study Groups

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- 84 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

Group Type: EXPERIMENTAL

Metformin XR plus liraglutide

Intervention Type: DRUG

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)

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 -84 weeks (end study) Placebo-start 1 injection SC QD step up to a max dose as tolerated

Group Type: ACTIVE_COMPARATOR

Metformin XR plus placebo

Intervention Type: DRUG

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

Interventions

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 Type: 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)

Intervention Type: DRUG

Other Intervention Names

Metformin XR is generic; Victoza

Eligibility 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

Novo Nordisk A/S

INDUSTRY

Sponsor Role: collaborator

Woman's

OTHER

Sponsor Role: lead

Responsible Party

Karen Elkind-Hirsch

Scientific Director of Research

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Karen E Elkind-Hirsch, Ph.D.

Role: PRINCIPAL_INVESTIGATOR

Woman's Hospital, Louisiana

Renee Harris, M.D.

Role: STUDY_DIRECTOR

Woman's Hospital, Louisiana

Locations

Woman's Hospital

Baton Rouge, Louisiana, United States

Countries

United States

References

Elkind-Hirsch KE, Shaler D, Harris R. Postpartum treatment with liraglutide in combination with metformin versus metformin monotherapy to improve metabolic status and reduce body weight in overweight/obese women with recent gestational diabetes: A double-blind, randomized, placebo-controlled study. J Diabetes Complications. 2020 Apr;34(4):107548. doi: 10.1016/j.jdiacomp.2020.107548. Epub 2020 Feb 1.

Reference Type: DERIVED

PMID: 32046931 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

RP10-012

Identifier Type: -

Identifier Source: org_study_id