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

• ClinicalTrials.gov Identifier: NCT01234649
• Recruitment Status: Completed
• First Posted: November 4, 2010
• Results First Posted: July 26, 2019
• Last Update Posted: July 26, 2019
• Sponsor: Woman's
• Collaborator: Novo Nordisk A/S
• Information provided by (Responsible Party): Karen Elkind-Hirsch, Woman's

Study Description

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.

Condition or disease	Intervention/treatment	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

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 153 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, 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)
• Actual Study Start Date: August 11, 2011
• Actual Primary Completion Date: April 24, 2019
• Actual Study Completion Date: June 14, 2019

Arms and Interventions

Arm	Intervention/treatment
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- 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	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 -84 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

Outcome Measures

Primary Outcome Measures :

1. Insulin Secretion-Sensitivity Index (IS-SI) [ Time Frame: 84 weeks of treatment ]
   IS-SI in liraglutide-metformin (LIRA-MET) therapy compared to metformin alone (PLacebo-MET)

Secondary Outcome Measures :

1. Fasting Blood Glucose (FBG) [ Time Frame: 84 weeks of treatment ]
   Fasting glucose levels in LIRA-MET group compared with PL-MET group
2. Mean Glucose During OGTT (MBG) [ Time Frame: 84 weeks of treatment ]
   MBG derived from average glucose measured during OGTT in LIRA-MET group compared with PL-MET group
3. Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) [ Time Frame: 84 weeks of treatment ]
   HOMA-IR, a measure of insulin resistance derived from fasting values, in LIRA-MET group compared with PL-MET group
4. Matsuda Insulin Sensitivity Index Derived From OGTT [ Time Frame: 84 weeks of treatment ]
   OGTT- derived insulin sensitivity index in LIRA-MET group compared with PL-MET group
5. Insulinogenic Index (IGI) /HOMA-IR [ Time Frame: 84 weeks of treatment ]
   IGI/HOMA-IR, a measure of early insulin response corrected by fasting insulin resistance, in LIRA-MET group compared with PL-MET group
6. Absolute Body Weight [ Time Frame: 84 weeks of treatment ]
   Body weight in LIRA-MET group compared with PL-MET group
7. Change in Body Weight From Baseline to End of Study (Expressed as % Compared to Baseline) [ Time Frame: Change from baseline (time 0) to study end (84 weeks) ]
   Change in body weight from baseline to end o f study in LIRA-MET group compared with PL-MET group. The number was derived from final weight minus baseline and normalized to a percent.
8. Body Mass Index (BMI) [ Time Frame: 84 weeks of treatment ]
   BMI, a measure of total body adiposity, in LIRA-MET group compared with PL-MET group
9. Waist Circumference (WC) [ Time Frame: 84 weeks of treatment ]
   Waist size (measure of truncal adiposity) with LIRA-MET compared to PL-MET
10. Waist-to-Hip Ratio (WHR) [ Time Frame: 84 weeks of treatment ]
    Waist circumference divided by hip circumference (a measure of central adiposity) in LIRA-MET group compared with PL-MET group
11. Waist to Height Ratio (WHtR) [ Time Frame: 84 weeks of treatment ]
    Waist circumference divided by height (measure of body fat distribution) in LIRA-MET group compared with PL-MET group
12. Total Cholesterol (CHOL) Levels [ Time Frame: 84 weeks of treatment ]
    CHOL levels in LIRA-MET group compared with PL-MET group
13. High Density Lipoprotein Cholesterol (HDL-C) Levels [ Time Frame: 84 weeks of treatment ]
    HDL-C levels in LIRA-MET group compared with PL-MET group
14. Low Density Lipoprotein Cholesterol (LDL-C) Levels [ Time Frame: 84 weeks of treatment ]
    LDL-Cholesterol levels in LIRA-MET group compared with PL-MET group
15. Triglyceride (TRG) Levels [ Time Frame: 84 weeks of treatment ]
    TRG concentrations in LIRA-MET group compared with PL-MET group
16. Triglyceride to High Density Lipoprotein Cholesterol Ratio TRG/HDL-C) [ Time Frame: 84 weeks of treatment ]
    TRG/HDL-Cholesterol levels in LIRA-MET group compared with PL-MET group
17. Systolic Blood Pressure [ Time Frame: 84 weeks of treatment ]
    SBP in LIRA-MET group compared with PL-MET group
18. Diastolic Blood Pressure [ Time Frame: 84 weeks of treatment ]
    DBP in LIRA-MET group compared with PL-MET group
19. Alanine Aminotransferase (ALT) Levels [ Time Frame: 84 weeks of treatment ]
    Hepatic enzyme, ALT, associated with insulin resistance, in LIRA-MET group compared with PL-MET group
20. Aspartate Aminotransferase (AST) [ Time Frame: 84 weeks of treatment ]
    The hepatic marker, AST, associated with insulin resistance in LIRA-MET group compared with PL-MET group
21. Alanine Aminotransferase /Aspartate Aminotransferase (ALT/AST) Ratio [ Time Frame: 84 weeks of treatment ]
    ALT/AST ratio, used to assess liver function in LIRA-MET group compared with PL-MET group

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 45 Years (Adult)
• Sexes 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

Locations

United States, Louisiana

Woman's Hospital

Baton Rouge, Louisiana, United States, 70815

Sponsors and Collaborators

Woman's

Novo Nordisk A/S

Investigators

• Principal Investigator: Karen E Elkind-Hirsch, Ph.D.; Woman's Hospital, Louisiana
• Study Director: Renee Harris, M.D.; Woman's Hospital, Louisiana

  Study Documents (Full-Text)

Documents provided by Karen Elkind-Hirsch, Woman's:

Study Protocol and Statistical Analysis Plan  [PDF] September 19, 2017

Informed Consent Form  [PDF] September 21, 2017

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Karen Elkind-Hirsch, Scientific Director of Research, Woman's
• ClinicalTrials.gov Identifier: NCT01234649
• Other Study ID Numbers: RP10-012
• First Posted: November 4, 2010
• Results First Posted: July 26, 2019
• Last Update Posted: July 26, 2019
• Last Verified: July 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Karen Elkind-Hirsch, Woman's:

gestational diabetes mellitus; type 2 diabetes mellitus; metabolic dysfunction; impaired fasting glucose; impaired glucose tolerance; incretin mimetic

Additional relevant MeSH terms:

Diabetes, Gestational; Diabetes Mellitus; Diabetes Mellitus, Type 2; Metabolic Syndrome; Glucose Intolerance; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Insulin Resistance; Hyperinsulinism; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Hyperglycemia; Metformin; Liraglutide; Hypoglycemic Agents; Physiological Effects of Drugs; Incretins; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists