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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus; Metabolic Syndrome; Impaired Glucose Tolerance; Gestational Diabetes Mellitus; Disorder of Glucose Regulation
• Intervention / Treatment: Drug: Metformin XR plus liraglutide; Drug: Metformin XR plus placebo

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 Type: Interventional
• Enrollment (Actual): 153
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70815
      • Woman's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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 Names: Metformin XR is generic

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin Secretion-Sensitivity Index (IS-SI)	IS-SI in liraglutide-metformin (LIRA-MET) therapy compared to metformin alone (PLacebo-MET)	84 weeks of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fasting Blood Glucose (FBG)	Fasting glucose levels in LIRA-MET group compared with PL-MET group	84 weeks of treatment
Mean Glucose During OGTT (MBG)	MBG derived from average glucose measured during OGTT in LIRA-MET group compared with PL-MET group	84 weeks of treatment
Homeostasis Model Assessment of Insulin Resistance (HOMA-IR)	HOMA-IR, a measure of insulin resistance derived from fasting values, in LIRA-MET group compared with PL-MET group	84 weeks of treatment
Matsuda Insulin Sensitivity Index Derived From OGTT	OGTT- derived insulin sensitivity index in LIRA-MET group compared with PL-MET group	84 weeks of treatment
Insulinogenic Index (IGI) /HOMA-IR	IGI/HOMA-IR, a measure of early insulin response corrected by fasting insulin resistance, in LIRA-MET group compared with PL-MET group	84 weeks of treatment
Absolute Body Weight	Body weight in LIRA-MET group compared with PL-MET group	84 weeks of treatment
Change in Body Weight From Baseline to End of Study (Expressed as % Compared to Baseline)	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.	Change from baseline (time 0) to study end (84 weeks)
Body Mass Index (BMI)	BMI, a measure of total body adiposity, in LIRA-MET group compared with PL-MET group	84 weeks of treatment
Waist Circumference (WC)	Waist size (measure of truncal adiposity) with LIRA-MET compared to PL-MET	84 weeks of treatment
Waist-to-Hip Ratio (WHR)	Waist circumference divided by hip circumference (a measure of central adiposity) in LIRA-MET group compared with PL-MET group	84 weeks of treatment
Waist to Height Ratio (WHtR)	Waist circumference divided by height (measure of body fat distribution) in LIRA-MET group compared with PL-MET group	84 weeks of treatment
Total Cholesterol (CHOL) Levels	CHOL levels in LIRA-MET group compared with PL-MET group	84 weeks of treatment
High Density Lipoprotein Cholesterol (HDL-C) Levels	HDL-C levels in LIRA-MET group compared with PL-MET group	84 weeks of treatment
Low Density Lipoprotein Cholesterol (LDL-C) Levels	LDL-Cholesterol levels in LIRA-MET group compared with PL-MET group	84 weeks of treatment
Triglyceride (TRG) Levels	TRG concentrations in LIRA-MET group compared with PL-MET group	84 weeks of treatment
Triglyceride to High Density Lipoprotein Cholesterol Ratio TRG/HDL-C)	TRG/HDL-Cholesterol levels in LIRA-MET group compared with PL-MET group	84 weeks of treatment
Systolic Blood Pressure	SBP in LIRA-MET group compared with PL-MET group	84 weeks of treatment
Diastolic Blood Pressure	DBP in LIRA-MET group compared with PL-MET group	84 weeks of treatment
Alanine Aminotransferase (ALT) Levels	Hepatic enzyme, ALT, associated with insulin resistance, in LIRA-MET group compared with PL-MET group	84 weeks of treatment
Aspartate Aminotransferase (AST)	The hepatic marker, AST, associated with insulin resistance in LIRA-MET group compared with PL-MET group	84 weeks of treatment
Alanine Aminotransferase /Aspartate Aminotransferase (ALT/AST) Ratio	ALT/AST ratio, used to assess liver function in LIRA-MET group compared with PL-MET group	84 weeks of treatment

Collaborators and Investigators

• Sponsor: Woman's
• Collaborators: 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

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): August 11, 2011
• Primary Completion (Actual): April 24, 2019
• Study Completion (Actual): June 14, 2019

Study Registration Dates

• First Submitted: November 3, 2010
• First Submitted That Met QC Criteria: November 3, 2010
• First Posted (Estimate): November 4, 2010

Study Record Updates

• Last Update Posted (Actual): July 26, 2019
• Last Update Submitted That Met QC Criteria: July 19, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: type 2 diabetes mellitus; gestational diabetes mellitus; impaired fasting glucose; metabolic dysfunction; impaired glucose tolerance; incretin mimetic
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Insulin Resistance; Hyperinsulinism; Pregnancy Complications; Hyperglycemia; Diabetes Mellitus; Diabetes Mellitus, Type 2; Metabolic Syndrome; Glucose Intolerance; Diabetes, Gestational; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Liraglutide; Metformin
• Other Study ID Numbers: RP10-012

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No