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

Study Overview
=================
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

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)

Conditions
-----------------
Gestational Diabetes Mellitus, Type 2 Diabetes Mellitus, Metabolic Syndrome, Impaired Glucose Tolerance, Disorder of Glucose Regulation

Intervention / Treatment
-----------------
* Drug: Metformin XR plus placebo
* Drug: Metformin XR plus liraglutide


Participation Criteria
=================
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 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin XR plus liraglutide<br>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<br>* 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)<br>* Other names: Victoza;|
| Active Comparator: Metformin XR plus placebo<br>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<br>* 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<br>* 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
gestational diabetes mellitus, type 2 diabetes mellitus, metabolic dysfunction, impaired fasting glucose, impaired glucose tolerance, incretin mimetic