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

Phase 3

Completed

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

Interventions: Drug: Metformin XR plus placebo
Drug: Metformin XR plus liraglutide

Registration Number: NCT01234649

Lead Sponsor: Woman's

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

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 153

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Metformin XR plus placebo	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
Metformin XR plus liraglutide	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

Primary Outcome Measures

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

Secondary Outcome Measures

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