Clinical trial NCT01234649: Combined Liraglutide and Metformin Therapy in Women With Previous Gestational Diabetes Mellitus (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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Gestational Diabetes Mellitus
Type 2 Diabetes Mellitus
Metabolic Syndrome
Impaired Glucose Tolerance
Disorder of Glucose Regulation
Keywords: gestational diabetes mellitus
type 2 diabetes mellitus
metabolic dysfunction
impaired fasting glucose
impaired glucose tolerance
incretin mimetic
Lead sponsor: Woman's
Sponsor class: OTHER
Collaborators: name: Novo Nordisk A/S
First posted: 2010-11-04
Enrollment: 153
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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

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

Primary outcomes:
measure: Insulin Secretion-Sensitivity Index (IS-SI)
timeFrame: 84 weeks of treatment
Secondary outcomes:
measure: Fasting Blood Glucose (FBG)
timeFrame: 84 weeks of treatment
measure: Mean Glucose During OGTT (MBG)
timeFrame: 84 weeks of treatment
measure: Homeostasis Model Assessment of Insulin Resistance (HOMA-IR)
timeFrame: 84 weeks of treatment
measure: Matsuda Insulin Sensitivity Index Derived From OGTT
timeFrame: 84 weeks of treatment
measure: Insulinogenic Index (IGI) /HOMA-IR
timeFrame: 84 weeks of treatment
measure: Absolute Body Weight
timeFrame: 84 weeks of treatment
measure: Change in Body Weight From Baseline to End of Study (Expressed as % Compared to Baseline)
timeFrame: Change from baseline (time 0) to study end (84 weeks)
measure: Body Mass Index (BMI)
timeFrame: 84 weeks of treatment
measure: Waist Circumference (WC)
timeFrame: 84 weeks of treatment
measure: Waist-to-Hip Ratio (WHR)
timeFrame: 84 weeks of treatment
measure: Waist to Height Ratio (WHtR)
timeFrame: 84 weeks of treatment
measure: Total Cholesterol (CHOL) Levels
timeFrame: 84 weeks of treatment
measure: High Density Lipoprotein Cholesterol (HDL-C) Levels
timeFrame: 84 weeks of treatment
measure: Low Density Lipoprotein Cholesterol (LDL-C) Levels
timeFrame: 84 weeks of treatment
measure: Triglyceride (TRG) Levels
timeFrame: 84 weeks of treatment
measure: Triglyceride to High Density Lipoprotein Cholesterol Ratio TRG/HDL-C)
timeFrame: 84 weeks of treatment
measure: Systolic Blood Pressure
timeFrame: 84 weeks of treatment
measure: Diastolic Blood Pressure
timeFrame: 84 weeks of treatment
measure: Alanine Aminotransferase (ALT) Levels
timeFrame: 84 weeks of treatment
measure: Aspartate Aminotransferase (AST)
timeFrame: 84 weeks of treatment
measure: Alanine Aminotransferase /Aspartate Aminotransferase (ALT/AST) Ratio
timeFrame: 84 weeks of treatment
Other outcomes:
Locations:
city: Baton Rouge
country: United States
facility: Woman's Hospital
state: Louisiana
Study officials:
affiliation: Woman's Hospital, Louisiana
name: Karen E Elkind-Hirsch, Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Woman's Hospital, Louisiana
name: Renee Harris, M.D.
role: STUDY_DIRECTOR
References:
citation: 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.