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

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

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