Sitagliptin + Metformin Compared to Metformin Monotherapy and Placebo in Women With a Recent GDM

Gestational diabetes mellitus (GDM) is defined as "any degree of glucose intolerance with
onset or first recognition during pregnancy." GDM is one of the most frequent metabolic
disorders occurring during pregnancy. Approximately 7% of all pregnancies in the United
States are complicated by gestational diabetes resulting in more than 200,000 cases annually.
There is epidemiologic evidence associating GDM with insulin resistance, glucose intolerance,
and type 2 diabetes (DM2). Among all the risk factors of diabetes mellitus, the experience of
gestational diabetes is the strongest one.

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.
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. 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.
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. Inhibition of dipeptidyl peptidase-4 (DPP-4) increases the concentration of
GLP-1 and 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 combination sitagliptin-plus metformin is more effective than metformin alone or
placebo in improving metabolic parameters, specifically the impact on β-cell function, in
at-risk women with a recent history of GDM.

Inclusion Criteria:

- Females 18 years to 42 years of age who experienced gestational diabetes mellitus
(GDM) during recent (within 12 months) pregnancy with prediabetic hyperglycemia
determined by an oral glucose tolerance test (OGTT) with 75 g glucose postpartum.
Study subjects will be inclusive of prior GDM women with impaired fasting glucose
(IFG), impaired glucose tolerance (IGT), or both (IFG/IGT) postpartum.

- Written consent for participation in the study

Exclusion Criteria:

- Cholestasis during the past pregnancy

- Any hepatic diseases in the past (viral hepatitis, toxic hepatic damage, jaundice of
unknown etiology)

- Serum aspartate transaminase (AST) and/or alanine aminotransferase (ALT) level
exceeding more than twice normal lab values

- Presence of hypersensitivity to sitagliptin or other DPP-4 inhibitor

- Current use of metformin, thiazolidinediones, GLP-1 receptor agonists, DPP-4
inhibitors, or weight loss medications (prescription or over the counter [OTC])

- Prior use of medication to treat diabetes except gestational diabetes

- Use of drugs known to exacerbate glucose tolerance

- History of diabetes or prior use of medications to treat diabetes except GDM

- Creatinine clearance less than 60 ml/min

- Pregnancy planned during the coming two years

- Currently lactating

- Patient not willing to use adequate contraception during study period (unless
sterilized)