Clinical trial NCT01856907: Sitagliptin + Metformin Compared to Metformin Monotherapy and Placebo in Women With a Recent GDM
Official title: A Randomized Pilot Study Evaluating Combination Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Plus Metformin Compared to Metformin Monotherapy and Placebo on Metabolic Abnormalities in Women With a Recent History of GDM
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Disorder of Glucose Regulation
Keywords: prediabetes
impaired fasting/impaired glucose tolerance
post gestational diabetes
diabetes prevention
Lead sponsor: Woman's
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2013-05-20
Enrollment: 36
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 42
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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. 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. Studies are needed for optimal postpartum and long-term health of women who have had GDM. 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 DM2. 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 (a DPP-4 inhibitor)-plus metformin is more effective than metformin alone or placebo in improving metabolic parameters, specifically the impact on β-cell function, in prior GDM women with glucose abnormalities.

Detailed description: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Normalization of Glucose Levels
timeFrame: 16 weeks
Secondary outcomes:
measure: Fasting Blood Glucose
timeFrame: 16 weeks
measure: Mean Blood Glucose Level From the Oral Glucose Tolerance Test (OGTT)
timeFrame: 16 weeks
measure: Fasting Insulin Resistance
timeFrame: 16 weeks
measure: Matsuda Index of Insulin Sensitivity
timeFrame: 16 weeks
measure: Oral Disposition Index
timeFrame: 16 weeks
measure: Triglyceride/HDL-Cholesterol Ratio
timeFrame: 16 weeks
measure: Body Mass Index
timeFrame: 16 weeks
measure: Waist Circumference
timeFrame: 16 weeks
measure: Waist-to-Height Ratio
timeFrame: 16 weeks
Other outcomes:
measure: Liver Enzymes as Safety Measure
timeFrame: 16 weeks
Locations:
city: Baton Rouge
country: United States
facility: Woman's Hospital
state: Louisiana
Study officials:
affiliation: Woman's Hospital, Louisiana
name: Karen Elkind-Hirsch, Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Woman's Hospital, Louisiana
name: Martha Paterson, M.D.
role: PRINCIPAL_INVESTIGATOR
References: