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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Disorder of Glucose Regulation

Intervention / Treatment
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* Drug: Sitagliptin-Metformin
* Drug: Metformin
* Drug: Placebo pill


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 42 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sitagliptin-Metformin<br>50 mg/1000 mg twice a day (BID) | Drug: Sitagliptin-Metformin<br>* Experimental -dipeptidyl peptidase-4 (DPP-4) inhibitor- oral medication<br>* Other names: Janumet;|
| Placebo Comparator: Placebo pill<br>1 pill/BID for 16 weeks | Drug: Placebo pill<br>* Will evaluate effect of lifestyle and diet only<br>* Other names: placebo control;|
| Active Comparator: Metformin<br>1000 mg BID | Drug: Metformin<br>* Biguanide- insulin sensitizer<br>* Other names: Glucophage;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Normalization of Glucose Levels | Normalization of glucose in patients with abnormal glucose levels is defined as a fasting glucose level of <100 mg/dL and a 2-hour glucose level following a 75 gram oral glucose load of <140 mg/dL | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fasting Blood Glucose | Blood glucose in the fasting state | 16 weeks | 
| Mean Blood Glucose Level From the Oral Glucose Tolerance Test (OGTT) | The mean blood glucose is calculated by averaging the 4 blood glucose levels measure during a 75 gm oral glucose tolerance test . This involves summing the glucose levels measured at baseline, and 1/2 hour,1 hour and 2 hours after the glucose load and dividing by 4.. | 16 weeks | 
| Fasting Insulin Resistance | Insulin resistance calculated from fasting glucose and insulin levels known as HOMA-IR | 16 weeks | 
| Matsuda Index of Insulin Sensitivity | Composite insulin sensitivity index calculated from from glucose and insulin levels obtained during the OGTT | 16 weeks | 
| Oral Disposition Index | Measure of pancreatic beta cell compensatory action known as IS-SI | 16 weeks | 
| Triglyceride/HDL-Cholesterol Ratio | The ratio of triglyceride to HDL cholesterol is used as an indirect measure of insulin resistance | 16 weeks | 
| Body Mass Index | Measure of body weight corrected by height | 16 weeks | 
| Waist Circumference | Measure of central fat | 16 weeks | 
| Waist-to-Height Ratio | Measure of central obesity adjusted for stature | 16 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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prediabetes, impaired fasting/impaired glucose tolerance, post gestational diabetes, diabetes prevention