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

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

Sponsors

Lead sponsor: Woman's

Collaborator: Merck Sharp & Dohme Corp.

Source Woman's
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.

Overall Status Completed
Start Date September 28, 2013
Completion Date September 28, 2017
Primary Completion Date September 5, 2017
Phase Phase 4
Study Type Interventional
Primary Outcome
Measure Time Frame
Normalization of Glucose Levels 16 weeks
Secondary Outcome
Measure Time Frame
Fasting Blood Glucose 16 weeks
Mean Blood Glucose Level From the Oral Glucose Tolerance Test (OGTT) 16 weeks
Fasting Insulin Resistance 16 weeks
Matsuda Index of Insulin Sensitivity 16 weeks
Oral Disposition Index 16 weeks
Triglyceride/HDL-Cholesterol Ratio 16 weeks
Body Mass Index 16 weeks
Waist Circumference 16 weeks
Waist-to-Height Ratio 16 weeks
Enrollment 36
Condition
Intervention

Intervention type: Drug

Intervention name: Sitagliptin-Metformin

Description: Experimental -dipeptidyl peptidase-4 (DPP-4) inhibitor- oral medication

Arm group label: Sitagliptin-Metformin

Other name: Janumet

Intervention type: Drug

Intervention name: Metformin

Description: Biguanide- insulin sensitizer

Arm group label: Metformin

Other name: Glucophage

Intervention type: Drug

Intervention name: Placebo pill

Description: Will evaluate effect of lifestyle and diet only

Arm group label: Placebo pill

Other name: placebo control

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)

Gender: Female

Minimum age: 18 Years

Maximum age: 42 Years

Healthy volunteers: No

Overall Official
Location
facility Woman's Hospital
Location Countries

United States

Verification Date

January 2018

Responsible Party

Responsible party type: Principal Investigator

Investigator affiliation: Woman's

Investigator full name: Karen Elkind-Hirsch

Investigator title: Director of Research

Keywords
Has Expanded Access No
Number Of Arms 3
Arm Group

Arm group label: Sitagliptin-Metformin

Arm group type: Experimental

Description: 50 mg/1000 mg twice a day (BID)

Arm group label: Placebo pill

Arm group type: Placebo Comparator

Description: 1 pill/BID for 16 weeks

Arm group label: Metformin

Arm group type: Active Comparator

Description: 1000 mg BID

Patient Data No
Study Design Info

Allocation: Randomized

Intervention model: Parallel Assignment

Primary purpose: Treatment

Masking: Single (Investigator)

Source: ClinicalTrials.gov