Disorder of Glucose Regulation
Conditions
Keywords
prediabetes, impaired fasting/impaired glucose tolerance, post gestational diabetes, diabetes prevention
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.
Interventions
Experimental -dipeptidyl peptidase-4 (DPP-4) inhibitor- oral medication
DRUGMetformin
Biguanide- insulin sensitizer
DRUGPlacebo pill
Will evaluate effect of lifestyle and diet only
Sponsors
Merck Sharp & Dohme LLC
Woman's
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 42 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Normalization of Glucose Levels | 16 weeks | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fasting Blood Glucose | 16 weeks | Blood glucose in the fasting state |
| Mean Blood Glucose Level From the Oral Glucose Tolerance Test (OGTT) | 16 weeks | 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.. |
| Fasting Insulin Resistance | 16 weeks | Insulin resistance calculated from fasting glucose and insulin levels known as HOMA-IR |
| Matsuda Index of Insulin Sensitivity | 16 weeks | Composite insulin sensitivity index calculated from from glucose and insulin levels obtained during the OGTT |
| Triglyceride/HDL-Cholesterol Ratio | 16 weeks | The ratio of triglyceride to HDL cholesterol is used as an indirect measure of insulin resistance |
| Body Mass Index | 16 weeks | Measure of body weight corrected by height |
| Waist Circumference | 16 weeks | Measure of central fat |
| Waist-to-Height Ratio | 16 weeks | Measure of central obesity adjusted for stature |
| Oral Disposition Index | 16 weeks | Measure of pancreatic beta cell compensatory action known as IS-SI |
Other
| Measure | Time frame | Description |
|---|---|---|
| Liver Enzymes as Safety Measure | 16 weeks | Number of patients with no clinically significant changes in liver enzymes-measure of liver enzymes was a study safety endpoint |
Countries
United States
Participant flow
Recruitment details
The study was conducted from November 2014 to September 2017. Patients were recruited from the Woman's Hospital Metabolic Clinic
Pre-assignment details
. Patients were eligible for randomization if they had impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or both (IFG/IGT) by OGTT. Patients with diabetes or normal glucose tolerance were excluded.
Participants by arm
| Arm | Count |
|---|---|
| Sitagliptin-Metformin 50 mg/1000 mg BID
Sitagliptin-Metformin: Experimental -DPP-4 inhibitor- oral medication | 12 |
| Placebo Pill 1 pill/BID for 16 weeks
Placebo pill: Will evaluate effect of lifestyle and diet only | 12 |
| Metformin 1000 mg BID
Metformin: Biguanide- insulin sensitizer | 12 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Pregnancy | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Sitagliptin-Metformin | Placebo Pill | Metformin | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 12 Participants | 12 Participants | 36 Participants |
| Hyperglycemia | 12 Participants | 12 Participants | 12 Participants | 36 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 2 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 9 Participants | 10 Participants | 29 Participants |
| Region of Enrollment United States | 12 participants | 12 participants | 12 participants | 36 participants |
| Sex/Gender, Customized Patients | 12 Participants | 12 Participants | 12 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 3 / 12 | 0 / 12 | 3 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 0 / 12 |
Outcome results
Primary
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
Time frame: 16 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sitagliptin-Metformin | Normalization of Glucose Levels | 9 Participants |
| Placebo Pill | Normalization of Glucose Levels | 2 Participants |
| Metformin | Normalization of Glucose Levels | 4 Participants |
Comparison: Study change from dysglycemia to normal glucose statep-value: 0.035McNemar
Secondary
Body Mass Index
Measure of body weight corrected by height
Time frame: 16 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin-Metformin | Body Mass Index | 32.6 kg/meters^2 | Standard Deviation 8 |
| Placebo Pill | Body Mass Index | 33.5 kg/meters^2 | Standard Deviation 9 |
| Metformin | Body Mass Index | 33.6 kg/meters^2 | Standard Deviation 6 |
Comparison: Factorial repeated measures ANOVA with Bonferroni contrast testp-value: 0.002ANOVA
Secondary
Fasting Blood Glucose
Blood glucose in the fasting state
Time frame: 16 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin-Metformin | Fasting Blood Glucose | 96 mg/dL | Standard Deviation 13 |
| Placebo Pill | Fasting Blood Glucose | 101 mg/dL | Standard Deviation 13 |
| Metformin | Fasting Blood Glucose | 93 mg/dL | Standard Deviation 6 |
Comparison: Subjects (SS)/ Treatment Group x repeated measures (visit) designp-value: 0.044ANOVA
Secondary
Fasting Insulin Resistance
Insulin resistance calculated from fasting glucose and insulin levels known as HOMA-IR
Time frame: 16 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin-Metformin | Fasting Insulin Resistance | 2.4 index | Standard Deviation 1.2 |
| Placebo Pill | Fasting Insulin Resistance | 4.7 index | Standard Deviation 3.8 |
| Metformin | Fasting Insulin Resistance | 2.6 index | Standard Deviation 1.7 |
Comparison: Factorial repeated measures ANOVA with Bonferroni contrast testp-value: 0.047ANOVA
Secondary
Matsuda Index of Insulin Sensitivity
Composite insulin sensitivity index calculated from from glucose and insulin levels obtained during the OGTT
Time frame: 16 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin-Metformin | Matsuda Index of Insulin Sensitivity | 6.2 index | Standard Deviation 3.9 |
| Placebo Pill | Matsuda Index of Insulin Sensitivity | 5.0 index | Standard Deviation 4.9 |
| Metformin | Matsuda Index of Insulin Sensitivity | 5.2 index | Standard Deviation 4 |
Comparison: Factorial repeated measures ANOVA with Bonferroni contrast testp-value: 0.017ANOVA
Secondary
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..
Time frame: 16 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin-Metformin | Mean Blood Glucose Level From the Oral Glucose Tolerance Test (OGTT) | 113 mg/dL | Standard Deviation 19 |
| Placebo Pill | Mean Blood Glucose Level From the Oral Glucose Tolerance Test (OGTT) | 132 mg/dL | Standard Deviation 17 |
| Metformin | Mean Blood Glucose Level From the Oral Glucose Tolerance Test (OGTT) | 143 mg/dL | Standard Deviation 20 |
Comparison: Factorial repeated measures ANOVA with Bonferroni contrast testp-value: 0.034ANOVA
Secondary
Oral Disposition Index
Measure of pancreatic beta cell compensatory action known as IS-SI
Time frame: 16 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin-Metformin | Oral Disposition Index | 427 index | Standard Deviation 231 |
| Placebo Pill | Oral Disposition Index | 194 index | Standard Deviation 93 |
| Metformin | Oral Disposition Index | 170 index | Standard Deviation 109 |
Comparison: Factorial repeated measures ANOVA with Bonferroni contrast testp-value: 0.014ANOVA
Secondary
Triglyceride/HDL-Cholesterol Ratio
The ratio of triglyceride to HDL cholesterol is used as an indirect measure of insulin resistance
Time frame: 16 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin-Metformin | Triglyceride/HDL-Cholesterol Ratio | 3.3 Ratio | Standard Deviation 1.4 |
| Placebo Pill | Triglyceride/HDL-Cholesterol Ratio | 4.5 Ratio | Standard Deviation 3.1 |
| Metformin | Triglyceride/HDL-Cholesterol Ratio | 2.7 Ratio | Standard Deviation 1.5 |
Comparison: Factorial repeated measures ANOVA with Bonferroni contrast testp-value: 0.042ANOVA
Secondary
Waist Circumference
Measure of central fat
Time frame: 16 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin-Metformin | Waist Circumference | 90 centimeters | Standard Deviation 14 |
| Placebo Pill | Waist Circumference | 93 centimeters | Standard Deviation 17 |
| Metformin | Waist Circumference | 93 centimeters | Standard Deviation 13 |
Comparison: Factorial repeated measures ANOVA with Bonferroni contrast testp-value: 0.004ANOVA
Secondary
Waist-to-Height Ratio
Measure of central obesity adjusted for stature
Time frame: 16 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin-Metformin | Waist-to-Height Ratio | .54 Ratio | Standard Deviation 0.09 |
| Placebo Pill | Waist-to-Height Ratio | .57 Ratio | Standard Deviation 0.1 |
| Metformin | Waist-to-Height Ratio | .58 Ratio | Standard Deviation 0.07 |
Comparison: Factorial repeated measures ANOVA with Bonferroni contrast testp-value: 0.004ANOVA
Other Pre-specified
Liver Enzymes as Safety Measure
Number of patients with no clinically significant changes in liver enzymes-measure of liver enzymes was a study safety endpoint
Time frame: 16 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sitagliptin-Metformin | Liver Enzymes as Safety Measure | 0 Participants |
| Placebo Pill | Liver Enzymes as Safety Measure | 0 Participants |
| Metformin | Liver Enzymes as Safety Measure | 0 Participants |
p-value: 0.9Fisher Exact