Type 2 Diabetes
Conditions
Keywords
diabetes, continuous glucose monitoring, exenatide, insulin glargine
Brief summary
The primary purpose of this study is to compare the effect on 24-hour blood glucose patterns, HbA1c, and weight management when adding insulin glargine, or exenatide, or a combination of insulin glargine and exenatide to metformin.
Detailed description
The primary objective of this study was to characterize the diurnal glucose patterns produced by insulin glargine alone, exenatide (GLP-1 agonist) alone and the combination of insulin glargine and exenatide in subjects taking stable dose of metformin and to evaluate their efficacy in terms of improvement in glucose exposure, variability, stability, incidence of hypoglycemia and weight management. An ancillary study was approved as part of this study. The purpose of the ancillary study was to use CGM to characterize the glycemic response to a fixed breakfast meal consumed by study participants receiving different medications.
Interventions
DRUGExenatide
5 mcg BID (twice daily) for 1 month increasing to 10 mcg BID for the remainder of the study
DRUGInsulin Glargine
.1 unit per kg to start, titrated based on Continuous Glucose Monitoring results
Sponsors
International Diabetes Center at Park Nicollet
Sanofi
HealthPartners Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Subjects were randomized and then told the medications they were randomized to. Since the medications were already on the market, there was no need for masking for any involved individuals.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Male or female subjects ≥18 and ≤75 years of age * Clinical diagnosis of type 2 diabetes * Diabetes duration ≥ 1 year * HbA1c ≥7.0% * Currently treated with metformin (HbA1c ≤9%) or metformin/sulfonylurea (SU) (HbA1c ≤8%)or SU alone (HbA1c ≤8%)
Exclusion criteria
* Previously treated with insulin or incretin-based therapy * Treated with a thiazolidinedione within past 6 weeks * Taken oral or injected prednisone or cortisone medications in the previous 30 days * Any pancreatic disease or at high risk of pancreatitis (history of alcohol abuse, active gallbladder disease) * Serum creatinine \>1.4mg/dL (women) or \>1.5 mg/dL (men) * eGFR (Estimated Glomerular Filtration Rate) \<30 ml/min (using MDRD/ Modification of Diet in Renal Disease equation) * ALT(Alanine Transaminase) \> 2x Upper Limit of Normal (ULN) * Presence of any severe medical or psychological condition or chronic conditions/infections that in the opinion of the Investigator would compromise he subject's safety or successful participation in the study * Currently pregnant or planning pregnancy during the study period * Unable to follow the study protocol * Unable to speak, read and write in English * Uncontrolled hyperglycemia with HbA1c \> 9% on metformin or \>8% on SU or metformin/SU combination or ketonuria requiring immediate insulin therapy * At the investigator's discretion for other medical or psychological reasons
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HbA1c Change | baseline to final visit (32 weeks) | Measure the changes in HbA1C attributable to exenatide, insulin glargine and their combination. Employ CGM with AGP analysis to determine if there is an incremental benefit for subjects who do not reach target to add exenatide to insulin glargine or insulin glargine to exenatide in patients taking metformin. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Incidence of Hypoglycemia (Degree) | baseline to final visit (32 weeks) | Employ Continuous Glucose Monitoring (CGM) with Ambulatory Glucose Profile (AGP) analysis to characterize the diurnal patterns produced by oral medications (metformin) used in the treatment of type 2 diabetes. Employ CGM to measure the effect of exenatide, insulin glargine and exenatide plus insulin glargine in terms of underlying physiological defects and alter medications in a manner that improves- iv. Incidence of hypoglycemia (degree) Change from baseline was calculated as mean incidence percentage at baseline minus mean incidence percentage at final visit (32 weeks) |
| Change From Baseline in Glucose Stability (Absolute Hourly Rate of Change in Median Curve) | baseline to final visit (32 weeks) | Employ Continuous Glucose Monitoring (CGM) with Ambulatory Glucose Profile (AGP) analysis to characterize the diurnal patterns produced by oral medications (metformin) used in the treatment of type 2 diabetes. Employ CGM to measure the effect of exenatide, insulin glargine and exenatide plus insulin glargine in terms of underlying physiological defects and alter medications in a manner that improves iii. Glucose stability (absolute hourly rate of change in median curve) Change from baseline was calculated as mean absolute hourly rate of change in median curve at baseline minus rate at final visit (32 weeks). Mean absolute hourly rate of change in the smoothed median curve is calculated as delta subscript MC = (\|p subscript 50 zero - p subscript 50 23\|+Sum superscript 23 subscript i = 1\| p subscript 50i - p subscript 50 i-1\| over T. i = hour of day p subscript 50i = smoothed 50th percentile value for ith hour of day T = total # of non-missing hourly smoothed percentiles |
| Change From Baseline in Incidence of Hypoglycemia (Frequency) | baseline to final visit (32 weeks) | Employ Continuous Glucose Monitoring (CGM) with Ambulatory Glucose Profile (AGP) analysis to characterize the diurnal patterns produced by oral medications (metformin) used in the treatment of type 2 diabetes. Employ CGM to measure the effect of exenatide, insulin glargine and exenatide plus insulin glargine in terms of underlying physiological defects and alter medications in a manner that improves- iv. Incidence of hypoglycemia (frequency) Change from baseline was calculated as mean incidence rate at baseline minus mean incidence rate at final visit (32 weeks) |
| Change From Baseline in Glucose Exposure (Area Under the Diurnal Median Curve or AUC) | baseline - final visit (32 weeks) | Employ Continuous Glucose Monitoring (CGM) with Ambulatory Glucose Profile (AGP) analysis to characterize the diurnal patterns produced by oral medications (metformin) used in the treatment of type 2 diabetes. Employ CGM to measure the effect of exenatide, insulin glargine and exenatide plus insulin glargine in terms of underlying physiological defects and alter medications in a manner that improves- i. Glucose exposure (area under the diurnal median curve) Change from baseline was calculated as area under the diurnal median curve at baseline minus AUC value at final visit (32 weeks). AUC is calculated using modified rectangle method AUC = sum of superscript 23, subscript i=0 P subscript 50i I = hour of day P subscript 50i = smoother 50th percentile value for ith hour of day |
| Change From Baseline in Weight Changes | baseline - final visit (32 weeks) | Measure the changes in weight attributable to exenatide, insulin glargine and their combinations. Employ CGM with AGP analysis to determine if there is an incremental benefit for subjects who do not reach target to add exenatide to insulin glargine or insulin glargine to exenatide in patients taking metformin. Change from baseline was calculated as weight in pounds at baseline minus weight in pounds at final visit (32 weeks). |
| Change From Baseline in CGM Glucose Variability | baseline to final visit (32 weeks) | Employ Continuous Glucose Monitoring (CGM) with Ambulatory Glucose Profile (AGP) analysis to characterize the diurnal patterns produced by oral medications (metformin) used in the treatment of type 2 diabetes. Employ CGM to measure the effect of exenatide, insulin glargine and exenatide plus insulin glargine in terms of underlying physiological defects and alter medications in a manner that improves- ii. Glucose variability (inter-quartile range) IQR is the difference between the 75th and 25th percentiles. Change from baseline was calculated as IQR at baseline minus IQR value at final visit (32 weeks). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Exenatide 5 mcg BID for 1 month increasing to 10 mcg BID for the remainder of the study
Exenatide: refer to Arm detail | 16 |
| Insulin Glargine .1 unit per kg to start, titrated based on Continuous Glucose Monitoring results
Insulin Glargine: refer to Arm detail | 17 |
| Exenatide + Insulin Glargine Exenatide: 5 mcg BID (twice daily) for 1 month increasing to 10 mcg BID for the remainder of the study
\+ Insulin Glargine: 0.1 unit per kg to start, titrated based on Continuous Glucose Monitoring results | 16 |
| Total | 49 |
Baseline characteristics
| Characteristic | Exenatide | Insulin Glargine | Exenatide + Insulin Glargine | Total |
|---|---|---|---|---|
| Age, Continuous | 58.6 years STANDARD_DEVIATION 7.8 | 53.8 years STANDARD_DEVIATION 7.4 | 56.7 years STANDARD_DEVIATION 8.7 | 56.3 years STANDARD_DEVIATION 8 |
| Region of Enrollment United States | 16 Participants | 17 Participants | 16 Participants | 49 Participants |
| Sex: Female, Male Female | 6 Participants | 10 Participants | 7 Participants | 23 Participants |
| Sex: Female, Male Male | 10 Participants | 7 Participants | 9 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 20 / 20 | 10 / 20 | 13 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 | 0 / 20 |
Outcome results
Primary
HbA1c Change
Measure the changes in HbA1C attributable to exenatide, insulin glargine and their combination. Employ CGM with AGP analysis to determine if there is an incremental benefit for subjects who do not reach target to add exenatide to insulin glargine or insulin glargine to exenatide in patients taking metformin.
Time frame: baseline to final visit (32 weeks)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide | HbA1c Change | Baseline | 6.4 %HbA1c | Standard Deviation 0.3 |
| Exenatide | HbA1c Change | Final - Week 32 | 7.8 %HbA1c | Standard Deviation 0.6 |
| Insulin Glargine | HbA1c Change | Baseline | 6.4 %HbA1c | Standard Deviation 0.5 |
| Insulin Glargine | HbA1c Change | Final - Week 32 | 7.6 %HbA1c | Standard Deviation 0.5 |
| Exenatide + Insulin Glargine | HbA1c Change | Baseline | 6.2 %HbA1c | Standard Deviation 0.5 |
| Exenatide + Insulin Glargine | HbA1c Change | Final - Week 32 | 7.6 %HbA1c | Standard Deviation 0.7 |
Secondary
Change From Baseline in CGM Glucose Variability
Employ Continuous Glucose Monitoring (CGM) with Ambulatory Glucose Profile (AGP) analysis to characterize the diurnal patterns produced by oral medications (metformin) used in the treatment of type 2 diabetes. Employ CGM to measure the effect of exenatide, insulin glargine and exenatide plus insulin glargine in terms of underlying physiological defects and alter medications in a manner that improves- ii. Glucose variability (inter-quartile range) IQR is the difference between the 75th and 25th percentiles. Change from baseline was calculated as IQR at baseline minus IQR value at final visit (32 weeks).
Time frame: baseline to final visit (32 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Change From Baseline in CGM Glucose Variability | -9 mg/dL | Standard Deviation 9.1 |
| Insulin Glargine | Change From Baseline in CGM Glucose Variability | -7.7 mg/dL | Standard Deviation 19.4 |
| Exenatide + Insulin Glargine | Change From Baseline in CGM Glucose Variability | -12.1 mg/dL | Standard Deviation 14 |
Secondary
Change From Baseline in Glucose Exposure (Area Under the Diurnal Median Curve or AUC)
Employ Continuous Glucose Monitoring (CGM) with Ambulatory Glucose Profile (AGP) analysis to characterize the diurnal patterns produced by oral medications (metformin) used in the treatment of type 2 diabetes. Employ CGM to measure the effect of exenatide, insulin glargine and exenatide plus insulin glargine in terms of underlying physiological defects and alter medications in a manner that improves- i. Glucose exposure (area under the diurnal median curve) Change from baseline was calculated as area under the diurnal median curve at baseline minus AUC value at final visit (32 weeks). AUC is calculated using modified rectangle method AUC = sum of superscript 23, subscript i=0 P subscript 50i I = hour of day P subscript 50i = smoother 50th percentile value for ith hour of day
Time frame: baseline - final visit (32 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Change From Baseline in Glucose Exposure (Area Under the Diurnal Median Curve or AUC) | -1207.1 mg/dL*24hr | Standard Deviation 661.1 |
| Insulin Glargine | Change From Baseline in Glucose Exposure (Area Under the Diurnal Median Curve or AUC) | -1476.2 mg/dL*24hr | Standard Deviation 849.2 |
| Exenatide + Insulin Glargine | Change From Baseline in Glucose Exposure (Area Under the Diurnal Median Curve or AUC) | -1315 mg/dL*24hr | Standard Deviation 953.9 |
Secondary
Change From Baseline in Glucose Stability (Absolute Hourly Rate of Change in Median Curve)
Employ Continuous Glucose Monitoring (CGM) with Ambulatory Glucose Profile (AGP) analysis to characterize the diurnal patterns produced by oral medications (metformin) used in the treatment of type 2 diabetes. Employ CGM to measure the effect of exenatide, insulin glargine and exenatide plus insulin glargine in terms of underlying physiological defects and alter medications in a manner that improves iii. Glucose stability (absolute hourly rate of change in median curve) Change from baseline was calculated as mean absolute hourly rate of change in median curve at baseline minus rate at final visit (32 weeks). Mean absolute hourly rate of change in the smoothed median curve is calculated as delta subscript MC = (\|p subscript 50 zero - p subscript 50 23\|+Sum superscript 23 subscript i = 1\| p subscript 50i - p subscript 50 i-1\| over T. i = hour of day p subscript 50i = smoothed 50th percentile value for ith hour of day T = total # of non-missing hourly smoothed percentiles
Time frame: baseline to final visit (32 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Change From Baseline in Glucose Stability (Absolute Hourly Rate of Change in Median Curve) | -2 mg/dL/hr | Standard Deviation 2.7 |
| Insulin Glargine | Change From Baseline in Glucose Stability (Absolute Hourly Rate of Change in Median Curve) | -2.9 mg/dL/hr | Standard Deviation 4.4 |
| Exenatide + Insulin Glargine | Change From Baseline in Glucose Stability (Absolute Hourly Rate of Change in Median Curve) | -2 mg/dL/hr | Standard Deviation 3.5 |
Secondary
Change From Baseline in Incidence of Hypoglycemia (Degree)
Employ Continuous Glucose Monitoring (CGM) with Ambulatory Glucose Profile (AGP) analysis to characterize the diurnal patterns produced by oral medications (metformin) used in the treatment of type 2 diabetes. Employ CGM to measure the effect of exenatide, insulin glargine and exenatide plus insulin glargine in terms of underlying physiological defects and alter medications in a manner that improves- iv. Incidence of hypoglycemia (degree) Change from baseline was calculated as mean incidence percentage at baseline minus mean incidence percentage at final visit (32 weeks)
Time frame: baseline to final visit (32 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Change From Baseline in Incidence of Hypoglycemia (Degree) | 1.7 percentage of measures under 70 mg/dL | Standard Deviation 2.7 |
| Insulin Glargine | Change From Baseline in Incidence of Hypoglycemia (Degree) | 1.7 percentage of measures under 70 mg/dL | Standard Deviation 1.8 |
| Exenatide + Insulin Glargine | Change From Baseline in Incidence of Hypoglycemia (Degree) | 1.3 percentage of measures under 70 mg/dL | Standard Deviation 1.1 |
Secondary
Change From Baseline in Incidence of Hypoglycemia (Frequency)
Employ Continuous Glucose Monitoring (CGM) with Ambulatory Glucose Profile (AGP) analysis to characterize the diurnal patterns produced by oral medications (metformin) used in the treatment of type 2 diabetes. Employ CGM to measure the effect of exenatide, insulin glargine and exenatide plus insulin glargine in terms of underlying physiological defects and alter medications in a manner that improves- iv. Incidence of hypoglycemia (frequency) Change from baseline was calculated as mean incidence rate at baseline minus mean incidence rate at final visit (32 weeks)
Time frame: baseline to final visit (32 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Change From Baseline in Incidence of Hypoglycemia (Frequency) | .7 episodes/day | Standard Deviation 0.8 |
| Insulin Glargine | Change From Baseline in Incidence of Hypoglycemia (Frequency) | .8 episodes/day | Standard Deviation 0.8 |
| Exenatide + Insulin Glargine | Change From Baseline in Incidence of Hypoglycemia (Frequency) | .6 episodes/day | Standard Deviation 0.4 |
Secondary
Change From Baseline in Weight Changes
Measure the changes in weight attributable to exenatide, insulin glargine and their combinations. Employ CGM with AGP analysis to determine if there is an incremental benefit for subjects who do not reach target to add exenatide to insulin glargine or insulin glargine to exenatide in patients taking metformin. Change from baseline was calculated as weight in pounds at baseline minus weight in pounds at final visit (32 weeks).
Time frame: baseline - final visit (32 weeks)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Change From Baseline in Weight Changes | -13.5 lbs (pounds) | Standard Deviation 10.2 |
| Insulin Glargine | Change From Baseline in Weight Changes | -0.5 lbs (pounds) | Standard Deviation 7.7 |
| Exenatide + Insulin Glargine | Change From Baseline in Weight Changes | -10.3 lbs (pounds) | Standard Deviation 10.5 |