Diabetes Mellitus, Type 2, Diabetes
Conditions
Keywords
Diabetes Mellitus, Type 2, Insulin, Insulin, Long-Acting, Insulin, Short Acting, Detemir, Liraglutide, GLP-1, Glucagon Like Peptide, Metformin, Uncontrolled Diabetes, Elevated A1c, Incretins
Brief summary
The aim of this clinical trial is to assess and compare the effect of insulin detemir in combination with liraglutide and metformin versus insulin detemir in combination with insulin aspart and metformin in subjects with very uncontrolled Type 2 Diabetes (A1c \> 10%).
Detailed description
The aim of this study is to compare a GLP-1 plus basal insulin and metformin treatment regimen to a basal-bolus plus metformin treatment regimen in patients with very uncontrolled (HbA1c\>10%) type 2 diabetes. The investigators will compare the two regimens with respect to efficacy in improving glycemic control, rate of hypoglycemia, change in weight, effect on patient quality of life, treatment burden, physician time, as well as healthcare related cost. The investigators hypothesize that at 26 weeks from randomization the two treatment regimens will have similar percentage of patients reaching A1c levels \<7.0%, while more patients on the GLP-1 plus basal insulin strategy will achieve the composite end point of A1c levels \<7.0% without severe hypoglycemia or significant weight gain.
Interventions
DRUGMetformin
Metformin will be started at 500 mg daily (or continued at current dose)and weekly titrated to 2000 mg or maximum tolerated dose (at least 1000 mg/day)
DRUGDetemir
Insulin detemir will be started in both groups at 0.3 units/kg or conversion 1:1 from dose of basal insulin prior to randomization. The titration will be primarily patient-driven, based on our study protocol table. Additional physician driven titration will be allowed in both groups if patient fails to intensify basal insulin dose as directed.
DRUGLiraglutide
Initial dose of 0.6 mg/day with weekly increments of 0.6 mg until dose of 1.8 mg/day or maximal tolerated dose (at least 1.2 mg/day)is reached
DRUGInsulin Aspart
Insulin aspart will be initiated at a dose of 0.3 units/kg/day divided among the number of meals taken daily and titrated based on physician clinical judgment with the goal of pre-prandial BG 70-130 mg/dL and post-prandial BG \<180
Sponsors
University of Texas Southwestern Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1\. Clinical diagnosis of type 2 diabetes with confirmed HbA1c level \>10% at time of enrollment, regardless of prior or current treatment regimens, or time since diagnosis.
Exclusion criteria
1. Age \<18 as the feasibility and safety of this treatment regimen should be first established in the adult population; if successful, a subsequent pediatric study will be proposed; 2. Type 1 diabetes as purposefully withholding meal-time insulin is contraindicated; 3. Clinical state requiring inpatient admission/treatment; 4. Contraindication or strong cautions to any of the study medications: 1. Creatinine above 1.4 mg/dl for women and 1.5 mg/dl for men (per metformin label) 2. History of lactic acidosis (per metformin label) 3. Advanced hepatic or cardiac disease (per metformin label) 4. Age \>80 years (per metformin label) 5. Chronic alcohol use (\>14 drinks/week) 6. History of pancreatitis (per liraglutide label) 7. Personal or family history of medullary thyroid cancer or MEN syndrome (per liraglutide label) 8. Pregnancy and lactation (per liraglutide label) 5. Any serious or unstable medical condition as it would interfere with treatment assignment as well as outcome measurement; 6. Any scheduled elective procedures/surgeries; 7. Active infections, including osteomyelitis; 8. Not willing to participate, unable to keep projected appointments, unwillingness to receive injectable treatment; unwillingness to perform 7-point glucose profiles over 2 consecutive days the weeks prior to Randomization (visit 1)and the week prior to visit 6 9. Non English speaking.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Randomization in A1c at Week 26 | Baseline and Week 26 | Change in glycosylated Hemoglobin A1c (A1c) from randomization to 26 weeks of therapy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Reaching Target A1c of <7% at Week 26 | Week 26 | — |
| Percentage of Participants Reaching Pre-specified Treatment Failure Outcome | week 13 | Treatment Failure defined as A1c\>10% at week 13 (visit 5) |
| Mean Change From Randomization in Body Weight | Week 0 (Randomization) , Week 26 | Change in body weight from randomization to end of study. |
| Composite End-point | Week 0 (Randomization) , Week 26 | Percentage of participants with glycosylated Hemoglobin A1c (A1c)\<8% AND no documented severe hypoglycemia (\<56 mg/dL) during the study AND no significant weight gain (\>3% from baseline) |
| Change in Diabetes Quality of Life (DQOL)Questionnaire Score- Least Squares Means | Week 0 (Randomization) , Week 26 | Diabetes Quality of Life (DQOL) questionnaires will be completed by the patient at the randomization and end-of study visits. ALL D-QOL domains are scored on a 1-5 scale, with a lower number representing better quality of life or treatment satisfaction. Outcome reported is difference between mean baseline and mean Week 26 score. |
| Change in Short Form-36 (SF-36) Questionnaire Score | Week 0 (Randomization) , Week 26 | Quality of life questionnaires will be completed by the patient at the randomization and end-of study visits. SF-36 is scored on a 1-100 scale; a higher score represents a better self-assessed health - for all domains. |
| Hypoglycemic Episodes | Week 0 (Randomization) , Week 2, week 4, week 13, Week 26 | Percentage of participants experiencing any episodes of documented hypoglycemia defined as CBG reading of \<70 mg/dl |
Countries
United States
Participant flow
Recruitment details
Total number of subjects consented is 157, total number of subjects randomized is 120, of those 120 only 110 are MITT data set
Participants by arm
| Arm | Count |
|---|---|
| Control: Metformin, Insulin Detemir, Insulin Aspart Metformin titrated to max tolerated dose (at least 1000 mg/day); Insulin detemir titrated based on the study protocol; Insulin Aspart titrated by the physician
Metformin: Metformin will be started at 500 mg daily (or continued at current dose)and weekly titrated to 2000 mg or maximum tolerated dose (at least 1000 mg/day)
Detemir: Insulin detemir will be started in both groups at 0.3 units/kg or conversion 1:1 from dose of basal insulin prior to randomization. The titration will be primarily patient-driven, based on our study protocol table. Additional physician driven titration will be allowed in both groups if patient fails to intensify basal insulin dose as directed.
Insulin Aspart: Insulin aspart will be initiated at a dose of 0.3 units/kg/day divided among the number of meals taken daily and titrated based on physician clinical judgment with the goal of pre-prandial BG 70-130 mg/dL and post-prandial BG \<180 | 61 |
| Metformin, Insulin Determir, Liraglutide Metformin titrated to max tolerated dose (at least 1000mg/day); Insulin detemir titrated based on the study protocol; Liraglutide titrated to max tolerated dose (at least 1.2 mg/day)
Metformin: Metformin will be started at 500 mg daily (or continued at current dose)and weekly titrated to 2000 mg or maximum tolerated dose (at least 1000 mg/day)
Detemir: Insulin detemir will be started in both groups at 0.3 units/kg or conversion 1:1 from dose of basal insulin prior to randomization. The titration will be primarily patient-driven, based on our study protocol table. Additional physician driven titration will be allowed in both groups if patient fails to intensify basal insulin dose as directed.
Liraglutide: Initial dose of 0.6 mg/day with weekly increments of 0.6 mg until dose of 1.8 mg/day or maximal tolerated dose (at least 1.2 mg/day)is reached | 59 |
| Total | 120 |
Baseline characteristics
| Characteristic | Control: Metformin, Insulin Detemir, Insulin Aspart | Metformin, Insulin Determir, Liraglutide | Total |
|---|---|---|---|
| Age, Continuous | 48.1 years STANDARD_DEVIATION 10 | 46.7 years STANDARD_DEVIATION 9 | 47.4 years STANDARD_DEVIATION 9.5 |
| HbA1c | 12.0 percentage of glycosylated hemoglobin STANDARD_DEVIATION 1.5 | 12.1 percentage of glycosylated hemoglobin STANDARD_DEVIATION 1.4 | 12.1 percentage of glycosylated hemoglobin STANDARD_DEVIATION 1.4 |
| Race/Ethnicity, Customized African-American | 30 Participants | 20 Participants | 50 Participants |
| Race/Ethnicity, Customized Hispanic | 21 Participants | 27 Participants | 48 Participants |
| Race/Ethnicity, Customized Non-Hispanic White | 10 Participants | 12 Participants | 22 Participants |
| Sex: Female, Male Female | 45 Participants | 40 Participants | 85 Participants |
| Sex: Female, Male Male | 16 Participants | 19 Participants | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 56 | 0 / 54 |
| other Total, other adverse events | 40 / 56 | 50 / 54 |
| serious Total, serious adverse events | 13 / 56 | 6 / 54 |
Outcome results
Primary
Mean Change From Randomization in A1c at Week 26
Change in glycosylated Hemoglobin A1c (A1c) from randomization to 26 weeks of therapy
Time frame: Baseline and Week 26
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Control: Metformin, Insulin Detemir, Insulin Aspart | Mean Change From Randomization in A1c at Week 26 | 3.4 Percentage of glycosylated hemoglobin |
| Metformin, Insulin Determir, Liraglutide | Mean Change From Randomization in A1c at Week 26 | 4.1 Percentage of glycosylated hemoglobin |
Secondary
Change in Diabetes Quality of Life (DQOL)Questionnaire Score- Least Squares Means
Diabetes Quality of Life (DQOL) questionnaires will be completed by the patient at the randomization and end-of study visits. ALL D-QOL domains are scored on a 1-5 scale, with a lower number representing better quality of life or treatment satisfaction. Outcome reported is difference between mean baseline and mean Week 26 score.
Time frame: Week 0 (Randomization) , Week 26
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Control: Metformin, Insulin Detemir, Insulin Aspart | Change in Diabetes Quality of Life (DQOL)Questionnaire Score- Least Squares Means | Diabetes Related Worry | 0.03 score on a scale |
| Control: Metformin, Insulin Detemir, Insulin Aspart | Change in Diabetes Quality of Life (DQOL)Questionnaire Score- Least Squares Means | Glycemic Control Perception | -1.1 score on a scale |
| Control: Metformin, Insulin Detemir, Insulin Aspart | Change in Diabetes Quality of Life (DQOL)Questionnaire Score- Least Squares Means | Treatment Satisfaction | -0.3 score on a scale |
| Control: Metformin, Insulin Detemir, Insulin Aspart | Change in Diabetes Quality of Life (DQOL)Questionnaire Score- Least Squares Means | Satisfaction with Insulin Treatment | -1.3 score on a scale |
| Control: Metformin, Insulin Detemir, Insulin Aspart | Change in Diabetes Quality of Life (DQOL)Questionnaire Score- Least Squares Means | Social or Vocational Worry | -0.02 score on a scale |
| Control: Metformin, Insulin Detemir, Insulin Aspart | Change in Diabetes Quality of Life (DQOL)Questionnaire Score- Least Squares Means | Willingness to Continue Insulin Treatment | -0.9 score on a scale |
| Control: Metformin, Insulin Detemir, Insulin Aspart | Change in Diabetes Quality of Life (DQOL)Questionnaire Score- Least Squares Means | Current Health Perception | -0.5 score on a scale |
| Control: Metformin, Insulin Detemir, Insulin Aspart | Change in Diabetes Quality of Life (DQOL)Questionnaire Score- Least Squares Means | LifeStyle Flexibility | -0.09 score on a scale |
| Control: Metformin, Insulin Detemir, Insulin Aspart | Change in Diabetes Quality of Life (DQOL)Questionnaire Score- Least Squares Means | Hypoglycemia Fear | 0.3 score on a scale |
| Control: Metformin, Insulin Detemir, Insulin Aspart | Change in Diabetes Quality of Life (DQOL)Questionnaire Score- Least Squares Means | Social Stigma | 0.1 score on a scale |
| Control: Metformin, Insulin Detemir, Insulin Aspart | Change in Diabetes Quality of Life (DQOL)Questionnaire Score- Least Squares Means | General Health Perception | -0.3 score on a scale |
| Metformin, Insulin Determir, Liraglutide | Change in Diabetes Quality of Life (DQOL)Questionnaire Score- Least Squares Means | Social Stigma | 0.01 score on a scale |
| Metformin, Insulin Determir, Liraglutide | Change in Diabetes Quality of Life (DQOL)Questionnaire Score- Least Squares Means | General Health Perception | -0.9 score on a scale |
| Metformin, Insulin Determir, Liraglutide | Change in Diabetes Quality of Life (DQOL)Questionnaire Score- Least Squares Means | Current Health Perception | -1.1 score on a scale |
| Metformin, Insulin Determir, Liraglutide | Change in Diabetes Quality of Life (DQOL)Questionnaire Score- Least Squares Means | Treatment Satisfaction | -0.6 score on a scale |
| Metformin, Insulin Determir, Liraglutide | Change in Diabetes Quality of Life (DQOL)Questionnaire Score- Least Squares Means | Diabetes Related Worry | -0.2 score on a scale |
| Metformin, Insulin Determir, Liraglutide | Change in Diabetes Quality of Life (DQOL)Questionnaire Score- Least Squares Means | Social or Vocational Worry | -0.2 score on a scale |
| Metformin, Insulin Determir, Liraglutide | Change in Diabetes Quality of Life (DQOL)Questionnaire Score- Least Squares Means | Hypoglycemia Fear | -0.2 score on a scale |
| Metformin, Insulin Determir, Liraglutide | Change in Diabetes Quality of Life (DQOL)Questionnaire Score- Least Squares Means | Glycemic Control Perception | -1.6 score on a scale |
| Metformin, Insulin Determir, Liraglutide | Change in Diabetes Quality of Life (DQOL)Questionnaire Score- Least Squares Means | Satisfaction with Insulin Treatment | -1.7 score on a scale |
| Metformin, Insulin Determir, Liraglutide | Change in Diabetes Quality of Life (DQOL)Questionnaire Score- Least Squares Means | Willingness to Continue Insulin Treatment | -1.1 score on a scale |
| Metformin, Insulin Determir, Liraglutide | Change in Diabetes Quality of Life (DQOL)Questionnaire Score- Least Squares Means | LifeStyle Flexibility | -0.2 score on a scale |
Secondary
Change in Short Form-36 (SF-36) Questionnaire Score
Quality of life questionnaires will be completed by the patient at the randomization and end-of study visits. SF-36 is scored on a 1-100 scale; a higher score represents a better self-assessed health - for all domains.
Time frame: Week 0 (Randomization) , Week 26
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Control: Metformin, Insulin Detemir, Insulin Aspart | Change in Short Form-36 (SF-36) Questionnaire Score | Physical Component Summary | -0.1 score on a scale |
| Control: Metformin, Insulin Detemir, Insulin Aspart | Change in Short Form-36 (SF-36) Questionnaire Score | Mental Component Summary | 0.04 score on a scale |
| Metformin, Insulin Determir, Liraglutide | Change in Short Form-36 (SF-36) Questionnaire Score | Physical Component Summary | 0.007 score on a scale |
| Metformin, Insulin Determir, Liraglutide | Change in Short Form-36 (SF-36) Questionnaire Score | Mental Component Summary | 0.09 score on a scale |
Secondary
Composite End-point
Percentage of participants with glycosylated Hemoglobin A1c (A1c)\<8% AND no documented severe hypoglycemia (\<56 mg/dL) during the study AND no significant weight gain (\>3% from baseline)
Time frame: Week 0 (Randomization) , Week 26
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Control: Metformin, Insulin Detemir, Insulin Aspart | Composite End-point | 16 percentage of participants |
| Metformin, Insulin Determir, Liraglutide | Composite End-point | 34 percentage of participants |
Secondary
Hypoglycemic Episodes
Percentage of participants experiencing any episodes of documented hypoglycemia defined as CBG reading of \<70 mg/dl
Time frame: Week 0 (Randomization) , Week 2, week 4, week 13, Week 26
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Control: Metformin, Insulin Detemir, Insulin Aspart | Hypoglycemic Episodes | 66.1 percentage of participants |
| Metformin, Insulin Determir, Liraglutide | Hypoglycemic Episodes | 35.2 percentage of participants |
Secondary
Mean Change From Randomization in Body Weight
Change in body weight from randomization to end of study.
Time frame: Week 0 (Randomization) , Week 26
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Control: Metformin, Insulin Detemir, Insulin Aspart | Mean Change From Randomization in Body Weight | 3.1 kilogram |
| Metformin, Insulin Determir, Liraglutide | Mean Change From Randomization in Body Weight | -0.6 kilogram |
Secondary
Percentage of Participants Reaching Pre-specified Treatment Failure Outcome
Treatment Failure defined as A1c\>10% at week 13 (visit 5)
Time frame: week 13
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Control: Metformin, Insulin Detemir, Insulin Aspart | Percentage of Participants Reaching Pre-specified Treatment Failure Outcome | 16.1 percentage of participants |
| Metformin, Insulin Determir, Liraglutide | Percentage of Participants Reaching Pre-specified Treatment Failure Outcome | 7.4 percentage of participants |
Secondary
Percentage of Participants Reaching Target A1c of <7% at Week 26
Time frame: Week 26
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Control: Metformin, Insulin Detemir, Insulin Aspart | Percentage of Participants Reaching Target A1c of <7% at Week 26 | 20 percentage of participants |
| Metformin, Insulin Determir, Liraglutide | Percentage of Participants Reaching Target A1c of <7% at Week 26 | 44 percentage of participants |