The Effect of Simple Basal Insulin Titration, Metformin Plus Liraglutide for Type 2 Diabetes With Very Elevated HbA1c - The SIMPLE Study

• Sponsor: University of Texas Southwestern Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01966978
• Collaborator: (none)
• Enrollment: 157
• Location: 1
• Arms: 2
• Duration (Months): 37
• Patients Per Site Per Month: 4.2

Study Details

Study Description

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%).

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2; Diabetes	Drug: Metformin; Drug: Detemir; Drug: Liraglutide; Drug: Insulin Aspart	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 157 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: The Effect of Simple Insulin Detemir Titration, Metformin Plus Liraglutide Compared to Simple Insulin Detemir Titration Plus Insulin Aspart and Metformin for Type 2 Diabetes With Very Elevated HbA1c - The SIMPLE Study: A 26 Week, Randomized, Open Label, Parallel-group, Intention to Treat Study
• Study Start Date: Nov 1, 2014
• Actual Primary Completion Date: Dec 1, 2017
• Actual Study Completion Date: Dec 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 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	Drug: 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); Other Names: Metformin tablets ; Drug: 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.; Other Names: Insulin Detemir subcutaneous once or twice daily ; Drug: 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; Other Names: Insulin Aspart Subcutaneous injection one to three times daily
Active Comparator: 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)	Drug: 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); Other Names: Metformin tablets ; Drug: 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.; Other Names: Insulin Detemir subcutaneous once or twice daily ; Drug: 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; Other Names: Liraglutide 6 mg/mL Subcutaneously

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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)

2. Percentage of Participants Reaching Target A1c of <7% at Week 26 [Week 26]

3. Percentage of Participants Reaching Pre-specified "Treatment Failure" Outcome [week 13]

   Treatment Failure defined as A1c>10% at week 13 (visit 5)

4. Mean Change From Randomization in Body Weight [Week 0 (Randomization) , Week 26]

   Change in body weight from randomization to end of study.

5. 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

6. 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.

7. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts 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:

5. Creatinine above 1.4 mg/dl for women and 1.5 mg/dl for men (per metformin label)

6. History of lactic acidosis (per metformin label)

7. Advanced hepatic or cardiac disease (per metformin label)

8. Age >80 years (per metformin label)

9. Chronic alcohol use (>14 drinks/week)

10. History of pancreatitis (per liraglutide label)

11. Personal or family history of medullary thyroid cancer or MEN syndrome (per liraglutide label)

12. Pregnancy and lactation (per liraglutide label)

13. Any serious or unstable medical condition as it would interfere with treatment assignment as well as outcome measurement;

14. Any scheduled elective procedures/surgeries;

15. Active infections, including osteomyelitis;

16. 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

17. Non English speaking.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UT Southwestern Medical Center	Dallas	Texas	United States	02720

Sponsors and Collaborators

• University of Texas Southwestern Medical Center

Investigators

• Principal Investigator: Ildiko Lingvay, UT Southwestern Medical Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 6, 2014

More Information

Publications

None provided.

• Responsible Party: Ildiko Lingvay, MD, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT01966978
• Other Study ID Numbers: STU 072013-030
• First Posted: Oct 22, 2013
• Last Update Posted: Oct 22, 2019
• Last Verified: Oct 1, 2019

• Keywords provided by Ildiko Lingvay, MD, University of Texas Southwestern Medical Center: Diabetes Mellitus, Type 2; Insulin; Insulin, Long-Acting; Insulin, Short Acting; Detemir; Liraglutide; GLP-1; Glucagon Like Peptide; Metformin; Uncontrolled Diabetes; Elevated A1c; Incretins
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin; Insulin, Globin Zinc; Metformin; Insulin Aspart; Insulin, Long-Acting; Insulin degludec, insulin aspart drug combination; Liraglutide; Insulin Detemir

Study Results

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

Arm/Group Title	Control: Metformin, Insulin Detemir, Insulin Aspart	Metformin, Insulin Determir, Liraglutide
Arm/Group Description	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	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
Period Title: Overall Study
STARTED	61	59
COMPLETED	44	46
NOT COMPLETED	17	13

Baseline Characteristics

Arm/Group Title	Control: Metformin, Insulin Detemir, Insulin Aspart	Metformin, Insulin Determir, Liraglutide	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	61	59	120
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.1 (10.0)	46.7 (9.0)	47.4 (9.5)
Sex: Female, Male (Count of Participants)
Female	45 73.8%	40 67.8%	85 70.8%
Male	16 26.2%	19 32.2%	35 29.2%
Race/Ethnicity, Customized (Count of Participants)
Hispanic	21 34.4%	27 45.8%	48 40%
Non-Hispanic White	10 16.4%	12 20.3%	22 18.3%
African-American	30 49.2%	20 33.9%	50 41.7%
HbA1c (percentage of glycosylated hemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of glycosylated hemoglobin]	12.0 (1.5)	12.1 (1.4)	12.1 (1.4)

Outcome Measures

1. Primary Outcome

Title	Mean Change From Randomization in A1c at Week 26
Description	Change in glycosylated Hemoglobin A1c (A1c) from randomization to 26 weeks of therapy
Time Frame	Baseline and Week 26

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control: Metformin, Insulin Detemir, Insulin Aspart	Metformin, Insulin Determir, Liraglutide
Arm/Group Description	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	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
Measure Participants	44	46
Mean (95% Confidence Interval) [Percentage of glycosylated hemoglobin]	3.4	4.1

2. Secondary Outcome

Title	Composite End-point
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control: Metformin, Insulin Detemir, Insulin Aspart	Metformin, Insulin Determir, Liraglutide
Arm/Group Description	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	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
Measure Participants	44	46
Number [percentage of participants]	16 26.2%	34 57.6%

3. Secondary Outcome

Title	Percentage of Participants Reaching Target A1c of <7% at Week 26
Time Frame	Week 26

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control: Metformin, Insulin Detemir, Insulin Aspart	Metformin, Insulin Determir, Liraglutide
Arm/Group Description	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	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
Measure Participants	44	46
Number [percentage of participants]	20 32.8%	44 74.6%

4. Secondary Outcome

Title	Percentage of Participants Reaching Pre-specified "Treatment Failure" Outcome
Description	Treatment Failure defined as A1c>10% at week 13 (visit 5)
Time Frame	week 13

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control: Metformin, Insulin Detemir, Insulin Aspart	Metformin, Insulin Determir, Liraglutide
Arm/Group Description	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	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
Measure Participants	44	46
Number [percentage of participants]	16.1 26.4%	7.4 12.5%

5. Secondary Outcome

Title	Mean Change From Randomization in Body Weight
Description	Change in body weight from randomization to end of study.
Time Frame	Week 0 (Randomization) , Week 26

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control: Metformin, Insulin Detemir, Insulin Aspart	Metformin, Insulin Determir, Liraglutide
Arm/Group Description	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	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
Measure Participants	44	46
Mean (95% Confidence Interval) [kilogram]	3.1	-0.6

6. Secondary Outcome

Title	Hypoglycemic Episodes
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control: Metformin, Insulin Detemir, Insulin Aspart	Metformin, Insulin Determir, Liraglutide
Arm/Group Description	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	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
Measure Participants	44	46
Number [percentage of participants]	66.1 108.4%	35.2 59.7%

7. Secondary Outcome

Title	Change in Diabetes Quality of Life (DQOL)Questionnaire Score- Least Squares Means
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control: Metformin, Insulin Detemir, Insulin Aspart	Metformin, Insulin Determir, Liraglutide
Arm/Group Description	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	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
Measure Participants	44	46
General Health Perception	-0.3	-0.9
Current Health Perception	-0.5	-1.1
Treatment Satisfaction	-0.3	-0.6
Diabetes Related Worry	0.03	-0.2
Social or Vocational Worry	-0.02	-0.2
Hypoglycemia Fear	0.3	-0.2
Glycemic Control Perception	-1.1	-1.6
Satisfaction with Insulin Treatment	-1.3	-1.7
Willingness to Continue Insulin Treatment	-0.9	-1.1
LifeStyle Flexibility	-0.09	-0.2
Social Stigma	0.1	0.01

8. Secondary Outcome

Title	Change in Short Form-36 (SF-36) Questionnaire Score
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control: Metformin, Insulin Detemir, Insulin Aspart	Metformin, Insulin Determir, Liraglutide
Arm/Group Description	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	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
Measure Participants	44	46
Physical Component Summary	-0.1	0.007
Mental Component Summary	0.04	0.09

Adverse Events

Time Frame	6 months (Baseline to Week 26)
Adverse Event Reporting Description	Adverse events were collected both by self-report as well as review of the electronic health record. Nausea, vomiting, headache, diarrhea and abdominal pain were pre-defined events of special interest and proactively elicited at each visit from all patients.
Arm/Group Title	Control: Metformin, Insulin Detemir, Insulin Aspart		Metformin, Insulin Determir, Liraglutide
Arm/Group Description	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		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
All Cause Mortality
	Control: Metformin, Insulin Detemir, Insulin Aspart		Metformin, Insulin Determir, Liraglutide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/56 (0%)		0/54 (0%)
Serious Adverse Events
	Control: Metformin, Insulin Detemir, Insulin Aspart		Metformin, Insulin Determir, Liraglutide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/56 (23.2%)		6/54 (11.1%)
Cardiac disorders
chest pain	0/56 (0%)		1/54 (1.9%)
hypertension	0/56 (0%)		1/54 (1.9%)
myocardial infarction	1/56 (1.8%)		1/54 (1.9%)
Endocrine disorders
Diabetic Ketoacidosis	4/56 (7.1%)		0/54 (0%)
Eye disorders
vitreal hemmorhage	0/56 (0%)		1/54 (1.9%)
glaucoma	0/56 (0%)		1/54 (1.9%)
Gastrointestinal disorders
Small Bowel Obstruction	1/56 (1.8%)		0/54 (0%)
Lower GI bleed	1/56 (1.8%)		0/54 (0%)
Infections and infestations
bacteremia	1/56 (1.8%)		0/54 (0%)
Injury, poisoning and procedural complications
puncture wound	1/56 (1.8%)		0/54 (0%)
Investigations
Fall	2/56 (3.6%)		0/54 (0%)
Musculoskeletal and connective tissue disorders
Osteomyelitis	1/56 (1.8%)		0/54 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
nasopharyngeal carcinoma	1/56 (1.8%)		0/54 (0%)
Pregnancy, puerperium and perinatal conditions
Pregnancy	0/56 (0%)		1/54 (1.9%)
Psychiatric disorders
psychiatric inpatient hospitalization	0/56 (0%)		1/54 (1.9%)
Renal and urinary disorders
Urinary Tract Infection	1/56 (1.8%)		0/54 (0%)
nephrotic syndrome	1/56 (1.8%)		0/54 (0%)
Respiratory, thoracic and mediastinal disorders
Pneumonia	2/56 (3.6%)		0/54 (0%)
Respiratory Distress	2/56 (3.6%)		0/54 (0%)
Skin and subcutaneous tissue disorders
Facial Burn	1/56 (1.8%)		0/54 (0%)
Other (Not Including Serious) Adverse Events
	Control: Metformin, Insulin Detemir, Insulin Aspart		Metformin, Insulin Determir, Liraglutide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	40/56 (71.4%)		50/54 (92.6%)
Gastrointestinal disorders
GI	28/56 (50%)		42/54 (77.8%)
Investigations
Other AE	9/56 (16.1%)		4/54 (7.4%)
Nervous system disorders
headache	10/56 (17.9%)		14/54 (25.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.