Type 2 Diabetes
Conditions
Keywords
Incretins, Liraglutide, Glargine, Randomized controlled trial, basal insulin, hospital discharge, inpatient diabetes
Brief summary
High blood glucose levels in hospitalized patients with diabetes are associated with increased risk of medical complications and death. Improved glucose control with insulin injections may improve clinical outcome and prevent some of the hospital complications. Increasing evidence indicates that incretin-based agents are safe and effective for the hospital management of patients with type 2 diabetes (T2D). Liraglutide is a once-daily human glucagon-like peptide (GLP-1) analogue approved for the treatment of T2D. Liraglutide has been shown to lower blood glucose, stimulate endogenous insulin secretion, decrease plasma glucagon levels, inhibit gastric emptying, reduce food intake and body weight and improve ß-cell function when administered subcutaneously. Liraglutide increases insulin secretion in a glucose-dependent manner (i.e., only when plasma glucose levels are elevated), resulting in low-risk of hypoglycemia when used as monotherapy. When compared to insulin glargine therapy, the use of GLP-1 has resulted in comparable reduction in HbA1c level, lower rates of hypoglycemia and less weight gain. No prospective studies; however, have compared the efficacy and safety of liraglutide in the hospital setting or after hospital discharge. The primary objective is to compare the safety and efficacy of liraglutide (Victoza®) versus glargine insulin in combination to oral anti-diabetic agents (OADs: metformin, sulfonylureas, nateglinide, repaglinide or pioglitazone) on glycemic control after 26 weeks of treatment in medicine patients with T2D after hospital discharge.
Detailed description
Specific Aim: To determine whether treatment with liraglutide (Victoza®) will result in similar glycemic control (HbA1c at 26 weeks) and a lower rate of hypoglycemic events compared to treatment with glargine (Lantus®) in patients with T2D after hospital discharge. Patients with poorly controlled (HbA1c \>7%-10%) T2D treated with diet or oral antidiabetic agents or low dose insulin naïve (0.4u/kg/day) prior to admission will be randomized to liraglutide or glargine in combination to OADs at hospital discharge.
Interventions
DRUGLiraglutide + OADs
Liraglutide subcutaneously daily
DRUGGlargine + OADs
Glargine once daily subcutaneously
Sponsors
Novo Nordisk A/S
Emory University
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. Males or females between the ages of 18 and 80 years discharged after hospital admission from non- ICU general surgery and medicine services (excluding gastrointestinal and cardiac surgeries). 2. Admission HbA1c between 7% and 10% 3. Patients with T2D treated with diet alone or with oral antidiabetic agents as monotherapy or in combination therapy (excluding GLP1 receptor agonists) or on low-dose insulin therapy (TDD ≤0.4 unit/kg/day) prior to admission. 4. Subjects with a hospital admission BG \< 400 mg/dL without laboratory evidence of diabetic ketoacidosis (serum bicarbonate \< 18 mEq/L or positive serum or urinary ketones). 5. BMI \> 25 Kg/m2 and ≤ 45 Kg/m2
Exclusion criteria
1. Age \< 18 or \> 80 years. 2. Subjects with stress hyperglycemia (BG \> 140 mg/dL and HbA1c \< 6.5%) 3. Subjects with a history of type 1 diabetes 4. Treatment with insulin or GLP-1 analogs during the past 3 months prior to admission. 5. Recurrent severe hypoglycemia or hypoglycemic unawareness. 6. Subjects with gastrointestinal obstruction, gastroparesis, or those expected to require gastrointestinal suction. 7. History of medullary thyroid cancer or multiple endocrine neoplasias 8. Patients with acute or chronic pancreatitis, pancreatic cancer, or gallbladder disease. 9. Patients with clinically significant hepatic disease (cirrhosis, jaundice, end-stage liver disease, portal hypertension) and elevated ALT and AST \> 3 times upper limit of normal, or significantly impaired renal function (GFR \< 30 ml/min). 10. Treatment with oral or injectable corticosteroid (equivalent or higher than prednisone 5mg/day), parenteral nutrition, and immunosuppressive treatment. 11. Mental condition rendering the subject unable to understand the nature, scope, and possible consequences of the study. 12. Female subjects who are pregnant or breastfeeding at the time of enrollment into the study. 13. Females of childbearing potential who are not using adequate contraceptive methods (as required by local law or practice).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Glycemic Control at Hospital Discharge and 6 Months Follow up | Hospital discharge, 6 months (26 weeks) | To determine differences in HbA1c concentration at 26 weeks from discharge between liraglutide and glargine insulin therapy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hypoglycemic Episodes | After discharge, average 6 months | Number of participants who had at least one hypoglycemic event (\<70 mg/dl) and severe hypoglycemic event (\<40 mg/dl) |
| HbA1c <7.0% and no Hypoglycemia | After discharge, average 6 months | Percent of patients with 26 week HbA1c \<7.0% and no hypoglycemia |
| HbA1c <7.0% and no Weight Gain | After discharge, average 6 months | Percent of patients with 26 week HbA1c \<7.0% and no weight gain |
| Change in Body Weight From Baseline | After discharge, average 6 months | Change in body weight from baseline after 6 months of follow up (26 weeks) |
| Change in BMI | Baseline, and follow up after discharge (average 6 months) | Change in BMI after 6 months from baseline |
| Total Daily Dose of Insulin | After discharge, average 6 months | Evaluate the total daily dose of insulin needed in the group receiving glargine |
| Fasting and Postprandial Blood Glucose (BG) Concentration After Follow up of 26 Weeks | After discharge, average at 3 months (12 week) and 6 months (26 weeks) | To determine differences in BG concentration between liraglutide and glargine insulin therapy |
| Cardiovascular Risk Factor: Heart Rate | 26 weeks post-intervention | Cardiovascular risk: heart rate at baseline and 26 weeks post-intervention |
| Cardiovascular Risk Factor: Lipid Profile | 26 weeks post-intervention | Lipid profile was measured with total cholesterol level results at 26 weeks post-intervention. This outcome was not part of standard of care. |
| Emergency Room Visits and Readmissions | After discharge, average 6 months | Number of participants who had at least one emergency room visit and hospital readmissions |
| Acute Renal Failure | After discharge, average 6 months | Acute renal failure during the 26-week follow-up defined as a clinical diagnosis of acute renal failure with documented new-onset abnormal renal function (increment in creatinine \> 0.5 mg/dL from baseline) |
| Self-measured Blood Glucose (SMBG) 7-point Profiles at 26 Weeks Follow up | 26 weeks post-intervention | Number of participants that reported self-measured blood glucose (SMBG) 7-point profiles at 26 weeks follow up |
| Change in Cardiovascular Risk Factors: Blood Pressure | Baseline, 26 weeks post-intervention | Cardiovascular risk factors including changes in systolic and diastolic blood pressure from baseline to 26 weeks post-intervention |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Liraglutide + OADs Liraglutide once daily in combination to oral anti-diabetic agents (OADs)
Liraglutide + OADs: Liraglutide subcutaneously daily | 136 |
| Glargine + OADs Glargine once daily in combination to oral anti-diabetic agents (OADs)
Glargine + OADs: Glargine once daily subcutaneously | 137 |
| Total | 273 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 10 | 0 |
| Overall Study | Death | 2 | 1 |
| Overall Study | Hospital readmission | 2 | 9 |
| Overall Study | Lost to Follow-up | 38 | 27 |
| Overall Study | Rejected the need of injections | 4 | 7 |
Baseline characteristics
| Characteristic | Liraglutide + OADs | Glargine + OADs | Total |
|---|---|---|---|
| Age, Continuous | 56.1 years STANDARD_DEVIATION 9.5 | 55.9 years STANDARD_DEVIATION 11.2 | 56.1 years STANDARD_DEVIATION 10.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 97 Participants | 95 Participants | 192 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 16 Participants | 15 Participants | 31 Participants |
| Race (NIH/OMB) White | 23 Participants | 27 Participants | 50 Participants |
| Region of Enrollment Argentina | 3 participants | 3 participants | 6 participants |
| Region of Enrollment United States | 133 participants | 134 participants | 267 participants |
| Sex: Female, Male Female | 47 Participants | 61 Participants | 108 Participants |
| Sex: Female, Male Male | 89 Participants | 76 Participants | 165 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 136 | 1 / 137 |
| other Total, other adverse events | 0 / 136 | 0 / 137 |
| serious Total, serious adverse events | 52 / 136 | 54 / 137 |
Outcome results
Primary
Glycemic Control at Hospital Discharge and 6 Months Follow up
To determine differences in HbA1c concentration at 26 weeks from discharge between liraglutide and glargine insulin therapy
Time frame: Hospital discharge, 6 months (26 weeks)
Population: Number of subjects analyzed at 6 months differs from overall number of subjects analyzed, due to patients unable to complete the trial: 56 in the Liraglutide Arm and 44 in the Glargine Arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Liraglutide + OADs | Glycemic Control at Hospital Discharge and 6 Months Follow up | HbA1C at hospital discharge | 8.3 % (mmol/mol) | Standard Deviation 0.9 |
| Liraglutide + OADs | Glycemic Control at Hospital Discharge and 6 Months Follow up | HbA1C at 6 months post-intervention | 7.13 % (mmol/mol) | Standard Deviation 1.3 |
| Glargine + OADs | Glycemic Control at Hospital Discharge and 6 Months Follow up | HbA1C at hospital discharge | 8.4 % (mmol/mol) | Standard Deviation 0.8 |
| Glargine + OADs | Glycemic Control at Hospital Discharge and 6 Months Follow up | HbA1C at 6 months post-intervention | 7.68 % (mmol/mol) | Standard Deviation 1.69 |
Secondary
Acute Renal Failure
Acute renal failure during the 26-week follow-up defined as a clinical diagnosis of acute renal failure with documented new-onset abnormal renal function (increment in creatinine \> 0.5 mg/dL from baseline)
Time frame: After discharge, average 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Liraglutide + OADs | Acute Renal Failure | 1 Participants |
| Glargine + OADs | Acute Renal Failure | 3 Participants |
Secondary
Cardiovascular Risk Factor: Heart Rate
Cardiovascular risk: heart rate at baseline and 26 weeks post-intervention
Time frame: 26 weeks post-intervention
Population: This outcome included patients with available heart rate data at 26 weeks follow-up.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Liraglutide + OADs | Cardiovascular Risk Factor: Heart Rate | Heart rate at baseline (discharge) | 79 beats/min | Standard Deviation 14 |
| Liraglutide + OADs | Cardiovascular Risk Factor: Heart Rate | Heart rate at 6 months post-discharge | 83 beats/min | Standard Deviation 13 |
| Glargine + OADs | Cardiovascular Risk Factor: Heart Rate | Heart rate at baseline (discharge) | 79 beats/min | Standard Deviation 14 |
| Glargine + OADs | Cardiovascular Risk Factor: Heart Rate | Heart rate at 6 months post-discharge | 79 beats/min | Standard Deviation 14 |
Secondary
Cardiovascular Risk Factor: Lipid Profile
Lipid profile was measured with total cholesterol level results at 26 weeks post-intervention. This outcome was not part of standard of care.
Time frame: 26 weeks post-intervention
Population: Total cholesterol was measured in 9 subjects only due to limited funding.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide + OADs | Cardiovascular Risk Factor: Lipid Profile | 190 mg/dL | Standard Deviation 6 |
| Glargine + OADs | Cardiovascular Risk Factor: Lipid Profile | 130 mg/dL | Standard Deviation 56 |
Secondary
Change in BMI
Change in BMI after 6 months from baseline
Time frame: Baseline, and follow up after discharge (average 6 months)
Population: This outcome only included participants with available data for BMI at baseline and follow up of 26 weeks.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Liraglutide + OADs | Change in BMI | Baseline BMI | 33.5 kg/m2 | Standard Deviation 5.3 |
| Liraglutide + OADs | Change in BMI | BMI at 26 weeks follow up | 32.7 kg/m2 | Standard Deviation 6.8 |
| Glargine + OADs | Change in BMI | Baseline BMI | 33.3 kg/m2 | Standard Deviation 5.3 |
| Glargine + OADs | Change in BMI | BMI at 26 weeks follow up | 33.3 kg/m2 | Standard Deviation 6.2 |
Secondary
Change in Body Weight From Baseline
Change in body weight from baseline after 6 months of follow up (26 weeks)
Time frame: After discharge, average 6 months
Population: This outcome only included participants with available data for body weight in Kgs at baseline and 26 weeks follow up.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Liraglutide + OADs | Change in Body Weight From Baseline | Baseline weight at discharge | 101.0 Kgs | Standard Deviation 20.6 |
| Liraglutide + OADs | Change in Body Weight From Baseline | Weight at six months | 97.2 Kgs | Standard Deviation 19.9 |
| Liraglutide + OADs | Change in Body Weight From Baseline | Weight change from baseline (discharge) to 6 months after discharge | -4.77 Kgs | Standard Deviation 8 |
| Glargine + OADs | Change in Body Weight From Baseline | Baseline weight at discharge | 98.2 Kgs | Standard Deviation 18 |
| Glargine + OADs | Change in Body Weight From Baseline | Weight at six months | 98.3 Kgs | Standard Deviation 22.1 |
| Glargine + OADs | Change in Body Weight From Baseline | Weight change from baseline (discharge) to 6 months after discharge | 0.6 Kgs | Standard Deviation 11 |
Secondary
Change in Cardiovascular Risk Factors: Blood Pressure
Cardiovascular risk factors including changes in systolic and diastolic blood pressure from baseline to 26 weeks post-intervention
Time frame: Baseline, 26 weeks post-intervention
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Liraglutide + OADs | Change in Cardiovascular Risk Factors: Blood Pressure | Diastolic blood pressure at baseline | 79 mmHg | Standard Deviation 11 |
| Liraglutide + OADs | Change in Cardiovascular Risk Factors: Blood Pressure | Diastolic blood pressure at 26 weeks follow up | 80 mmHg | Standard Deviation 13 |
| Liraglutide + OADs | Change in Cardiovascular Risk Factors: Blood Pressure | Systolic blood pressure at baseline | 134 mmHg | Standard Deviation 17 |
| Liraglutide + OADs | Change in Cardiovascular Risk Factors: Blood Pressure | Systolic blood pressure at 26 weeks follow up | 136 mmHg | Standard Deviation 22 |
| Glargine + OADs | Change in Cardiovascular Risk Factors: Blood Pressure | Systolic blood pressure at 26 weeks follow up | 135 mmHg | Standard Deviation 19 |
| Glargine + OADs | Change in Cardiovascular Risk Factors: Blood Pressure | Diastolic blood pressure at baseline | 77 mmHg | Standard Deviation 12 |
| Glargine + OADs | Change in Cardiovascular Risk Factors: Blood Pressure | Systolic blood pressure at baseline | 130 mmHg | Standard Deviation 17 |
| Glargine + OADs | Change in Cardiovascular Risk Factors: Blood Pressure | Diastolic blood pressure at 26 weeks follow up | 79 mmHg | Standard Deviation 14 |
Secondary
Emergency Room Visits and Readmissions
Number of participants who had at least one emergency room visit and hospital readmissions
Time frame: After discharge, average 6 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Liraglutide + OADs | Emergency Room Visits and Readmissions | Number of participants with at least one ER visit | 31 Participants |
| Liraglutide + OADs | Emergency Room Visits and Readmissions | Number of participants with at least one hospital readmission | 35 Participants |
| Glargine + OADs | Emergency Room Visits and Readmissions | Number of participants with at least one ER visit | 23 Participants |
| Glargine + OADs | Emergency Room Visits and Readmissions | Number of participants with at least one hospital readmission | 43 Participants |
Secondary
Fasting and Postprandial Blood Glucose (BG) Concentration After Follow up of 26 Weeks
To determine differences in BG concentration between liraglutide and glargine insulin therapy
Time frame: After discharge, average at 3 months (12 week) and 6 months (26 weeks)
Population: The number of subjects analyzed in this outcome at different time points from the overall number of subjects analyzed in other timepoints because it includes only those participants who were able to provide blood glucose results at the specified time points reported (12 and 26 weeks).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Liraglutide + OADs | Fasting and Postprandial Blood Glucose (BG) Concentration After Follow up of 26 Weeks | Postprandial blood glucose at 26 weeks follow up | 8.23 mmol/L | Standard Deviation 2.8 |
| Liraglutide + OADs | Fasting and Postprandial Blood Glucose (BG) Concentration After Follow up of 26 Weeks | Fasting blood glucose at 26 weeks follow up | 7.61 mmol/L | Standard Deviation 2.2 |
| Liraglutide + OADs | Fasting and Postprandial Blood Glucose (BG) Concentration After Follow up of 26 Weeks | Fasting blood glucose at 12 weeks | 7.96 mmol/L | Standard Deviation 3.3 |
| Liraglutide + OADs | Fasting and Postprandial Blood Glucose (BG) Concentration After Follow up of 26 Weeks | Post-prandial blood glucose at 12 weeks | 7.67 mmol/L | Standard Deviation 1.6 |
| Glargine + OADs | Fasting and Postprandial Blood Glucose (BG) Concentration After Follow up of 26 Weeks | Fasting blood glucose at 12 weeks | 7.70 mmol/L | Standard Deviation 2.6 |
| Glargine + OADs | Fasting and Postprandial Blood Glucose (BG) Concentration After Follow up of 26 Weeks | Post-prandial blood glucose at 12 weeks | 9.32 mmol/L | Standard Deviation 8.8 |
| Glargine + OADs | Fasting and Postprandial Blood Glucose (BG) Concentration After Follow up of 26 Weeks | Postprandial blood glucose at 26 weeks follow up | 8.72 mmol/L | Standard Deviation 2.3 |
| Glargine + OADs | Fasting and Postprandial Blood Glucose (BG) Concentration After Follow up of 26 Weeks | Fasting blood glucose at 26 weeks follow up | 8.56 mmol/L | Standard Deviation 3.8 |
Secondary
HbA1c <7.0% and no Hypoglycemia
Percent of patients with 26 week HbA1c \<7.0% and no hypoglycemia
Time frame: After discharge, average 6 months
Population: This outcome included only participants with available data for both variables: HbA1c and hypoglycemia
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Liraglutide + OADs | HbA1c <7.0% and no Hypoglycemia | 34 Participants |
| Glargine + OADs | HbA1c <7.0% and no Hypoglycemia | 29 Participants |
Secondary
HbA1c <7.0% and no Hypoglycemia
Percent of patients with 12 week HbA1c \<7.0% and no hypoglycemia
Time frame: After discharge, average 12 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Liraglutide + OADs | HbA1c <7.0% and no Hypoglycemia | 40 Participants |
| Glargine + OADs | HbA1c <7.0% and no Hypoglycemia | 31 Participants |
Secondary
HbA1c <7.0% and no Weight Gain
Percent of patients with 26 week HbA1c \<7.0% and no weight gain
Time frame: After discharge, average 6 months
Population: This outcome included only participants with available data for both variables: HbA1c and weight
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Liraglutide + OADs | HbA1c <7.0% and no Weight Gain | 32 Participants |
| Glargine + OADs | HbA1c <7.0% and no Weight Gain | 21 Participants |
Secondary
Hypoglycemic Episodes
Number of participants who had at least one hypoglycemic event (\<70 mg/dl) and severe hypoglycemic event (\<40 mg/dl)
Time frame: After discharge, average 6 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Liraglutide + OADs | Hypoglycemic Episodes | Participants who had at least one hypoglycemic events (<70 mg/dl) | 18 Participants |
| Liraglutide + OADs | Hypoglycemic Episodes | Participants who had at least one severe hypoglycemic event (<40 mg/dl) | 2 Participants |
| Glargine + OADs | Hypoglycemic Episodes | Participants who had at least one hypoglycemic events (<70 mg/dl) | 31 Participants |
| Glargine + OADs | Hypoglycemic Episodes | Participants who had at least one severe hypoglycemic event (<40 mg/dl) | 3 Participants |
Secondary
Self-measured Blood Glucose (SMBG) 7-point Profiles at 26 Weeks Follow up
Number of participants that reported self-measured blood glucose (SMBG) 7-point profiles at 26 weeks follow up
Time frame: 26 weeks post-intervention
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Liraglutide + OADs | Self-measured Blood Glucose (SMBG) 7-point Profiles at 26 Weeks Follow up | 34 Participants |
| Glargine + OADs | Self-measured Blood Glucose (SMBG) 7-point Profiles at 26 Weeks Follow up | 34 Participants |
Secondary
Total Daily Dose of Insulin
Evaluate the total daily dose of insulin needed in the group receiving glargine
Time frame: After discharge, average 6 months
Population: This outcome analyzed participants with available medication dose for the 26 weeks follow up.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide + OADs | Total Daily Dose of Insulin | 0 IU per day | Standard Deviation 0 |
| Glargine + OADs | Total Daily Dose of Insulin | 20.9 IU per day | Standard Deviation 11.1 |