Type 1 Diabetes
Conditions
Brief summary
The glucose lowering effects of GLP-1 agonists are well established in subjects with type 2 diabetes, however, these have not been studied prospectively in subjects with type 1 diabetes. The investigators have, therefore, designed this study to investigate the central hypothesis that in patients with type 1 diabetes, Liraglutide has a glucose lowering effect. A major secondary objective of this study is to elucidate the mechanisms responsible for its glucose lowering effects and those involved in reducing the insulin dose. The specific aims of this proposal are: Hypothesis 1: Treatment with Liraglutide in patients with type 1 diabetes decreases HbA1c, fasting, postprandial and the overall mean glucose concentrations while decreasing the dose of insulin required. Hypothesis 2: Treatment with Liraglutide in patients with type 1 diabetes decreases basal and postprandial glucagon concentrations and increases basal and postprandial C-peptide concentrations. Hypothesis 3: Treatment with Liraglutide in patients with type 1 diabetes delays gastric emptying.
Detailed description
The control of glucose homeostasis in subjects with type 1 diabetes is fragile since exogenous insulin cannot compensate for changing requirements and is not precise either in terms of the dose or the bio-availability of the insulin injected. Furthermore, in the near total absence of insulin secretion, the physiological post prandial inhibition of glucagon secretion by the α-cell is also probably deficient in all type 1 diabetics. Thus, there is a need for therapies beyond insulin that can further improve glycemic control and reduce fluctuations in glucose in these subjects. The investigators have recently shown that Liraglutide, a glucagon like peptide (GLP)-1 analogue with duration of action of 24 hours, when added to insulin in subjects with well controlled type 1 diabetes reduces mean and standard deviation of blood glucose, HbA1c and insulin requirements. Since C-peptide concentrations did not alter following Liraglutide, it is likely that the suppression of glucagon may have contributed to this effect. The glucose lowering effects of GLP-1 agonists are well established in subjects with type 2 diabetes, however, these have not been studied prospectively in subjects with type 1 diabetes. The investigators have, therefore, designed this study to investigate the central hypothesis that in patients with type 1 diabetes, Liraglutide has a glucose lowering effect. A major secondary objective of this study is to elucidate the mechanisms responsible for its glucose lowering effects and those involved in reducing the insulin dose. The specific aims of this proposal are: Hypothesis 1: Treatment with Liraglutide in patients with type 1 diabetes decreases HbA1c, fasting, postprandial and the overall mean glucose concentrations while decreasing the dose of insulin required. Aim 1.1: To compare the HbA1c, mean fasting, glucose, mean weekly glucose, standard deviation of weekly blood glucose concentrations as recorded by continuous glucose monitoring and the dose of insulin required prior to and following 52 weeks of treatment with 1.8 mg of liraglutide daily. Aim 1.2: To compare the postprandial glucose concentrations following a test meal before and after 52 weeks of treatment with 1.8 mg of liraglutide daily. Hypothesis 2: Treatment with Liraglutide in patients with type 1 diabetes decreases basal and postprandial glucagon concentrations and increases basal and postprandial C-peptide concentrations. Aim 2.1: To compare the basal and postprandial glucagon and C-peptide concentrations following a test meal before and after 52 weeks of treatment with 1.8 mg of liraglutide daily. Hypothesis 3: Treatment with Liraglutide in patients with type 1 diabetes delays gastric emptying. Aim 3.1: To compare the gastric emptying as measured by acetaminophen absorption before and after treatment with 1.8 mg of daily subcutaneous liraglutide.
Interventions
DRUGLiraglutide 1.8mg
DRUGPlacebo
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University at Buffalo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
1. Type 1 Diabetes on continuous subcutaneous insulin infusion (CSII; also known as insulin pump) or multiple (four or more) injections of insulin per day. 2. Regularly measuring blood sugars four times daily. 3. HbA1c of less than 8.5%. 4. Well versed with carbohydrate counting. 5. Age 18-75 years. 6. BMI 20-40 kg/m2
Exclusion criteria
1. Type 1 diabetes for less than 6 months; 2. Coronary event or procedure (myocardial infarction, unstable angina, coronary artery bypass, surgery or coronary angioplasty) in the previous four weeks; 3. Hepatic disease (transaminase \> 3 times normal) or cirrhosis; 4. Renal impairment (serum eGFR \< 30ml/min/1.73m2); 5. HIV or Hepatitis B or C positive status; 6. Participation in any other concurrent clinical trial; 7. Any other life-threatening, non-cardiac disease; 8. Use of an investigational agent or therapeutic regimen within 30 days of study. 9. history of pancreatitis 10. pregnancy 11. inability to give informed consent 12. history of gastroparesis 13. history of medullary thyroid carcinoma or MEN 2 syndrome.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HbA1c (%) | 52 Weeks | HbA1c measured at baseline and after 52 weeks of treatment with Liraglutide or placebo. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Weekly Glucose Concentrations. | 52 Weeks | Mean weekly glucose concentrations measured by CGM at baseline and at 52 weeks |
| Body Weight | 52 weeks | Body weight in Kg measured at weeks 0 (baseline) and at 52 weeks after treatment with liraglutide or placebo |
Countries
United States
Participant flow
Pre-assignment details
Exclusion Criteria: Type 1 diabetes for less than 6 months. Coronary event or procedure (myocardial infraction, unstable angina, coronary artery bypass surgery or coronary angioplasty) in the previous four weeks. Hepatic disease (transamine \> 3 times normal) or cirrhosis. Renal impairment (serum eGFR \< 30 mL/min/1.73m2).
Participants by arm
| Arm | Count |
|---|---|
| Liraglutide 1.8mg Daily Injection
Liraglutide 1.8mg | 29 |
| Placebo Daily Injection
Placebo | 27 |
| Total | 56 |
Baseline characteristics
| Characteristic | Liraglutide 1.8mg | Placebo | Total |
|---|---|---|---|
| Age, Customized Age | 45 years STANDARD_DEVIATION 2 | 47 years STANDARD_DEVIATION 3 | 46 years STANDARD_DEVIATION 2.5 |
| Body Mass Index (BMI) | 28.9 Kg/m2 STANDARD_DEVIATION 1.1 | 29.1 Kg/m2 STANDARD_DEVIATION 1.6 | 29.0 Kg/m2 STANDARD_DEVIATION 1.2 |
| HbA1c (%) | 7.92 percentage of hemoglobin STANDARD_DEVIATION 0.19 | 7.50 percentage of hemoglobin STANDARD_DEVIATION 0.18 | 7.71 percentage of hemoglobin STANDARD_DEVIATION 0.18 |
| 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 | 3 Participants | 2 Participants | 5 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 | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) White | 24 Participants | 23 Participants | 47 Participants |
| Sex/Gender, Customized Gender female | 17 Participants | 13 Participants | 30 Participants |
| Sex/Gender, Customized Gender male | 12 Participants | 14 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 20 |
| other Total, other adverse events | 0 / 26 | 0 / 20 |
| serious Total, serious adverse events | 0 / 26 | 0 / 20 |
Outcome results
Primary
HbA1c (%)
HbA1c measured at baseline and after 52 weeks of treatment with Liraglutide or placebo.
Time frame: 52 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Liraglutide | HbA1c (%) | week 0 | 7.92 Percent of Hemoglobin (%) | Standard Error 0.15 |
| Liraglutide | HbA1c (%) | week 52 | 7.45 Percent of Hemoglobin (%) | Standard Error 0.12 |
| Placebo | HbA1c (%) | week 0 | 7.48 Percent of Hemoglobin (%) | Standard Error 0.18 |
| Placebo | HbA1c (%) | week 52 | 7.58 Percent of Hemoglobin (%) | Standard Error 0.14 |
Secondary
Body Weight
Body weight in Kg measured at weeks 0 (baseline) and at 52 weeks after treatment with liraglutide or placebo
Time frame: 52 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Liraglutide | Body Weight | week 0 | 83.6 Kg | Standard Error 3.8 |
| Liraglutide | Body Weight | week 52 | 80.5 Kg | Standard Error 3.8 |
| Placebo | Body Weight | week 0 | 84.1 Kg | Standard Error 4 |
| Placebo | Body Weight | week 52 | 83.8 Kg | Standard Error 4 |
Secondary
Mean Weekly Glucose Concentrations.
Mean weekly glucose concentrations measured by CGM at baseline and at 52 weeks
Time frame: 52 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Liraglutide | Mean Weekly Glucose Concentrations. | week 0 | 173 mg/dL | Standard Error 5 |
| Liraglutide | Mean Weekly Glucose Concentrations. | week 52 | 156 mg/dL | Standard Error 6 |
| Placebo | Mean Weekly Glucose Concentrations. | week 0 | 160 mg/dL | Standard Error 6 |
| Placebo | Mean Weekly Glucose Concentrations. | week 52 | 156 mg/dL | Standard Error 6 |