Type 1 Diabetes
Conditions
Keywords
Diabetic ketoacidosis, Insulin, Type 1 Diabetes, glucose (sugar) control
Brief summary
1. To compare levels of ketone bodies (beta-hydroxybutyrate and acetoacetate) in plasma and urine following a single dose treatment of either liraglutide 1.8mg, dapagliflozin 10mg or placebo in insulinopenic state. 2. To compare plasma levels of free fatty acid, glucagon, hs-CRP, Ll-6 and IL-1 before and after administration of liraglutide/placebo.
Detailed description
Diabetic ketoacidosis is an important cause of mortality and morbidity in type 1 patients. The decreased ratio of insulin to glucagon in insulin deficient subjects promotes ketogenesis. In patients with type 1 diabetes, the suppressive effect of hyperglycemia and the paracrine inhibitory effect of insulin and GABA from the β cell on α cell are absent. Thus, plasma glucagon concentrations are elevated and in combination with insulin deficiency, lead to lipolysis, increased plasma FFA concentrations and an increased fatty acid supply to the liver. Thus, both fatty acid oxidation and ketogenesis are enhanced. Our recent work has shown that liraglutide, a GLP 1 agonist, improves glycemic control and reduces glycemic excursions in patients with type 1 diabetes within a few days of the initiation of treatment. With this background, the investigators hypothesize that suppression of glucagon with liraglutide in patients with type 1 diabetes may protect them from lipolysis, increased bio-availability of FFAs, ketogenesis and ketoacidosis. It is essential to investigate this area further as there are no prior studies that have investigated the acute effects of liraglutide on FFAs or ketogenesis. This study will be the first randomized controlled prospective study investigating the effect of liraglutide on ketogenesis. Also, it would be important to measure the mediators of inflammation at the same time to investigate whether there is a concomitant changes of inflammatory factors in parallel with the lipolysis and ketogenesis. After the screening visit, subjects who meet the inclusion and exclusion criteria will be randomized to receive a single dose of either liraglutide, dapagliflozin or placebo and will be monitored for a total of 8 hours.
Interventions
DRUGVictoza
Single dose of Liraglutide
DRUGPlacebo
Single dose of generic placebo
DRUGDapagliflozin 10mg Tab
single dose of 10 mg dapagliflozin
Sponsors
University at Buffalo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Type 1 Diabetes on continuous subcutaneous insulin infusion (CSII, also known as insulin pump). 2. Undetectable c peptide (c-peptide \< 0.1 ng/ml). 3. HbA1c of less than or equal to 8.5%. 4. Age 18-75 inclusive
Exclusion criteria
1. Type 1 diabetes for less than 12 months 2. Coronary event/ procedure (MI, Unstable angina, CABG, PCI) in the last 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. History of pancreatitis, i.e., history of gallstones, alcohol abuse and hypertriglyceridemia 7. Pregnancy 8. Inability to give informed consent 9. History of Gastroparesis 10. Personal or Family History of medullary thyroid carcinoma or MEN 2 syndrome 11. Alcoholism 12. Hypertriglyceridemia (\>500 mg/dl). 13. Those with history of bladder cancer , diabetic ketoacidosis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference in Ketone Bodies Formation After Single Dose of Liraglutide and Dapagliflozin | 8 hours | To compare levels of ketone bodies beta-hydroxybutyrate in plasma following a single dose treatment of either liraglutide 1.8mg,dapagliflozin 10mg or placebo in insulinopenic state. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Glucagon Levels. | 8 hours | This secondary endpoint compares change in glucagon concentrations (in pg/ml) from baseline at 8 hours following liraglutide and dapagliflozin compared to placebo |
| Change in Free Fatty Acid (FFA) Concentrations | 8 hours | This secondary endpoint compares the change in FFA concentrations (mM) from baseline at 8 hours following liraglutide and dapagliflozin compared to placebo |
| Change in Ghrelin Concentrations | 8 Hours | This secondary endpoint compares the change in ghrelin concentrations (pg/ml) from baseline at 8 hours following liraglutide and dapagliflozin compared to placebo |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Liraglutide 1.8 mg single dose of Victoza ( liraglutide) 1.8 mg
Victoza: Single dose of Liraglutide | 13 |
| Dapagliflozin 10 single dose of Farxiga ( dapagliflozin) 10 mg
Farxiga: Single dose of dapagliflozin | 17 |
| Placebo Single dose of placebo
Placebo: Single dose of generic placebo | 13 |
| Total | 43 |
Baseline characteristics
| Characteristic | Liraglutide 1.8 mg | Dapagliflozin 10 | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 17 Participants | 13 Participants | 43 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 17 Participants | 13 Participants | 43 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 7 Participants | 10 Participants | 7 Participants | 24 Participants |
| Sex: Female, Male Male | 6 Participants | 7 Participants | 6 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 17 | 0 / 13 |
| other Total, other adverse events | 0 / 13 | 0 / 17 | 0 / 13 |
| serious Total, serious adverse events | 0 / 13 | 0 / 17 | 0 / 13 |
Outcome results
Primary
Difference in Ketone Bodies Formation After Single Dose of Liraglutide and Dapagliflozin
To compare levels of ketone bodies beta-hydroxybutyrate in plasma following a single dose treatment of either liraglutide 1.8mg,dapagliflozin 10mg or placebo in insulinopenic state.
Time frame: 8 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide 1.8 mg | Difference in Ketone Bodies Formation After Single Dose of Liraglutide and Dapagliflozin | 0.08 mM | Standard Error 0.05 |
| Placebo | Difference in Ketone Bodies Formation After Single Dose of Liraglutide and Dapagliflozin | 0.25 mM | Standard Error 0.05 |
| Dapagliflozin | Difference in Ketone Bodies Formation After Single Dose of Liraglutide and Dapagliflozin | 0.21 mM | Standard Error 0.05 |
Secondary
Change in Free Fatty Acid (FFA) Concentrations
This secondary endpoint compares the change in FFA concentrations (mM) from baseline at 8 hours following liraglutide and dapagliflozin compared to placebo
Time frame: 8 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide 1.8 mg | Change in Free Fatty Acid (FFA) Concentrations | 0.1 mM | Standard Error 0.06 |
| Placebo | Change in Free Fatty Acid (FFA) Concentrations | 0.17 mM | Standard Error 0.06 |
| Dapagliflozin | Change in Free Fatty Acid (FFA) Concentrations | 0.11 mM | Standard Error 0.06 |
Secondary
Change in Ghrelin Concentrations
This secondary endpoint compares the change in ghrelin concentrations (pg/ml) from baseline at 8 hours following liraglutide and dapagliflozin compared to placebo
Time frame: 8 Hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide 1.8 mg | Change in Ghrelin Concentrations | -32 pg/mL | Standard Error 28 |
| Placebo | Change in Ghrelin Concentrations | 66 pg/mL | Standard Error 29 |
| Dapagliflozin | Change in Ghrelin Concentrations | 32 pg/mL | Standard Error 26 |
Secondary
Change in Glucagon Levels.
This secondary endpoint compares change in glucagon concentrations (in pg/ml) from baseline at 8 hours following liraglutide and dapagliflozin compared to placebo
Time frame: 8 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide 1.8 mg | Change in Glucagon Levels. | -19 pg/mL | Standard Error 14 |
| Placebo | Change in Glucagon Levels. | 1 pg/mL | Standard Error 6 |
| Dapagliflozin | Change in Glucagon Levels. | -15 pg/mL | Standard Error 5 |