Effects of Single Doses of Liraglutide and Dapagliflozin on Hyperglycemia and Ketogenesis in Type 1 Diabetes

Study Overview
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Brief Summary
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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. To compare plasma levels of free fatty acid, glucagon, hs-CRP, Il-6 and IL-1 before and after administration of liraglutide/Dapagliflozin/placebo.

Detailed Description
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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. On the other hand, addition of SGLT 2 inhibitor can shift these biochemical changes to other direction thus increasing ketogenesis /ketoacidosis. It is essential to investigate this area further as there are no prior studies that have investigated the acute effects of liraglutide/Dapagliflozin on FFAs or ketogenesis. This study will be the first randomized controlled prospective study investigating the effect of liraglutide/dapagliflozin 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. The same patient (as described in 8.3, cross over study), will get the other 2 treatments in random order in the following 2 visits (one week apart) for a total participation of 2 weeks+1 day.

Official Title
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Effects of Single Doses of Liraglutide and Dapagliflozin on Hyperglycemia and Ketogenesis in Type 1 Diabetes

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Drug: Farxiga
* Drug: Victoza
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 1 Diabetes on continuous subcutaneous insulin infusion (CSII, also known as insulin pump). Undetectable c peptide (c-peptide < 0.1 ng/ml). HbA1c of less than or equal to 8.5%. Age 18-75 inclusive Exclusion Criteria: Type 1 diabetes for less than 12 months Coronary event/ procedure (MI, Unstable angina, CABG, PCI) in the last four weeks Hepatic disease (Transaminase > 3 times normal) or Cirrhosis Renal impairment (serum eGFR <30ml/min/1.73m2) HIV or Hepatitis B or C positive status History of pancreatitis, i.e., history of gallstones, alcohol abuse and hypertriglyceridemia Pregnancy Inability to give informed consent History of Gastroparesis Personal or Family History of medullary thyroid carcinoma or MEN 2 syndrome Alcoholism Hypertriglyceridemia (>500 mg/dl). Those with history of bladder cancer , diabetic ketoacidosis

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: liraglutide 1.8 mg<br>single dose of Victoza ( liraglutide) 1.8 mg | Drug: Victoza<br>* Single dose of Liraglutide<br>* Other names: Liraglutide;|
| Experimental: dapagliflozin 10<br>single dose of Farxiga ( dapagliflozin) 10 mg | Drug: Farxiga<br>* Single dose of dapagliflozin<br>* Other names: dapagliflozin;|
| Placebo Comparator: Placebo<br>Single dose of placebo | Drug: Placebo<br>* Single dose of generic placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| difference in ketone bodies formation after single dose of liraglutide and dapagliflozin | 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. | 8 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| effect of liraglutide and dapagliflozin on glucagon concentrations | This secondary endpoint compares the area under the curve for glucagon over a period of 8 hours following liraglutide and dapagliflozin compared to placebo | 8 hours | 
| effect of liraglutide and dapagliflozin on Free Fatty Acid | This secondary endpoint compares the area under the curve for Free Fatty Acid over a period of 8 hours following liraglutide and dapagliflozin compared to placebo | 8 hours | 
| effect of liraglutide and dapagliflozin on C-Reactive Protein | This secondary endpoint compares the area under the curve for C-reactive protein over a period of 8 hours following liraglutide and dapagliflozin compared to placebo | 8 Hours | 
| effect of liraglutide and dapagliflozin on IL-6 and IL1-b | This secondary endpoint compares the area under the curve for IL-6 and IL1-b over a period of 8 hours following liraglutide and dapagliflozin compared to placebo | 8 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetic ketoacidosis, Insulin, Type 1 Diabetes, glucose (sugar) control, SGLT-2 inhibitors