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Effects of Single Doses of Liraglutide and Dapagliflozin on Hyperglycemia and Ketogenesis in Type 1 Diabetes (1974)

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ClinicalTrials.gov Identifier: NCT02777073
Recruitment Status : Completed
First Posted : May 19, 2016
Last Update Posted : February 9, 2017
Sponsor:
Information provided by (Responsible Party):
Paresh Dandona, University at Buffalo

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, Il-6 and IL-1 before and after administration of liraglutide/Dapagliflozin/placebo.

Condition or disease Intervention/treatment Phase
Type 1 Diabetes Drug: Farxiga Drug: Victoza Drug: Placebo Phase 3

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. 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.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 2 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Effects of Single Doses of Liraglutide and Dapagliflozin on Hyperglycemia and Ketogenesis in Type 1 Diabetes
Study Start Date : March 2016
Actual Primary Completion Date : December 2016
Actual Study Completion Date : December 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: liraglutide 1.8 mg
single dose of Victoza ( liraglutide) 1.8 mg
Drug: Victoza
Single dose of Liraglutide
Other Name: Liraglutide

Experimental: dapagliflozin 10
single dose of Farxiga ( dapagliflozin) 10 mg
Drug: Farxiga
Single dose of dapagliflozin
Other Name: dapagliflozin

Placebo Comparator: Placebo
Single dose of placebo
Drug: Placebo
Single dose of generic placebo




Primary Outcome Measures :
  1. difference in ketone bodies formation after single dose of liraglutide and dapagliflozin [ Time Frame: 8 hours ]
    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.


Secondary Outcome Measures :
  1. effect of liraglutide and dapagliflozin on glucagon concentrations [ Time Frame: 8 hours ]
    This secondary endpoint compares the area under the curve for glucagon over a period of 8 hours following liraglutide and dapagliflozin compared to placebo

  2. effect of liraglutide and dapagliflozin on Free Fatty Acid [ Time Frame: 8 hours ]
    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

  3. effect of liraglutide and dapagliflozin on C-Reactive Protein [ Time Frame: 8 Hours ]
    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

  4. effect of liraglutide and dapagliflozin on IL-6 and IL1-b [ Time Frame: 8 hours ]
    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



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02777073


Locations
United States, New York
ECMC Ambulatory Center, 3rd Floor
Buffalo, New York, United States, 14215
Sponsors and Collaborators
University at Buffalo

Responsible Party: Paresh Dandona, Distinguished Professor, University at Buffalo
ClinicalTrials.gov Identifier: NCT02777073     History of Changes
Other Study ID Numbers: 1974
First Posted: May 19, 2016    Key Record Dates
Last Update Posted: February 9, 2017
Last Verified: February 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Paresh Dandona, University at Buffalo:
Diabetic ketoacidosis
Insulin
Type 1 Diabetes
glucose (sugar) control
SGLT-2 inhibitors

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 1
Hyperglycemia
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Liraglutide
Hypoglycemic Agents
Physiological Effects of Drugs
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists