Effects of Single Doses of Liraglutide and Dapagliflozin on Hyperglycemia and Ketogenesis in Type 1 Diabetes
Condition: Type 1 Diabetes
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Hyperglycemia
Study type: Interventional
Phase: Phase 3

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.
    

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.
    

Intervention name(s): Farxiga; Victoza; Placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Single dose of dapagliflozin; Single dose of Liraglutide; Single dose of generic placebo
Other intervention name(s): dapagliflozin; Liraglutide
Intervention MeSH terms: Dapagliflozin; Liraglutide
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Diabetic ketoacidosis; Insulin; Type 1 Diabetes; glucose (sugar) control; SGLT-2 inhibitors