OR15-6 Dapagliflozin Induces Ketosis in Patients with Type 1 Diabetes

Program: Abstracts - Orals, Poster Previews, and Posters
Session: OR15-Novel Treatment for Diabetes - Focusing on GLP-1 and SGLT2
Clinical
Saturday, April 2, 2016: 11:45 AM-1:15 PM
Presentation Start Time: 1:00 PM
Room 157 (BCEC)

Helmsley Charitable Trust Abstract Awards in Type 1 Diabetes
Husam Ghanim*1, Nitesh D Kuhadiya1, Salman Khan2, Manisha Garg3, Kelly Green4, Sanaa Abuaysheh2 and Paresh Dandona3
1University at Buffalo, Buffalo, NY, 2Suny at Buffalo, 3Diabetes and Endocrinology Center of Western New York, Buffalo, NY, 4SUNY at Buffalo
Liraglutide and SGLT2 inhibitors have a beneficial role in the management of type 1 diabetes (T1D). We have now investigated triple therapy using a sequential combination of insulin, liraglutide and dapagliflozin in such patients. Since treatment with SGLT-2 inhibitors in T1D is associated with increased risk of diabetic ketoacidosis (DKA), we have also now investigated the effect of dapagliflozin on mediators of ketosis in patients on triple therapy. Thirty T1D patients on insulin and liraglutide therapy for at least last 6 months were randomized (in 2:1 ratio, drug: placebo) to receive either dapagliflozin 10mg or placebo daily for 12 weeks. Dapagliflozin was initiated at 5mg daily for one week and increased to 10mg daily thereafter. Twenty-six patients completed the study (Placebo=9; Dapagliflozin=17). The addition of dapagliflozin resulted in a decrease in HbA1c of 0.6±0.1% (p<0.01 vs placebo). Along with improved glycemic control there was a significant increase in glucagon concentrations by 35±13%(from 91±12 to 114±19pg/ml, p<0.05), hormone sensitive lipase(HSL) by 29±11%(from 4.95±0.66 to 16.32±0.75ng/ml,p<0.05), FFA(from 0.34±0.04 to 0.59±0.11mM; p<0.05), glycerol (from 11.2±2.4 to 13.6±3.5mg/L, NS), acetoacetate(from 0.32±0.09 to 0.53±0.11mM, p<0.05) and β-hydroxybutyrate(from 0.11±0.02 to 0.39±0.09mM, p<0.05) while there was no change in the placebo group. Urinary ketones(acetoacetate and β-hydroxybutyrate) levels also increased significantly from 0.68±0.19 to 1.28±0.34µM/mg creatinine (p<0.05). There was no change in plasma bicarbonate concentrations. There was no change in mean total insulin dose in either group. Serum β-hydroxybutyrate levels were related to FFA concentrations(r=0.374, p<0.05) and inversely to total insulin dose at 12 weeks(r=-0.297, p<0.05) but not to HSL or glucagon levels. Two patients in the dapagliflozin group suffered from DKA within a day after increasing the dose of dapagliflozin to 10mg and were withdrawn from the study. Both patients had an arterial pH of <7.10. One of these patients had euglycemic DKA with blood glucose concentrations <160mg/dl(total insulin dose fell from 33 to 26 units daily) while the other had marked hyperglycemia. Both were appropriately rehydrated and treated with intravenous insulin and reverted to the combination of insulin and liraglutide in the long term. We conclude that all patients treated with dapagliflozin experienced increased lipolysis stimulated by glucagon and HSL with an increase in plasma FFA concentrations; ketogenesis increased with a greater bio-availability of FFA and ketosis not amounting to DKA. However, the concomitant reduction in insulin and or the increased dose of dapagliflozin resulted in DKA in two patients. Caution needs to be exercised while decreasing insulin doses and increasing dapagliflozin doses in such patients.

Disclosure: NDK: Speaker, Astra Zeneca, Speaker, Novo Nordisk. PD: Speaker, Astra Zeneca, Speaker, Novo Nordisk. Nothing to Disclose: HG, SK, MG, KG, SA

*Please take note of The Endocrine Society's News Embargo Policy at https://www.endocrine.org/news-room/endo-annual-meeting/pr-resources-for-endo