Poster Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2016

Silent Diabetic Ketoacidosis: Sodium-Glucose Cotransporter 2 Inhibitor-Induced Euglycaemic Diabetic Ketoacidosis (#269)

Shamil D Cooray 1 , Yvonne Y Chow 1 , Roisin N Worsley 1 2 , Shoshana Sztal-Mazer 1 , Leon A Bach 1 3
  1. Department of Endocrinology and Diabetes, Alfred Hospital, Melbourne, Victoria, Australia
  2. Monash Alfred Psychiatry Research Centre, Monash University, Melbourne, Victoria, Australia
  3. Department of Medicine (Alfred), Monash University, Prahran, Victoria, Australia

Two recent cases of sodium-glucose cotransporter 2 (SGLT2) inhibitor-induced diabetic ketoacidosis (DKA) in patients with type 2 diabetes (T2DM) will be presented. Case one was a 51 year old male who developed severe DKA (pH 6.88, blood glucose 22 mmol/L) in the setting of a non-ST elevation myocardial infarction and recent substitution of a sulphonylurea with dapagliflozin together with metformin. Case two was a 48 year old female who developed euglycaemic diabetic ketoacidosis (euDKA, pH 7.18, blood glucose 7.1 mmol/L) two days after an elective craniotomy and clipping of a left middle cerebral artery aneurysm in the context of well-controlled T2DM on basal-bolus insulin, metformin and canagliflozin, which had been started a year earlier.

The incidence of DKA among patients with T2DM on SGLT2 inhibitors has been estimated to be 0.1-0.8 per 1,000 patient years (1). Concerningly, hyperglycaemia, usually the earliest warning sign for DKA, has been reported to be absent in most cases.

SGLT2 inhibitors may cause euDKA by increasing glucagon levels (2, 3) and by direct action on pancreatic alpha cells (4). Furthermore, animal studies suggest SGLT2 inhibitors may indirectly increase renal tubular reabsorption of ketone bodies (5).

Risk factors for SGLT2 inhibitor-induced euDKA may be classified into those factors which lead to: (a) decreased insulin supply such as underlying beta cell insufficiency or inappropriate reduction of exogenous insulin dose; or (b) increased glucagon such as physiologic stress, low carbohydrate diet, prolonged starvation or heavy alcohol intake. A prudent approach to prevent SGLT2 inhibitor-induced euDKA in patients with T2DM would include their temporary cessation during severe illness or major surgical procedures. Furthermore general practitioners, emergency medicine physicians and hospital medical staff must be educated on the need to check for capillary or urinary ketones in patients with T2DM on these agents when unwell, regardless of blood glucose levels.

  1. Erondu N, Desai M, Ways K, Meininger G. Diabetic Ketoacidosis and Related Events in the Canagliflozin Type 2 Diabetes Clinical Program. Diabetes Care. 2015;38(9):1680-6.
  2. Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. The Journal of Clinical Investigation. 2014;124(2):499-508.
  3. Merovci A, Solis-Herrera C, Daniele G, Eldor R, Fiorentino TV, Tripathy D, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. The Journal of Clinical Investigation.2014;124(2):509-14.
  4. Bonner C, Kerr-Conte J, Gmyr V, Queniat G, Moerman E, Thevenet J, et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nature medicine. 2015;21(5):512-7.
  5. Cohen JJ, Berglund F, Lotspeich WD. Renal tubular reabsorption of acetoacetate, inorganic sulfate and inorganic phosphate in the dog as affected by glucose and phlorizin. The American Journal of Physiology. 1956;184(1):91-6.