SGLT2 Inhibitor Induced Euglycemic DKA (EDKA) With Proximal Renal Tubular Acidosis (RTA) as a Rare Fatal Complication in a Non-Insulin Dependent Diabetic Patient: A Challenging Dilemma

Introduction: Diabetic Ketoacidosis (DKA) is characterized by a triad of hyperglycemia, acidemia, and ketonemia. Rarely, it would present with normal glucose levels making its diagnosis very challenging. The incidence of euglycemic DKA (eDKA) has increased with the introduction of the novel sodium-glucose cotransporter-2 inhibitors (SGLT2i). Currently, the reported incidence of SGLT2i induced DKA is 0.16–0.76 events per 1000 patient-years. We present a rare case of SGLT2i induced eDKA with proximal renal tubular acidosis (RTA). Case Presentation A 69 year-old male with type 2 diabetes mellitus presented to the hospital with severe respiratory distress, nausea and vomiting for 2 days. His home medications include metformin and canagliflozin. He was afebrile with respiratory rate 60 breaths/min. Arterial blood gas: pH 7.21, pCO2 9.2, pO2 223, HCO3 6. Blood glucose level was 120 mg/dl. Urinalysis was positive for large ketonuria >160 mg/dl and glycosuria >500 mg/dl. Serum anion gap and urine anion gap were elevated 29 mEq/L and 105 mEq/L respectively. Serum osmolarity and urine osmolality were elevated 296 mosm/kg and 653 mosm/kg respectively. Lactic acid was 5.3. Acetone was detected in blood. No source of infection was identified. Hemoglobin A1C was 5% and c-peptide was within normal range. Insulin and Islet cells antibodies were negative. DKA protocol was initiated until the anion gap closed. However, non-anion gap metabolic acidosis was persistent with profound hypophosphatemia. Repeat urinalysis showed glycosuria with pH ≤ 5.5, phosphaturia and generalized aminoaciduria. Ultimately, the patient elected to receive hospice care. Discussion: SGLT2i are currently recommended as second-line medications for type 2 diabetes mellitus. Their unique mechanism of action prevents glucose reabsorption from the proximal renal tubules. SGLT2i use is growing significantly, especially after recent clinical trials that demonstrated favorable protective effects. EDKA is precipitated by sepsis, acute illness, dehydration, or starvation. Once the diagnosis is suspected, SGLT2i should be stopped immediately. SGLT2i induced eDKA should be treated in a similar fashion as DKA. It is worth to note that SGLT2i half-life ranges from 11–17 hours, and despite drug discontinuation, glycosuria may persist for several days. What made our case unique and made the diagnosis challenging, was the normal blood glucose level, as well as other differentials that could have easily explained the acidosis including starvation ketosis and lactic acidosis. Also, the state of proximal RTA resembling renal Fanconi syndrome that occurred in correlation with canagliflozin therapy. To the best of our knowledge, this is the fourth reported case of proximal RTA with the use of canagliflozin resulting in life-threatening complications. The diagnosis was very challenging due to lack of awareness of this severe adverse effect.