Sodium-glucose Cotransporter 2 Inhibitor–induced Diabetic Ketoacidosis in a Type 2 Diabetic Patient

Sodium-glucose Cotransporter 2 Inhibitor–induced Diabetic Ketoacidosis in a Type 2 Diabetic Patient

Author's Accepted Manuscript Sodium Glucose Cotransporter-2 Inhibitor Induced Diabetic Ketoacidosis in a Type 2 Diabetic Patient Edna M. Juarez Ramir...

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Author's Accepted Manuscript

Sodium Glucose Cotransporter-2 Inhibitor Induced Diabetic Ketoacidosis in a Type 2 Diabetic Patient Edna M. Juarez Ramirez Tello MD, Menfil A. Orellana-Barrios MD, Kenneth Nugent MD

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S0002-9629(16)30212-9 http://dx.doi.org/10.1016/j.amjms.2016.03.014 AMJMS144

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Cite this article as: Edna M. Juarez Ramirez Tello MD, Menfil A. Orellana-Barrios MD, Kenneth Nugent MD, Sodium Glucose Cotransporter-2 Inhibitor Induced Diabetic Ketoacidosis in a Type 2 Diabetic Patient, Am J Med Sci, http://dx.doi.org/ 10.1016/j.amjms.2016.03.014 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

TITLE PAGE Title: Sodium Glucose Cotransporter-2 Inhibitor Induced Diabetic Ketoacidosis in a Type 2 Diabetic Patient Short Title: SGLT-2 inhibitor induced DKA Authors: Edna M. Juarez Ramirez Tello, MD1 Menfil A. Orellana-Barrios, MD1 Kenneth Nugent, MD1 1. Texas Tech University Health Sciences Center, Department of Internal Medicine 3601 4th Street, MS 9410 Lubbock, TX 79430 United States of America

Corresponding Author: Menfil A. Orellana-Barrios, MD 3601 4th Street, MS 9410 Lubbock, TX 79430 United States of America Email: [email protected] ; [email protected]

Summary conflict of interest statements EMJRT: none MAOB: none KN: none Funding source Not applicable

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Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a novel drug class for the treatment of type 2 diabetes mellitus (DMII) that work by decreasing renal glucose reabsorption. Almost 2 years after approval in the U.S., the U.S. Food and Drug Administration issued a Drug Safety communication about the potential risk of developing diabetic ketoacidosis (DKA) while taking these SGLT2 inhibitors. 1 We recently encountered a 36-year-old Hispanic man with 16-year history of diabetes mellitus type II (DMII), hyperlipidemia, and hypertension who presented to the emergency room with a 2-week history of nausea, vomiting, fatigue, and headaches. His symptom onset coincided with changing his regular DMII medications (metformin 1g BID, glyburide 5mg QD) to canagliflozin (Invokana©) 300mg daily plus metformin 1g BID for uncontrolled HgbA1c levels (10.9%). Due to the increasing vomiting, he stopped canaglifozin within 3 days but continued metformin. At his 3 week follow-up, canagliflozin was restarted at a decreased dose of 100mg daily. Again, his symptoms returned so he went to the ER. On admission, physical exam was remarkable for obesity (BMI 36 kg/m 2), tachycardia (102 beats per minute), dry oral mucosa, and acanthosis nigricans. Laboratory evaluation revealed glucose 219 mg/dL, bicarbonate 8 mmol/L, anion gap 38, high serum acetone (>1.0 mmol/L), sodium 130 mmol/L, potassium 4.9 mmol/L, creatinine 0.5 mg/dL, BUN 19 mg/dL, lactic acid 1.1mmol/L, and WBC 10.4 k/µL. Arterial pH was 7.25, and PCO2 was 21mmHg. He was started on insulin drip and IV fluids. After treatment, the anion gap closed, his symptoms improved, and he was started on insulin detemir 30 units daily. The patient’s blood glucose on remained within a range of 167-248 mg/dL. Glutamic acid decarboxylaxeauto-65 antibody was negative. He was discharged on Metformin 1g BID and insulin detemir 30 units daily. At 4 months follow up, he had not had any other ketoacidosis episodes, although he still presented high HgbA1c levels (11%). His insulin was increased to 45 units daily and lifestyle changes were enforced.

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SGLT2 inhibitors are a novel drug class for the treatment of type 2 diabetes mellitus that lower the renal threshold of glucose, enhance glucose excretion, and decrease glucose reabsorption. These drugs help to achieve serum glucose and HbA1c goals, weight loss, and even blood pressure control by inhibition of the renin angiotensin aldosterone system. Almost 2 years after its approval in the U.S. for the treatment of type 2 diabetes mellitus (DM) and after multiple post marketing clinical research reports, the U.S. Food and Drug Administration issued a Drug Safety communication based on the data base of the Adverse Event Communicating System.1 A large adverse event analysis has been published, including 17,596 type 2 diabetic patients from randomized studies of canagliflozin through May 2011.2 The incidence of serious adverse events of DKA and related events was 0.07% (12 patients). The incidence of DKA and related events by treatment group was 0.07% (4 of 5,337), 0.11% (6 of 5,350), and 0.03% (2 of 6,909) with canagliflozin 100 and 300 mg and comparator (12 out of the 15 randomized controlled trials used placebo only, one used placebo plus sitagliptin, one used metformin XR, and one used sitagliptin only as comparator), respectively. In this review, 6 patients were identified as latent auto immune diabetes of the adult or type 1 diabetes or tested positive for GAD65 antibodies. The incidence of DKA in type 2 DM was 0.2% (1 of 5,334), 0.06% (3 of 5,347), and 0.03% (2 of 6,909) with canagliflozin 100, 300, and comparator, respectively, with corresponding incidence rates of 0.13, 0.381, and 0.238 per 1000 patient years, respectively. These patients are predominantly male, Caucasian, older, with lower BMI, higher HgbA1C% and a longer duration of diabetes. However, other randomized trials performed with different drugs of the same class have failed to demonstrate a similar profile of DKA adverse events. The pathophysiology underlying DKA with SGLT2 inhibitors likely involves several biochemical events. A non-selective SGLT1/SGLT2 inhibitor (phlorizin) has been shown to promote renal tubular reabsorption of acetoacetate by increasing the sodium concentration in the renal tubular fluid and, thereby, increase ketone reabsorption mediated by an electrochemical gradient.3 Luseogliflozin, a 3

selective oral SGLT2 inhibitor which received its first marketing approval for the treatment of T2DM in Japan in March 2014, has been shown to be associated with increased serum ketones in glucose monitoring clinical trials.4 SGLT2 is expressed on alpha cells of pancreatic islets, and an increase on glucagon serum levels after administration of dapagliflozin and empagliflozin could explain the ketogenic effects by direct drug pancreatic stimulation.5 A contributor to ketone production in type I diabetes patients could be that, given improved glycemic control while on SGLT2 inhibitors, the amount of insulin used is reduced and does not meet requirements for all other basal functions, predisposing to lipolysis and an increased production of ketone bodies. Replacing a sulfonylurea and adding an SGLT2 inhibitor, as in our patient, may theoretically contribute to further insulin deficiency. Animal studies have shown a decrease in glucose induced insulin secretion regulated by a glucagon mediated kisspeptin-1 liver hepatic secretion. 5 Our case illustrates an atypical presentation of DKA in a patient with type 2 diabetes mellitus with blood glucose <250 mg/dl, which did not correlate with the increased anion gap. In our patient it is very likely that 16 years of being type 2 diabetes had severely impaired his pancreatic insulin reserves which possibly could predispose him to his clinical presentation. Although extensive research has been done on the functioning and regulatory pathways of SGLT, more data are needed to understand the physiology behind the inhibition of its function in the human body. Clinicians need to monitor patients on SGLT2 inhibitors for ketoacidosis. Late onset of type 1 DM needs to be rule out before starting SGLT2 to minimize the risk of this complication. In addition, this class of drugs provides an opportunity to further study the pathophysiology of ketoacidosis.

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References

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FDA, 2016; http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm. Accessed Jan 15, 2016 Erondu N, Desai M, Ways K, Meininger G. Diabetic Ketoacidosis and Related Events in the Canagliflozin Type 2 Diabetes Clinical Program. Diabetes Care 2015;38:1680-1686. Diabetes Care. 2016;39:E19-E19. 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;184:91-96. Nishimura R, Osonoi T, Kanada S, et al. Effects of luseogliflozin, a sodium-glucose co-transporter 2 inhibitor, on 24-h glucose variability assessed by continuous glucose monitoring in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled, crossover study. Diabetes Obesity & Metabolism. 2015;17:800-804. Taylor SI, Blau JE, Rother KI. SGLT2 Inhibitors May Predispose to Ketoacidosis. The Journal of clinical endocrinology and metabolism. 2015;100:2849-2852.

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